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AChEIs (Acetylcholinesterase Inhibitors)/Huperzine A Dangers


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#1 Rags847

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Posted 29 July 2008 - 08:39 AM


Lot of interest in Huperzine A on here. I've never taken it or thoroughly researched it until now.
Here is a lot of research to read (well worth reading) and contemplate and debate. These are all interesting studies, carefully sifted through, with information you probably haven't read before.
I hope to increase the complexity of the discussion of Huperzine A on this board.
Huperzine A shouldn't be taken blindly and just based off of a few glowing reports on here or on some internet website that sells it.

[Uh, this thread isn't for people who don't like to read and think. Those looking for a perky soundbite - move along!]



Caution even from those who sell it:

Off of Relentless Improvement.

Huperzine A (Huperzia serrata) (aerial plant) 50 mcg

Dosage and Use
Take one capsule daily, or as recommended by a healthcare practitioner.

Do not take more than four doses in any week, and do not use Huperzine A on a chronic basis.*

Caution
Because vitamin E inhibits blood clotting, it should not be used if excessive bleeding is occurring. Since Huperzine A inhibits the enzyme acetylcholinesterase, it should not be used on a chronic basis. The reason for this is that some acetylcholinesterase is needed to suppress excessive amounts of the neurotransmitter acetylcholine from accumulating in the body. While most people over age 30 need more acetylcholine, too much can cause unpleasant side effects. Most healthy people safety boost acetylcholine levels by taking precursors [my edit: Huperzine A is not a precursor] such as choline and phosphatidylcholine along with pantothenic acid. The COGNITEX formula contains these acetylcholine precursor agents. Do not take Huperzine A if you are taking other acetylcholinesterase inhibitors like Aricept or Tacrine.

INTERACTIONS
DRUGS
Acetylcholinesterase Inhibitors: Use of huperzine A along with the acetylcholinesterase inhibitors donepezil or tacrine may produce additive effects, including additive adverse effects. Other acetylcholinesterase inhibitors include neostigmine, physostigmine and pyridostigmine, and use of these agents along with huperzine A may produce additive effects, including additive adverse effects.
Cholinergic Drugs: Use of huperzine A along with cholinergic drugs, such as bethanechol, may produce additive effects, including additive adverse effects.

Because of possible adverse effects in those with seizure disorders, cardiac arrhythmias and asthma, those with these disorders should avoid huperzine A. Those with irritable bowel disease, inflammatory bowel disease and malabsorption syndromes should avoid huperzine A.

Warnings:
Keep out of reach of children.
Do not exceed recommended dose.
Do not purchase if outer seal is broken or damaged.
If you have a bad reaction to product discontinue use immediately.
When using nutritional supplements, please inform your physician if you are undergoing treatment for a medical condition or if you are pregnant or lactating.


Off of the LEF site:
"Healthy people, on the other hand, need acetylcholinesterase to regulate acetylcholine levels in their brains."
http://www.lef.org/m...2000_qanda.html

"Do not take more than four doses in any week and do not use Huperzine A on a chronic basis."
http://www.lef.org/n.../item00627.html



Warnings about pharmaceutical grade versus health store/website Huperzine A:
http://64.233.169.10...-...;cd=6&gl=us



Consider ACh levels (during the day and at night) and memory consolidation:

Slow-wave sleep, acetylcholine, and memory consolidation


http://www.pnas.org/...101/7/1795.full


[My comments and questions] If one has a lot of ACh during the day from a choline-donator would the breakdown mechanism (AChE) work harder to break it down and lower ACh levels for during sleep or would they remain high overnight? If one used a cholinesterase inhibitor how high would one's ACh levels chonically be overnight? Huperzine A is described as potent and selective and what concerns me is this line from the recent FDA study below ("Gradual recovery of AChE activity then occurs, but even 48h after the last dose red blood cell AChE was about 10% below control (pre-dose) values."). So, it is long acting and ACh levels are still higher than baseline levels even two days after the dose.
Concerning? Or would ACh levels still be higher than baseline two days after dosing with CDP-Choline, say? Anyone know of any studies showing how long the effect of a choline-donor lasts? It is great to have ACh and more working memory, but wouldn't be at all great if what I read and learned during the day wasn't being processed into long-term memory as effectively overnight.
LTM is where it is at!

A very recent study here (part of the FDA's clinical trial of Huperzine A):

1: Chem Biol Interact. 2008 May 3. [Epub ahead of print]Posted Image <script language="JavaScript1.2">Links
Protection of red blood cell acetylcholinesterase by oral huperzine A against ex vivo soman exposure: Next generation prophylaxis and sequestering of acetylcholinesterase over butyrylcholinesterase.
Haigh JR, Johnston SR, Peppernay A, Mattern PJ, Garcia GE, Doctor BP, Gordon RK, Aisen PS. Walter Reed Army Institute of Research, Division of Biochemistry, 503 Robert Grant Road, Silver Spring, MD 20910-7500, USA.

As part of a phase Ib clinical trial to determine the tolerability and safety of the highly specific acetylcholinesterase (AChE) inhibitor huperzine A, twelve (12) healthy elderly individuals received an escalating dose regimen of huperzine A (100, 200, 300, and 400mug doses, twice daily for a week at each dose), with three (3) individuals as controls receiving a placebo. Using the WRAIR whole blood cholinesterase assay, red blood cell AChE and plasma butyrylcholinesterase (BChE) were measured in unprocessed whole blood samples from the volunteers following each dose, and then for up to 48h following the final and highest (400mug) dose to monitor the profile of inhibition and recovery of AChE. Significant inhibition of AChE was observed, ranging from 30-40% after 100mug to >50% at 400mug, and peaking 1.5h after the last dose. Gradual recovery of AChE activity then occurs, but even 48h after the last dose red blood cell AChE was about 10% below control (pre-dose) values. Huperzine A levels in plasma peaked 1.5h after the final 400mug dose (5.47+/-2.15ng/mL). Plasma BChE was unaffected by huperzine A treatment (as expected). Aliquots of huperzine A-containing (from three individuals) and placebo blood samples were exposed ex vivo to the irreversible nerve agent soman (GD) for 10min, followed by removal of unbound huperzine and soman from the blood by passing through a small C(18) reverse phase spin column. Eluted blood was diluted in buffer, and aliquots taken at various time intervals for AChE and BChE activity measurement to determine the time taken to achieve full return in activity of the free enzyme (dissociation from the active site of AChE by huperzine A), and thus the proportion of AChE that can be protected from soman exposure. Huperzine A-inhibited red blood cell (RBC) AChE activity was restored almost to the level that was initially inhibited by the drug. The increased doses of huperzine A used were well tolerated by these patients and in this ex vivo study sequestered more red blood cell AChE than has been previously demonstrated for pyridostigmine bromide (PB), indicating the potential improved prophylaxis against organophosphate (OP) poisoning.

PMID: 18572153 [PubMed - as supplied by publisher].



A slew of really excellent reads follows, starting with a three-part exploration of brain cholinesterase and various theoretical and practical implications:



Med Hypotheses. 2004;63(2):285-97.Posted Image Links
Brain cholinesterases: I. The clinico-histopathological and biochemical basis of Alzheimer's disease.
Shen ZX. 2436 Rhode Island Avenue N. #3, Golden Valley, MN 55427-5011, USA. zhengxshen@yahoo.com

Substantial evidence is presented demonstrating that it is the cholinesterases (ChEs) that constitute the organizer, the connector and the safeguard for multiple neurochemical functions and mature anatomical architecture of the brain. In Alzheimer's disease (AD), the histopathological characteristics are initially and primarily associated with the degeneration of the acetylcholinesterase (AChE) system in various brain regions. Multiple classic and/or putative neurotransmitters and neuromodulators, virtually all the peptide hormones of the endocrine and neuroendocrine systems in the brain, their specific synthesizing and hydrolyzing marker enzymes and associated uptake processes (transporters), and receptors, do not actually participate in the formation of senile plaques and neurofibrillary tangles in the brains of patients suffering from AD. The massive perturbation in different neurochemicals seen in AD is essentially caused by the ChEs-associated pathology. The graded patterns of brain ChEs expression affect the preferential vulnerability and severity of the AD clinico-pathologic presentation. It seems that the common law in nature may also dominate the destiny of brain ChEs system, i.e., the weaker the cells express AChE, the more susceptible the cells are to AD degeneration, and vice versa.

PMID: 15236793 [PubMed - indexed for MEDLINE]


Med Hypotheses. 2004;63(2):308-21.Posted Image Links
Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease.
Shen ZX. 2436 Rhode Island Avenue #3, Golden valley, MN 55427-5011, USA. zhengxshen@yahoo.com

Currently available evidence demonstrates that cholinesterases (ChEs), owing to their powerful enzymatic and non-catalytic actions, unusually strong electrostatics, and exceptionally ubiquitous presence and redundancy in their capacity as the connector, the organizer and the safeguard of the brain, play fundamental role(s) in the well-being of cells, tissues, animal and human lives, while they present themselves adequately in quality and quantity. The widespread intracellular and extracellular membrane networks of ChEs in the brain are also subject to various insults, such as aging, gene anomalies, environmental hazards, head trauma, excessive oxidative stress, imbalances and/or deficits of organic constituents. The loss and the alteration of ChEs on the outer surface membranous network may initiate the formation of extracellular senile plaques and induce an outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the intracellular compartments membranous network may give rise to the development of intracellular neurofibrillary tangles and induce an inside-out cascade of AD. The abnormal patterns of glycosylation and configuration changes in ChEs may be reflecting their impaired metabolism at the molecular and cellular level and causing the enzymatic and pharmacodynamical modifications and neurotoxicity detected in brain tissue and/or CSF of patients with AD and in specimens in laboratory experiments. The inflammatory reactions mainly arising from ChEs-containing neuroglial cells may facilitate the pathophysiologic process of AD. It is proposed that brain ChEs may serve as a central point rallying various hypotheses regarding the etio-pathogenesis of AD.

PMID: 15236795 [PubMed - indexed for MEDLINE]



Med Hypotheses. 2004;63(2):298-307.Posted Image Links
Brain cholinesterases: III. Future perspectives of AD research and clinical practice.
Shen ZX. 2436 Rhode Island Ave. N. #3, Golden Valley, MN 55427-5011, USA. zhengxshen@yahoo.com

Alzheimer's disease (AD) is initially and primarily associated with the degeneration and alteration in the metabolism of cholinesterases (ChEs). The use of ChEs inhibitors to treat Alzheimer's condition, on the basis of the cholinergic hypothesis of the disease, is, therefore, without grounds. Most disturbing is the fact that the currently available anti-ChEs are designed to inhibit normal ChEs in the brain and throughout the body, but not the abnormal ones. Based on the acetylcholinesterase (AChE) deficiency theory, treatment should be designed to protect the cranial ChEs system from alteration and/or to help that system fight against degeneration through restoring its homeostatic action for brain structure and function instead. The overlap in the clinical, biochemical, molecular-cellular, and pathological alterations seen in patients with AD and individuals with many other brain disorders, which has bewildered many investigators, may now be explained by the shared underlying mismetabolism of brain ChEs. The abnormal metabolism of ChEs existing in asymptomatic subjects may indicate that the system is "at risk" and deserves serious attention. Future perspectives of ChEs research in vivo and in vitro in connection with AD and clinical diagnosis, prevention and treatment are proposed. Several potentially useful therapeutic and preventive means and pharmacological agents in this regard are identified and discussed, such as physical and intellectual stimulation, and a class of drugs including vitamin E, R-(-)-deprenyl (deprenyl, selegiline), acetyl L-carnitine, cytidine diphosphocholine (CDP-choline), centrophenoxine, L-phenylalanine, naloxone, galactose, and lithium, that have been proven to be able to stimulate AChE activity. Their working mechanisms may be through directly changing the configuration of AChE molecules and/or correcting micro- and overall environmental biological conditions for ChEs.

PMID: 15236794 [PubMed - indexed for MEDLINE]


Med Hypotheses. 2008;70(1):43-51. Epub 2007 Jun 22.Posted Image Links
Rationale for diagnosing deficiency of ChEs and for applying exogenous HuChEs to the treatment of diseases.
Shen ZX. Zhengxshen@yahoo.com

Recent evidence strongly demonstrates that acetylcholine (ACh) is not only involved in the function of the central and peripheral nervous systems, including the parasympathetic and somatic systems, but also acts as a ubiquitous cell signaling molecule or cytotransmitter, and as a hormone with paracrine, juxtacrine and autocrine properties. This active molecule exerts versatile and potent functions primarily through its specific nicotinic and muscarinic receptors (nAChRs and mAChRs, respectively). These functions modulate numerous biomechanisms, including cell growth, survival, proliferation and differentiation, cell-cell contact, cell cycle, locomotion, electrical activity, immune function, apoptosis, organization of the cytoskeleton, trophic functions, secretion, adhesion, resorption, and stress-response-regulation. By nature, the precise ACh levels and responses from receptors must be controlled and regulated by its degrading enzymes, the cholinesterases (ChEs), namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Once ChEs become critically deficient in quality and quantity, ACh signaling will be uncontrollably aberrant and persistent. An in-depth account of the fundamental roles of ChEs, comprising their diverse soluble and membrane-bound forms, in maintaining the functional equilibrium of ACh in the macro and microenvironment has been undertaken. This work also covers ACh receptors, signaling pathways, other interdependent and interrelated substances, functional processes, role of ChEs as first-line gatekeepers and defenses for the architecture of cells, tissues and organisms, physically, chemically, and structurally. The mechanisms of many diseases ranging from the acute cholinergic crisis to the chronic degenerative and hypergenerative disorders such as Alzheimer's disease, cancers, atopic dermatitis, may involve a deficiency of ChEs or imbalance between ACh and ChEs, initially or consequentially. It is therefore essential to ascertain a ChE deficiency, or an imbalance between ACh and ChEs, in tissues and body fluids in order for conducting clinical diagnosis, prevention and treatment. An argument is put forward on the rationale of applying exogenous human ChEs to reverse enzymatic deficiency and correct the imbalance between ACh and ChEs, to repair the affected receptors and protect against their further loss in the body, and consequently to alleviate the signs and symptoms of diseases. Evidence is adduced for the safety and efficacy of ChEs treatment.

PMID: 17587508 [PubMed - indexed for MEDLINE]


Int J Neuropsychopharmacol. 2006 Feb;9(1):101-24. Epub 2005 Aug 5.Posted Image Links
Targeting acetylcholinesterase and butyrylcholinesterase in dementia.
Lane RM, Potkin SG, Enz A. Novartis Neuroscience, Novartis Pharmaceuticals Corporation, NJ, USA.

The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.

PMID: 16083515 [PubMed - indexed for MEDLINE]


Clin Neuropharmacol. 2004 May-Jun;27(3):141-9.Posted Image Links
Acetylcholinesterase and its inhibition in Alzheimer disease.
Lane RM, Kivipelto M, Greig NH. Novartis Neuroscience, Novartis Pharmaceuticals Corp., East Hanover, NJ 07936-1080, USA. roger.lane@novartis.com

Until recently, the only established function of acetylcholinesterase (AChE) was the termination of cholinergic neurotransmission. Therefore, the use of AChE inhibitors to treat symptoms caused by cholinergic imbalances in Alzheimer disease (AD) represented a rational approach. However, it is now clear that AChE and the cholinergic system may have broader effects in AD. Of particular interest may be signal transduction pathways mediated through cholinergic receptors that promote nonamyloidogenic amyloid precursor protein processing and decrease tau phosphorylation, and the role of AChE in the aggregation of beta-amyloid (Abeta) peptide. In addition, the neuronal and nonneuronal cholinergic systems have important roles in the modulation of regional cerebral blood flow. These findings may modify the overly simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment and ignores the potential of cholinergic therapies as disease-modifying agents. Chronic increases in AChE activity may exacerbate neurodegenerative processes, make clinically relevant levels of AChE inhibition more difficult to achieve, and cause the therapeutic value of cholinesterase inhibitors (ChE-Is) to be limited and temporary. Rapidly reversible ChE-Is appear to increase AChE activity over the longer term whereas, remarkably, irreversible or very slowly reversible ChE-Is do not seem to have this effect. If such differences between ChE-Is are shown to have clinical correlates, this may prompt reconsideration of the rationale and expectations of some agents in the long-term management of AD.

PMID: 15190239 [PubMed - indexed for MEDLINE]


1: Drugs Aging. 2006;23(6):503-11.Links
Acetylcholinesterase inhibitors and sleep architecture in patients with Alzheimer's disease.
Cooke JR, Loredo JS, Liu L, Marler M, Corey-Bloom J, Fiorentino L, Harrison T, Ancoli-Israel S. Department of Medicine, University of California, San Diego, California, USA.

BACKGROUND AND OBJECTIVE: Studies suggest that some acetylcholinesterase inhibitors (AChEIs) increase rapid eye movement (REM) sleep and nightmares in patients with Alzheimer's disease (AD) but few have studied their effect on other sleep parameters. The objective of this study was to examine differences in sleep architecture in AD patients taking different AChEIs. METHODS: 76 participants (51 men, 25 women) [mean age = 78.2 years; SD = 7.7] with mild to moderate AD underwent medication history screening as well as polysomnography to determine the percentage of each sleep stage. Participants were divided into groups based on AChEI used: donepezil (n = 41), galantamine (n = 15), rivastigmine (n = 8) or no AChEI (n = 12). General univariate linear model analyses were performed. RESULTS: AChEI therapy had a significant effect on the percentage of stage 1 (p = 0.01) and stage 2 (p = 0.03) sleep. Patients in the donepezil group had a significantly lower percentage of stage 1 sleep than patients in the galantamine group (mean = 17.3%, SD = 11.7 vs 29.2%, SD = 15.0, respectively; p = 0.01), but there was no significant difference between the donepezil group and the rivastigmine (mean = 25.0%, SD = 12.3) or no AChEI groups (mean = 27.6%, SD = 17.7) in this respect. No significant differences in percentage of stage 1 between other groups were seen. Patients in the donepezil group also had a significantly higher percentage of stage 2 sleep than patients in the no AChEI group (mean = 63.6%, SD = 14.4 vs 51.4%, SD = 16.9, respectively; p = 0.04), but there was no significant difference between the donepezil group and either the galantamine group (mean = 56.5%, SD = 8.7) or the rivastigmine group (mean = 59.9%, SD = 8.4). There were no significant differences between groups in terms of percentage REM sleep or other sleep parameters. CONCLUSION: Subgroups of AD patients (classified according to AChEI treatment) in this study differed with respect to the amount of stage 1 and stage 2 sleep experienced, with the donepezil-treated group having the lowest percentage of stage 1 sleep and the highest percentage of stage 2 sleep. There was no significant difference in the amount of REM sleep between the groups. Our data suggest that sleep architecture may be affected by the use of donepezil in patients with AD. Although not elicited in this study because of the small sample size, there may be a class effect of AChEIs on sleep architecture. Double-blind, placebo-controlled studies are needed to better understand causality and the effect of each AChEI on sleep architecture in patients with AD.

PMID: 16872233 [PubMed - indexed for MEDLINE]


Chem Biol Interact. 2005 Dec 15;157-158:227-32. Epub 2005 Oct 27.Posted Image Links
Expression of cholinesterases in brain and non-brain tumours.
Vidal CJ. Departamento de Bioquímica y Biología Molecular-A, Edificio de Veterinaria, Universidad de Murcia, Apdo. 4021, E-30071 Murcia, Spain. cevidal@um.es

Although the involvement of cholinesterases (ChEs) in the removal of acetylcholine (ACh) at cholinergic synapses is firmly established, there is evidence to suggest that acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) take part in several cellular processes. The early expression of ChE genes during embryonic development and their role in morphogenesis and apoptosis have been explained on the basis of the non-cholinergic actions of ChEs. In addition, the effects of AChE and BuChE, their inhibitors and antisense oligonucleotides in proliferating cellular systems, together with the mitogenic actions of ACh, support a role for ChEs in cell cycle control. The anomalous expression of ChEs may increase cell proliferation and contribute to cancer growth or development. The aim of this report is to compile the available information on ChEs in cancerous tissues in order to stimulating the research to clarify the molecular mechanisms by which ChEs may participate in cancer. Future investigations may throw light into this intriguing issue which will be of benefit to humankind.

PMID: 16256970 [PubMed - indexed for MEDLINE]




Life Sci. 2003 Mar 28;72(18-19):2055-61.Posted Image Links
The non-neuronal cholinergic system in humans: expression, function and pathophysiology.
Wessler I, Kilbinger H, Bittinger F, Unger R, Kirkpatrick CJ. Institute of Pharmacology, University of Mainz, Obere Zahlbacher Str 67, D-55101 Mainz, Germany. wessler@uni-mainz.de

Acetylcholine, a prime example of a neurotransmitter, has been detected in bacteria, algae, protozoa, and primitive plants, indicating an extremely early appearance in the evolutionary process (about 3 billion years). In humans, acetylcholine and/or the synthesizing enzyme, choline acetyltransferase (ChAT), have been found in epithelial cells (airways, alimentary tract, urogenital tract, epidermis), mesothelial (pleura, pericardium), endothelial, muscle and immune cells (mononuclear cells, granulocytes, alveolar macrophages, mast cells). The widespread expression of non-neuronal acetylcholine is accompanied by the ubiquitous presence of cholinesterase and receptors (nicotinic, muscarinic). Thus, the non-neuronal cholinergic system and non-neuronal acetylcholine, acting as a local cellular signaling molecule, has to be discriminated from the neuronal cholinergic system and neuronal acetylcholine, acting as neurotransmitter. In the human placenta anti-ChAT immunoreactivity is found in multiple subcellular compartments like the cell membrane (microvilli, coated pits), endosomes, cytoskeleton, mitochondria and in the cell nucleus. These locations correspond with the results of experiments where possible functions of non-neuronal acetylcholine have been identified (proliferation, differentiation, organization of the cytoskeleton and the cell-cell contact, locomotion, migration, ciliary activity, immune functions). In the human placenta acetylcholine release is mediated by organic cation transporters. Thus, structural and functional differences are evident between the non-neuronal and neuronal cholinergic system. Enhanced levels of acetylcholine are detected in inflammatory diseases. In conclusion, it is time to revise the role of acetylcholine in humans. Its biological and pathobiological roles have to be elucidated in more detail and possibly, new therapeutical targets may become available. Copyright 2003 Elsevier Science Inc.

PMID: 12628456 [PubMed - indexed for MEDLINE]

J Pharmacol Sci. 2008 Feb;106(2):167-73. Epub 2008 Feb 16.Posted Image Links
Basic and clinical aspects of non-neuronal acetylcholine: overview of non-neuronal cholinergic systems and their biological significance.
Kawashima K, Fujii T. Department of Pharmacology, Kyoritsu College of Pharmacy, Minato-ku, Tokyo, Japan. koichiro-jk@piano.ocn.ne.jp

Acetylcholine (ACh) is a phylogenetically ancient molecule involved in cell-to-cell signaling in almost all life-forms on earth. Cholinergic components, including ACh, choline acetyltransferase, acetylcholinesterase, and muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively) have been identified in numerous non-neuronal cells and tissues, including keratinocytes, cancer cells, immune cells, urinary bladder, airway epithelial cells, vascular endothelial cells, and reproductive organs, among many others. Stimulation of the mAChRs and nAChRs elicits cell-specific functional and biochemical effects. These findings support the notion that non-neuronal cholinergic systems are expressed in certain cells and tissues and are involved in the regulation of their function and that cholinergic dysfunction is related to the pathophysiology of certain diseases. They also provide clues for development of drugs with novel mechanisms of action.

PMID: 18285657 [PubMed - indexed for MEDLINE]


1: Br J Pharmacol. 2008 May 26. [Epub ahead of print]Posted Image Links
Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans.
Wessler I, Kirkpatrick CJ. 1Institute of Pathology, University Hospital, Johannes Gutenberg-University, Mainz, Germany.

Animal life is controlled by neurons and in this setting cholinergic neurons play an important role. Cholinergic neurons release ACh, which via nicotinic and muscarinic receptors (n- and mAChRs) mediate chemical neurotransmission, a highly integrative process. Thus, the organism responds to external and internal stimuli to maintain and optimize survival and mood. Blockade of cholinergic neurotransmission is followed by immediate death. However, cholinergic communication has been established from the beginning of life in primitive organisms such as bacteria, algae, protozoa, sponge and primitive plants and fungi, irrespective of neurons. Tubocurarine- and atropine-sensitive effects are observed in plants indicating functional significance. All components of the cholinergic system (ChAT, ACh, n- and mAChRs, high-affinity choline uptake, esterase) have been demonstrated in mammalian non-neuronal cells, including those of humans. Embryonic stem cells (mice), epithelial, endothelial and immune cells synthesize ACh, which via differently expressed patterns of n- and mAChRs modulates cell activities to respond to internal or external stimuli. This helps to maintain and optimize cell function, such as proliferation, differentiation, formation of a physical barrier, migration, and ion and water movements. Blockade of n- and mACHRs on non-innervated cells causes cellular dysfunction and/or cell death. Thus, cholinergic signalling in non-neuronal cells is comparable to cholinergic neurotransmission. Dysfunction of the non-neuronal cholinergic system is involved in the pathogenesis of diseases. Alterations have been detected in inflammatory processes and a pathobiologic role of non-neuronal ACh in different diseases is discussed. The present article reviews recent findings about the non-neuronal cholinergic system in humans.British Journal of Pharmacology advance online publication, 26 May 2008; doi:10.1038/bjp.2008.185.

PMID: 18500366 [PubMed - as supplied by publisher]


Curr Alzheimer Res. 2005 Jul;2(3):307-18.Posted Image Links
Cholinesterases: roles in the brain during health and disease.
Ballard CG, Greig NH, Guillozet-Bongaarts AL, Enz A, Darvesh S. Department of Biomedical Sciences, Wolfson Centre for Age-related Diseases, Hodgkin Building, Guy's Campus, King's College, London, SE1 1UL, UK. clive.ballard@kcl.ac.uk

The cholinergic hypothesis of decline in dementia, whereby deficits in learning, memory and behavior are caused, at least in part, by decreased levels of acetylcholine (ACh) in the brain, first emerged more than 20 years ago. The role for acetylcholinesterase (AChE) and its inhibition in this scheme has long been accepted, but findings from preclinical experiments and clinical trials have placed butyrylcholinesterase (BuChE) alongside AChE as an important contributor to the occurrence, symptoms, progression and responses to treatment in dementia. A number of new lines of evidence suggest that both cholinesterase inhibitors (ChEs) may have broader functions in the CNS than previously thought, which relate to both 'classical' esterase activities of the enzymes as well as non-classical actions unrelated to their enzymatic function. Data suggest involvement of the ChEs in modulating glial activation, cerebral blood flow, the amyloid cascade, and tau phosphorylation. It has therefore been speculated that some actions of the ChEs could affect the underlying disease processes in Alzheimer's disease (AD), and that pharmacological manipulation with ChE inhibitors may affect long-term disease progression. Focusing on new findings relating to BuChE, we review recent evidence that has extended knowledge into the roles of ChEs in health, disease and aging.

PMID: 15974896 [PubMed - indexed for MEDLINE]


1: Neurochem Res. 2003 Apr;28(3-4):515-22.Posted Image Links
Cholinesterases: new roles in brain function and in Alzheimer's disease.
Giacobini E. University Hospitals of Geneva, Department of Geriatrics, University of Geneva, Medical school. CH-1226 Thônex, Geneva, Switzerland. Ezio.Giacobini@hcuge.ch

The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission--experimental or pathological, such as in AD--leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on beta-amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine.

PMID: 12675140 [PubMed - indexed for MEDLINE]


Mech Ageing Dev. 2001 Nov;122(16):2025-40.Posted Image Links
Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?
Amenta F, Parnetti L, Gallai V, Wallin A. Clinical Research Unit, Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Via Scalzino 3, 62032, Camerino, Italy. amenta@cambio.unicam.it

The observations of the loss of cholinergic function in neocortex and hippocampus in Alzheimer's disease (AD) developed the hypothesis that replacement of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numerous compounds in development for the treatment of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant benefit of these drugs on all symptom domains of AD. The first attempts in the treatment of AD with cholinergic precursors did not confirm a clinical utility of this class of compounds in well controlled clinical trials. However, cholinergic precursors most largely used such as choline and phosphatidylcholine (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways such as CDP-choline, choline alphoscerate and phosphatidylserine clearly enhanced ACh availability or release and provided a modest improvement of cognitive dysfunction in AD, these effects being more pronounced with choline alphoscerate. Although some positive results cannot be generalized due to the small numbers of patients studied, they probably would justify reconsideration of the most promising molecules in larger carefully controlled trials.

PMID: 11589920 [PubMed - indexed for MEDLINE]




Curr Med Chem. 2008;15(5):488-98.Posted Image Links
Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.
Amenta F, Tayebati SK. Dipartimento di Medicina Sperimentale e Sanità Pubblica, Università di Camerino, 62032 Camerino, Italy. francesco.amenta@unicam.it

Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.

PMID: 18289004 [PubMed - indexed for MEDLINE]




Crit Rev Neurobiol. 2005;17(3-4):161-217.Posted Image Links
Acetylcholine release from the central nervous system: a 50-year retrospective.
Phillis JW. Department of Physiology, Wayne State University, School of Medicine, Detroit, MI 48201, USA. jphillis@med.wayne.edu

Some 50 years have elapsed since Elliot et al. and MacIntosh & Oborin first reported a release of acetylcholine (ACh) from canine and feline cerebral cortices, respectively. In this review, subsequent developments in the field during the succeeding five decades are explored. The arrangement of material in the review is outlined in this abstract, concluding with some suggestions as to its potential significance. A number of technical advances during this period have contributed to a greater understanding of the role that ACh may play in the central nervous system. These include the relatively recent evolution of the microdialysis and transverse dialysis techniques that enabled investigators to explore ACh release in deep regions of the brain. Future studies will likely be refined with the use of microelectrode biosensors, which should allow real-time measurements of ACh concentrations at the synaptic level. Controversies arising from the use of cholinesterase inhibitors and muscarinic receptor antagonists to enhance release are being resolved as a result of a better understanding of the presynaptic actions of these agents. Future studies will also benefit from the recent development of clostridial and other neurotoxins to reduce ACh release in areas of the brain. The likelihood that ACh may act as a cotransmitter at synapses in conjunction with glutamic acid, nitric oxide, and adenosine triphosphate is also explored. Attention is focused on the elucidation of choline acetyl-transferase (ChAT)-containing pathways in the central nervous system using techniques such as immunohistochemistry, in situ hybridization, histochemistry of ChAT mRNA, acetylcholinesterase histochemistry, and the distribution of the vesicular ACh transporter. Such studies have defined several major groupings of cholinergic neurons in the brain, which provide ascending or descending projections to higher and lower central structures. A major section of the review is devoted to actual studies on ACh release in the brain and spinal cord. This presentation is in two sections. The text details some of the material that has been obtained in experiments over the past 50 years. In five Tables, the results obtained in the majority of release studies to date are summarized. Although the data obtained to date clearly support the hypothesis that ACh is involved in electroencephalographic activation associated with cerebral cortical arousal, this occurs while the animals appear to be awake with full postural control, suggesting that noncholinergic pathways to the cerebral cortex are also involved in such behavioral manifestations. The roles of acetylcholine in cognitive processes such as attention, learning, memory, responses to environmental changes, and motor activity still remain to be defined.

PMID: 17341198 [PubMed - indexed for MEDLINE]


Methods Find Exp Clin Pharmacol. 2006 Sep;28 Suppl B:1-56.Posted Image Links
Citicoline: pharmacological and clinical review, 2006 update.
Secades JJ, Lorenzo JL. Medical Department, Grupo Ferrer S.A., Barcelona, Spain.

Cytidine 5'-diphosphocholine, CDP-choline, or citicoline is an essential intermediate in the biosynthetic pathway of structural phospholipids in cell membranes, particularly phosphatidylcholine. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction. Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Thus, citicoline has been experimentally shown to increase norepinephrine and dopamine levels in the CNS. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging. In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated to cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. Citicoline is a safe drug, as shown by the toxicological tests conducted, that has no significant systemic cholinergic effects and is a well tolerated product. These pharmacological characteristics and the action mechanisms of citicoline suggest that this product may be indicated for treatment of cerebral vascular disease, head trauma (HT) of varying severity, and cognitive disorders of different causes. In studies conducted in the treatment of patients with HT, citicoline was able to accelerate recovery from post-traumatic coma and neurological deficits, achieving an improved final functional outcome, and to shorten hospital stay in these patients. Citicoline also improved the mnesic and cognitive disorders seen after HT of minor severity that constitute the so-called post-concussional syndrome. In the treatment of patients with acute ischemic cerebral vascular disease, citicoline accelerates recovery of consciousness and motor deficit, achieves a better final outcome, and facilitates rehabilitation of these patients. The other major indication of citicoline is for treatment of senile cognitive impairment, either secondary to degenerative diseases (e.g. Alzheimer disease) or to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, citicoline improves scores in cognitive rating scales, while in patients with senile dementia of the Alzheimer type it stops the course of disease, and neuroendocrine, neuroimmunomodulatory, and neurophysiological benefits have been reported. Citicoline has also been shown to be effective in Parkinson disease, drug addictions, and alcoholism, as well as in amblyopia and glaucoma. No serious side effects have occurred in any series of patients treated with citicoline, which attests to the safety of treatment with citicoline. © 2006 Prous Science. All rights reserved.

PMID: 17171187 [PubMed - indexed for MEDLINE]

Edited by Rags847, 29 July 2008 - 09:35 AM.

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#2 luv2increase

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Posted 29 July 2008 - 07:20 PM

Well, I'm convinced.


See, it is things like this that sometime frighten me 'just a little albeit' from ingesting so many different chemicals all the time. Just three days ago, I started taking my supplement from BAC that has huperzine A, vinpocetine , and glutamine in it (glutamine is ok) that I purchased months ago but never got around to trying.


I find out that I should stay clear of vinpocetine and now huperzine-A.

Much thanks to Rags for taking much time in beautifully putting together all this great information although heartbreaking about huperzine-A.


In reality, Rags may have just saved us from some pretty badly damaged brains and body systems down the road!

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#3 Rags847

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Posted 30 July 2008 - 05:46 PM

Well, I'm convinced.


See, it is things like this that sometime frighten me 'just a little albeit' from ingesting so many different chemicals all the time. Just three days ago, I started taking my supplement from BAC that has huperzine A, vinpocetine , and glutamine in it (glutamine is ok) that I purchased months ago but never got around to trying.


I find out that I should stay clear of vinpocetine and now huperzine-A.

Much thanks to Rags for taking much time in beautifully putting together all this great information although heartbreaking about huperzine-A.


In reality, Rags may have just saved us from some pretty badly damaged brains and body systems down the road!



Thanks, luv2increase. I started looking into Huperzine-A and ended up getting obsessed by my research and spent six hours on the computer straight, without a break.

My interest in supplementing and enhancing is to just gently tweak brain chemistry towards optimal functioning and to always mediate my self-prescribing through a concern for longterm safety and through the lens of gathered knowledge about what might actually be going on inbetween my ears.

For me, right now, it is choline precusors over AChEIs.
Choline precusors were originally tried in AD treatment and they were ineffective because they were using choline and lecithin. Now we have better ones like CDP-Choline. CDP-Choline effectively raises ACh levels and shows an excellent safety profile (based on toxicological tests conducted, that it has no significant systemic cholinergic effects, and that is a well tolerated product).
Just seems safer to slightly raise ACh levels through precursor routes (it would be along the lines of eating a high choline diet that day) and letting the brain's regulatory systems (ChEs) deal with the ACh increase, naturally.
Cholinesterases (ChEs) might just be too important for the body to directly mess with.
ChEs seem to have many other roles beyond the 'classic' (first discovered) role of terminating ACh-mediated neurotransmission. And if some of the studies and theorizing above are right, ChE inhibition could be really dangerous (setting off AD cascade and contributing to the pathophysiology of a number of diseases).

And thank you for your research into what is really going on with Vinpocetine!

#4 HereInTheHole

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Posted 30 July 2008 - 11:53 PM

That was interesting reading, Rags. Thanks for the work.

Am I wrong or was there only one study in that group? The first one "Protection of red blood cell acetylcholinesterase by oral huperzine A against ex vivo soman exposure" seems to be the only the evidence-backed study, and that was just a test of safety. The rest seem to be speculation. Interesting speculation, though.

Don't a few existing studies show an improvement in cognitive function from huperzine in patients with Alzheimer's disease? A quick search on Google reveals that there are even a few huperzine trials in progress. I haven't ruled huperzine out yet, but I am a little more cautious about it. We'll see what the researchers discover.

Edited by NarrativiumX, 31 July 2008 - 12:04 AM.


#5 Rags847

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Posted 31 July 2008 - 07:55 AM

That was interesting reading, Rags. Thanks for the work.

Am I wrong or was there only one study in that group? The first one "Protection of red blood cell acetylcholinesterase by oral huperzine A against ex vivo soman exposure" seems to be the only the evidence-backed study, and that was just a test of safety. The rest seem to be speculation. Interesting speculation, though.

Don't a few existing studies show an improvement in cognitive function from huperzine in patients with Alzheimer's disease? A quick search on Google reveals that there are even a few huperzine trials in progress. I haven't ruled huperzine out yet, but I am a little more cautious about it. We'll see what the researchers discover.


NarrativiumX, good questions. I'll look into them tomorrow when I have more time. Those were all pubmed abstracts. I wish I had full access to all the complete articles. Each sells for $35 or something. I wonder if when I return to school in Sept if I can get access to full articles.

ChEIs definitely cause an improvement in cognitive functioning in patients with AD (and probably in anyone). Huperzine inhibits ChE. ChE breaksdown (hydrolizes) ACh. So, the less ACh brokendown the longer it will be active and participate in cognition.

But that is not the question!

ChEIs as an AD therapy just treats the symptom. Like someone having cancer, say, and one of the surface symptoms was red splotches on the skin and there was a treatment to remove the red splotches. The cancer and the course of the cancer's progession is left uneffected. There is no cure for AD. There is no treatment, yet, that stops the AD degeneration or reverses it. ChEIs just give poor AD victims a few more months or years of slightly improved functioning (a good thing in and of itself). I am hopeful that researchers are getting closer to figuring out AD. There has been a lot of advancement in recent years into further understanding its origins and mechanisms. But the cholenergic theory of AD was the first (now 20+ years old and outdated) theory of AD. Things are more complex than that theory allows.

Now they know that AD involves the degeneration of ChE. ChEI therapy further lowers ChE just to temporarily prop up ACh and lessen the manifest expression of the disease (cognitive imparement). The disease continues to progess making it harder and harder to prop up ACh levels through ChEI treatment. In people with advanced levels of AD the ChEI treatment levels required become intolerable and a large percentage of AD patients need to discontinue treatment due to side effects.

Why would someone on this board, without AD, healthy, just trying to safely prop up ACh levels and cognitive powers, want to take ChEIs, which are always described as powerful drugs and when some of the papers above suggest that degrading ChE levels may be responsible for causing the changes in cell fuctioning that set off the AD cascade and may be responsible for other diseases or cause a faster progression of other diseases? Would you take a chemotherapy drug, say, if it had some cognitive benefit, yet you knew it had, or may have, have some disasterous effects on various cell fuctions?

AD suffers are in desperate straights and at the end of there lives (my grandmother suffered from it at the end of her life). The rational is there to use anything to prop up their ability to fuction and recognize there grandkids and remember their names.

But why should a healthy person take ChEIs?

I'll opt to take seemingly safer drugs like CDP-Choline, Piracetam, and D-Amphetamines or D-Methylphenidate, and leave the more powerful drugs like ChEIs and illegal Meth and illegal Cocaine, alone.

So, yes. ChEIs do prop up ACh and cognition. But the brain is complex and interconnected and the question should be, whatelse do ChEs do in the brain and body and what will be the longterm and global effect of self-prescribing ChEIs?

Edited by Rags847, 31 July 2008 - 08:51 AM.

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#6 HereInTheHole

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Posted 31 July 2008 - 04:54 PM

...

I'll opt to take seemingly safer drugs like CDP-Choline, Piracetam, and D-Amphetamines or D-Methylphenidate, and leave the more powerful drugs like ChEIs and illegal Meth and illegal Cocaine, alone.

So, yes. ChEIs do prop up ACh and cognition. But the brain is complex and interconnected and the question should be, whatelse do ChEs do in the brain and body and what will be the longterm and global effect of self-prescribing ChEIs?


What scares me the most about ChEIs are the declarative memory problems during sleep. This was with the cholinesterase inhibitor physostigmine. Huperzine might not have this problem, but as you point out, why risk it?

I'll leave unopened the bottle of huperzine that's coming in the mail and stick with the safe sources of choline.

Dang it. I mean thanks. :)

Edited by NarrativiumX, 31 July 2008 - 05:09 PM.


#7 Rags847

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Posted 01 August 2008 - 01:22 AM

Phase II was completed in Nov 2007.
So, when is Phase III?

http://clinicaltrial...8...zine&rank=1
http://www.drugs.com...ients-3310.html
http://www.alzforum....etail.asp?id=53
http://www.neurohitech.com/


Official Title: A Multi-Center, Double-Blind, Placebo-Controlled Therapeutic Trial to Determine Whether Natural Huperzine A Improves Cognitive Function

#8 HereInTheHole

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Posted 01 August 2008 - 02:20 AM

Phase II was completed in Nov 2007.
So, when is Phase III?

http://clinicaltrial...8...zine&rank=1
http://www.drugs.com...ients-3310.html
http://www.alzforum....etail.asp?id=53
http://www.neurohitech.com/


Official Title: A Multi-Center, Double-Blind, Placebo-Controlled Therapeutic Trial to Determine Whether Natural Huperzine A Improves Cognitive Function


Is it possible that Phase III has been finished but the pharma company is now working on altering the active molecule just enough to patent it? If they come out with the final results too soon -- assuming those results are positive -- other companies might race them to a patent. Just guessing. I don't know really know how this works.

#9 Rags847

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Posted 01 August 2008 - 02:56 AM

For those interested, a great talk on AD here:
The Molecular Basis of Memory Loss in Transgenic Models of Alzheimer's Disease
http://videocast.nih.gov/podcast.asp?14488

NIH (National Institutes Of Health) VideoCasting is quite the resource (over 4000 videos available):
http://videocast.nih.gov/default.asp
http://videocast.nih...Events.asp?c=16


Edited by Rags847, 01 August 2008 - 03:03 AM.


#10 Rags847

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Posted 01 August 2008 - 07:28 AM

For those interested in AD research, this is an excellent Dana Foundation video talk:

http://www.dana.org/...il.aspx?id=8232


Speaking of Science: Alzheimer's Disease: When Will We Find a Cure?


Tuesday, June 12, 2007
Dana Center, Washington, D.C.

#11 fritzer

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Posted 11 November 2010 - 02:05 AM

forgive me for bringing to life an old thread. My main Q is if Hupezine antagonizes NMDA rcs can it do this in the hypothalamus aswell thereby decreasing output of LH and decreasing testosterone?
tried looking into this but when i hit a1-sigma receptors etc i was over my head :)

Also, i want to comment:

As part of a phase Ib clinical trial to determine the tolerability and safety of the highly specific acetylcholinesterase (AChE) inhibitor huperzine A

this study found above in the OP. the thing is they only followed the plasma ACHe of the 400ug dose for 48hrs. and found 10% activity still. Now we all know half lives etc, and I would think if one was to take Hup A a 50ug dose whih would give 5-20% approx initial ACHe inhibition and then probably well below 2% 48hrs later given half life etc. It is just a thought.

I think dosing this stuff at 50mcg/uga day would potentially be ok in young healthy people. BUT we see people go on here taking 200mcg first day some taking 200mcg x 3... i think that is insane.
With 50mcg you are getting a nice Ach boost and it will affect your NMDA rcs far less... also with a half life of approx 5hrs in healthy subjects if taken at 7am by 10pm should be cleared down to <6mcg. If the 50mcg was taken in one dose, the 6mcg activity should be FAR less allowing normal memory consolidation to occur at sleep time... PROBABLY :)

regardless at doses of 200mcg + in healthy people wanting a "study aid" i believe the fear is all the bad things in the OP. you are going to have levels of 50mcg + still at bed time, lots of residual % ACHe action...

we see this with all things. people mega attack dose racetams (much safer) but still, if something helps why notjust take more for more help? MODERATION and starting SMALL is the key to this stuff

Edited by fritzer, 11 November 2010 - 02:09 AM.

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#12 aLurker

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Posted 14 November 2010 - 11:43 AM

So, I've ordered some more things and Huperzine A is among them. Mostly to see if its NMDA antagonism is enough to prevent tolerance to stims although sadly non-competitive NMDA antagonists seem to have way less evidence of being effective for this kind of thing compared to the uncompetitive ones. Any anecdotes about this in conjunction to stims or information about how potent the NMDA antagonism is at lower doses would be much appreciated.

I've looked at this thread earlier and became a little scared about AChEIs in general. Looking back at the thread now I realize most of the concerns brought up are hypotheses and speculation. I've far from made up my mind about this yet but I think it warrants some further consideration.

There are two concerns that stand out to me...

First: there is enough evidence to convince me it could mess with your sleep. Might not be a problem at lower doses taken in the morning. I think I would notice this which makes it less of a concern.

The most frightening concern here is illustrated by the following from the "Acetylcholinesterase and its inhibition in Alzheimer disease." abstract quoted by the OP:

Chronic increases in AChE activity may exacerbate neurodegenerative processes, make clinically relevant levels of AChE inhibition more difficult to achieve, and cause the therapeutic value of cholinesterase inhibitors (ChE-Is) to be limited and temporary. Rapidly reversible ChE-Is appear to increase AChE activity over the longer term whereas, remarkably, irreversible or very slowly reversible ChE-Is do not seem to have this effect.

So in which category does Huperzine A fall? I guess I'd have to read the study to find out what the authors think but from memory I recall that Huperzine A is a reversible inhibitor of AChE which brings into question whether or not it is "slow" enough for the authors to consider it benign. That the AChE levels at 400 mcg were lower than baseline after 48h suddenly doesn't look to bad with that in mind. I would be more concerned it the levels rebounded to higher levels rather than gradually went back to baseline.

I won't appeal to the argument that Huperzine A has been used for a very long time and is seemingly well tolerated since I suppose many using it are already at risk for Alzheimer's and therefore it would be impossible to tell if Huperzine A caused an earlier onset or if it warded off the decease with its many neuroprotective aspects.

Taken as a whole Huperzine A seems to have many beneficial aspects and it's probably the most promising NMDA antagonist when it comes to enhancing cognition, especially acutely. I hope to have more time to look into Huperzine A later.
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#13 medicineman

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Posted 14 November 2010 - 12:21 PM

If you are worried about its disturbing effect on memory consolidation during sleep, take it well before you sleep, taking into account its halflife of eight hours.

I dont think you need to worry much about the posts above, considering there isn't one, NOT ONE, solid link between cholinisterase inhibition and alzheimers. Like you said, the above is speculation. As meaningful as the theory of stress and stomach ulcers. Cholinesterase inhibitors are virtually never given to healthy volunteers on long enough basis to provide values for a followup study, thus the best you can do is make in vitro conjectures and speculation about the possible effects of hup a, or cholinesterase inhibitors.

If you take a dose as small as 50mcg or 100 a day, and cycle to four times a week, id say you have less to worry about huperzine and more to worry about the more solid factors contributing to AD, such as a. fib, diabetes mellitus, hyperlipidemia, CV disease, and other disease common processes.

Edited by medicineman, 14 November 2010 - 12:26 PM.


#14 aLurker

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Posted 14 November 2010 - 05:56 PM

Huperzine does indeed seem to be a non-competitive NMDA antagonist like I said but to correct myself these can be effective when it comes to reducing tolerance: and DXM for instance. Unsure if memantine is uncompetitive or non-competitive or whatever. I guess I have some reading to do later. Would anyone care to elucidate on what classes of NMDA antagonists are good for this purpose and how you would compare them using numbers or theories? There are no studies about Huperzine A and tolerance prevention that I know of so I'll have to interpolate from available data and of course try it in practise.

Medicineman, that's my conclusion as well.

#15 chrono

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Posted 15 November 2010 - 01:49 PM

also with a half life of approx 5hrs in healthy subjects if taken at 7am by 10pm should be cleared down to <6mcg. If the 50mcg was taken in one dose, the 6mcg activity should be FAR less allowing normal memory consolidation to occur at sleep time... PROBABLY :)

A big problem in this discussion seems to be the half-life value. Using google scholar, I've found references saying it's 5-6 hours [11] [12] or 12-13 hours [13] [14]. Hup A seems to exhibit two-compartment pharmacokinetics [13], so lower estimates may reflect an attempt at averaging. Whichever is the most meaningful number, the presence of 10% inhibition after 48h (10 5h half-lives, or effectively 0.4ug) demonstrates that significant amounts are still present after several days.


First: there is enough evidence to convince me it could mess with your sleep. Might not be a problem at lower doses taken in the morning. I think I would notice this which makes it less of a concern.

The memory concern aside, hup A messed with my ability to get to sleep more than anything else except perhaps amphetamine. I'm very careful not to take it more than about halfway through the day, unless I'm planning on staying up all night.


The most frightening concern here is illustrated by the following from the "Acetylcholinesterase and its inhibition in Alzheimer disease." abstract quoted by the OP:

Chronic increases in AChE activity may exacerbate neurodegenerative processes, make clinically relevant levels of AChE inhibition more difficult to achieve, and cause the therapeutic value of cholinesterase inhibitors (ChE-Is) to be limited and temporary. Rapidly reversible ChE-Is appear to increase AChE activity over the longer term whereas, remarkably, irreversible or very slowly reversible ChE-Is do not seem to have this effect.

Equally concerning (to my limited knowledge of this class of drugs) are the effects of lowered AChE activity. From the above abstracts:

the weaker the cells express AChE, the more susceptible the cells are to AD degeneration, and vice versa.


The loss and the alteration of ChEs on the outer surface membranous network may initiate the formation of extracellular senile plaques and induce an outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the intracellular compartments membranous network may give rise to the development of intracellular neurofibrillary tangles and induce an inside-out cascade of AD.


The mechanisms of many diseases ranging from the acute cholinergic crisis to the chronic degenerative and hypergenerative disorders such as Alzheimer's disease, cancers, atopic dermatitis, may involve a deficiency of ChEs or imbalance between ACh and ChEs, initially or consequentially.


recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression.

So if AChE has more functions than simply regulating the amount of synaptic ACh...what are the consequences of inhibiting a significant amount of it for most of the day, several days a week?



I dont think you need to worry much about the posts above, considering there isn't one, NOT ONE, solid link between cholinisterase inhibition and alzheimers.

So....until there's a multi-decade longitudinal study designed to show whether long-term usage of AChEIs in healthy subjects has the potential to cause undesirable neuronal effects, it should be considered safe? It's your brain, but reasonable possibilities should be taken seriously, even in the absence of any data capable of demonstrating solid links.


If you take a dose as small as 50mcg or 100 a day, and cycle to four times a week, id say you have less to worry about huperzine and more to worry about the more solid factors contributing to AD, such as a. fib, diabetes mellitus, hyperlipidemia, CV disease, and other disease common processes.

Honestly, you may be right, but what are you basing this on? A gut feeling? How theoretical is this evaluation compared to the concerns laid out in the abstracts in the OP? Are you sure that taking this for half of the days for X years is nothing to worry about? And in the context of the goal of most people at this site, pointing out that there are other diseases worth worrying about isn't a very compelling argument for safety.


Huperzine does indeed seem to be a non-competitive NMDA antagonist like I said but to correct myself these can be effective when it comes to reducing tolerance: and DXM for instance. Unsure if memantine is uncompetitive or non-competitive or whatever.

AFAIK un- and non-competitive mean the same thing. My understanding is that memantine is a noncompetitive NMDA channel blocker. It's activity-dependent, which means that at resting states it will block the channel, but when the neuron fires it will unblock and allow normal functioning. Its usefulness also has to do with its medium-low affinity compared to most other NMDA antagonists. Sorry I can't be more specific, but I've been looking into memantine this month, and the mechanism for combating tolerance doesn't seem to be very well-elucidated.

As far as I can tell, hup A's NMDA antagonism isn't going to be clinically relevant. It is capable of antagonizing NMDA current over a concentration of 0.1-300uM, with an IC50 of 45.4uM [1] or 126uM [2]. Another study found a concentration of .1uM had no effect on NMDA receptors [4]. The first study identifying NMDA action [1] suggested that an earlier paper demonstrating an ideal neuroprotective concentration of .1uM [15] was explainable through the NMDA mechanism. However, given the negligible to nonexistent activity at this dose, it seems more likely that the neuroprotection is the result of several other NMDA-independent mechanisms [16] [17]. Another point is that, unlike memantine, hup A's NMDA antagonism is not use- or voltage-dependent [2], which makes it much less appealing from a cognitive standpoint. And finally, enhanced induction of LTP is due to an NMDA-independent mechanism [18].

A trial administering 1mg to healthy humans produced a maximum plasma level of 8.9ug/L (.034uM) [5, cited in review [6]]; another study using a dosage of 400ug produced a max plasma concentration of 2.6ug/L (0.01uM) [7]. The first abstract from the OP resulted in plasma levels of 5.47ug/L (0.022uM), after escalating twice-daily dosing to 400ug over two weeks [8].

This last study also found >50% inhibition of plasma AChE. The in vitro IC50 for AChE inhibition is 0.082uM in rat cortex and 0.079uM in human erythrocyte membrane [3, cited in review [6]]. The plasma level of 0.022uM is much lower than the in vitro IC50 of ~0.080uM. This could be due to differences in plasma and brain partitioning (though odds are that CSF levels would be lower than plasma levels [9] [10], making this even more problematic). Evidently in vivo and in vitro levels do not mesh, for reasons that are not apparent to me.

However, what seems obvious is that the concentrations resulting from common dosages are many orders of magnitude lower than those necessary for meaningful NMDA receptor interaction.

Hopefully full texts will shed some more light on half-life and concentration amounts, at some point.

Edited by chrono, 15 November 2010 - 04:38 PM.
updated first and last sections

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#16 aLurker

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Posted 15 November 2010 - 02:45 PM

As far as I can tell, hup A's NMDA antagonism isn't going to be clinically relevant. The IC50 for NMDA current antagonism is 45.4uM [1] or 126uM [2]. The IC50 for AChE inhibition is 0.082uM [3], and a concentration of .1uM was found to have no effect on NMDA receptors [4].

The only figure I could find today for human plasma concentration was a trial of 1mg producing a maximum level of 8.9ug/L [5]; at 242g/mol, I believe this is a molar concentration of 0.034uM. This high dose doesn't quite gel with the in vitro IC50 numbers when compared to those measured in the first abstract in the OP; despite this, it seems clear that hup A isn't going to affect NMDA receptors at anything close to a relevant dose, by a margin of several orders of magnitude.

Hopefully full texts will shed some more light on half-life and concentration amounts, at some point.


Okay thanks a lot, I didn't have the time to go through that myself so I really appreciate the effort. Since you've been investigating memantine this post might interest you if you haven't seen it already, the entire thread is quite good actually. The search for something good to prevent tolerance with goes on, at least for me. NMDA antagonists look promising to a certain degree except that most of them seem to have cognitive side effects which are intolerable IMHO (though perhaps atomoxetine could help with tolerance). I'm also considering theanine. Perhaps preventing calcium influx would be a better approach? I'm upping my intake of zinc (link to ADHD) and magnesium (general health) either way to see if it helps somewhat.

#17 aLurker

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Posted 22 December 2010 - 11:41 AM

I've been looking up which herbs to try out and I found this study:

Screening of Indian medicinal plants for acetylcholinesterase inhibitory activity.

The cholinergic hypothesis of Alzheimer's disease (AD) has provided the rationale for the current pharmaco-therapy of this disease, in an attempt to reduce the cognitive decline caused by cholinergic deficits. Nevertheless, the search for potent and long-acting acetylcholinesterase (AChE) inhibitors that exert minimal side effects in AD patients is still ongoing. AChE inhibitors are currently the only approved therapy for the treatment of Alzheimer's disease; only a limited number of drugs are commercially available. Hydroalcohol extracts of six herbs, Andrographis paniculata, Centella asiatica, Evalvulus alsinoides, Nardostachys jatamansi, Nelumbo nucifera, Myristica fragrans used in Indian systems of medicine, were tested for in vitro acetylcholinesterase inhibitory activity based on Ellman's method in 96-well microplates using AChE obtained from bovine erythrocytes. The results showed that the hydroalcohol extract from Centella asiatica, Nardostachys jatamansi, Myristica fragrans, Evalvulus alsinoides inhibited 50% of AChE activity at concentrations of 100-150 microg/mL. Andrographis paniculata and Nelumbo nucifera extracts showed a weak inhibition of acetylcholinesterase with IC(50) values of 222.41 +/- 19.87 microg/mL and 185.55 +/- 21.24 microg/mL, respectively. Physostigmine was used as a standard and showed inhibition of acetylcholinesterase with an IC(50) value of 0.076 +/- 0.0042 microg/mL.


If the concentrations here are relevant it might indicate that long-term inhibition of AChE has been tried without any obvious side effects by many users of Ayurvedan medicine for hundreds of years. The use of gotu kola isn't exactly a novel fad.

The degree of AChEI might be a very detrimental factor here obviously. Huperzine A is obviously a much stronger AChEI since as chrono said it's in vitro IC50 for AChE inhibition is 0.082uM in rat cortex and 0.079uM in human erythrocyte membrane. But then again it is dosed accordingly too. The half-life of the AChEI is probably also a factor.

Admittedly this study is in vitro and I don't know relevant these concentrations are compared to the in vivo use of these herbs. I'd appreciate all the help I can get here.

Edited by aLurker, 22 December 2010 - 11:45 AM.


#18 Reformed-Redan

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Posted 27 January 2012 - 07:00 AM

If the concentrations here are relevant it might indicate that long-term inhibition of AChE has been tried without any obvious side effects by many users of Ayurvedan medicine for hundreds of years. The use of gotu kola isn't exactly a novel fad.

I don't think that is a valid argument. Side effects vary. In this case they can range from cancer to Alzheimer's. Especially under the conditions in the regions where these substances have been taken; it would be pretty hard to draw a correlation between side effects and the substance given.

Edited by redan, 27 January 2012 - 07:01 AM.


#19 unregistered_user

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Posted 25 February 2012 - 06:48 PM

So anyone here taking Huperzine A regularly? LifeMirage over at brainmeta.com (who happens to be an MD who claims to have prescribed Hup A to over 5,000 patients for something like 13 years) claims that it's perfectly safe, even for children, and doesn't see any reason to avoid it. See thread here: LifeMirage via Brainmeta.com on Huperzine A

Thoughts anyone? I am thinking of trying it. Could experimenting with 1 bottle be dangerous?

#20 Digital Nuro

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Posted 15 April 2012 - 10:02 PM

So anyone here taking Huperzine A regularly? LifeMirage over at brainmeta.com (who happens to be an MD who claims to have prescribed Hup A to over 5,000 patients for something like 13 years) claims that it's perfectly safe, even for children, and doesn't see any reason to avoid it. See thread here: LifeMirage via Brainmeta.com on Huperzine A Thoughts anyone? I am thinking of trying it. Could experimenting with 1 bottle be dangerous?


If I'm not mistaken that guy works for Cognitive Nutrition and was not certified or something along those lines. Theres a whole thread about how they company was deceiving people in forums here and other forums. Its been a while since I read about it but think that was the guy.

My own experiences with hupp A is safe just dont use it every day. I would suggest CDP choline, Uridine or brewers yeast as a much safer alternative if your worried.

#21 reversible

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Posted 05 November 2012 - 04:28 AM

Well, what should we make of studies that appear to indicate protective effects of AChEIs (including HupA, and also tetrahydrocannabinol) against major Alzheimer's-related biomarkers, like amyloidogenesis, and neuronal death in response to it?

http://www.ingentaco...000024/art00003

http://www.ncbi.nlm....pubmed/17945434

http://www.ncbi.nlm....pubmed/21289607

http://www.ncbi.nlm....pubmed/16862548

Moreover, what should we make of THC's ability to inhibit the formation of AD-causing amyloid plaque, attributed by researchers at Scripps to THC's AChEi activity? Although THC has considerably more complicated pharmacology than this, it is relevant here as an example of competitive, naturally-occurring AChEi inhibitor that is consumed on a routine basis by many, many people without apparent induction of dementia (and perhaps just the opposite via neurogenesis and inhibition of amyloidogenesis).

http://www.scripps.e...006/080906.html

http://www.ncbi.nlm....les/PMC2562334/

What shall we make of clinical data suggesting that long-term use of AChEi's in at least one population of AD patients resulted in lesser cognitive decline than that predicted for an untreated population?

"Overall the decline was less than that estimated if this cohort of patients had not been treated."

http://www.ncbi.nlm....pubmed/10793322

How about caffeine, since it also inhibits AChEi? Would it be a problem to consume it, say, every morning?

http://www.ncbi.nlm..../pubmed/2003276

How about the fact that chronic use of drugs that *reduce* cholinergic transmission via antagonism at post-synaptic receptors actually *do* constitute a risk factor for development of cognitive impairment? The converse of the usual post-synaptic receptor down-regulation argument doesn't make the right prediction here (this being a situation that should tend to produce receptor up-regulation).

http://www.scienceda...00713111724.htm

I'm very far from being convinced that the AChEis above are harmful.

And if they aren't, has anyone really benefited from a scary post with virtually zero direct empirical support (handwavy gestures in the direction of memory consolidation notwithstanding)?

Edited by reversible, 05 November 2012 - 04:31 AM.

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#22 chrono

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Posted 05 November 2012 - 04:01 PM

Great first post, reversible ^^ The problem is, studies showing certain helpful effects don't necessarily negate the possibility of other harmful effects. For instance, correcting for certain deficiencies in AD doesn't mean it might not still cause problems via other mechanisms, in AD or non-AD populations...and in general, AD models aren't all that useful in predicting how drugs will affect healthy individuals (due to massive dysfunction and the terminal nature of the illness), though it's frequently all we have to work with. THC is also a special case; I doubt its AChE inhibition is all that strong, and the effect seems to be downstream from CB1 anyhow. And it has so many effects that it's really not that useful for drawing conclusions, and Hup A is fairly selective in its mechanism.

And if they aren't, has anyone really benefited from a scary post with virtually zero direct empirical support (handwavy gestures in the direction of memory consolidation notwithstanding)?

Are you asking if anyone has benefited from trying to elucidate all the mechanisms of a largely experimental drug we're using in a non-clinical setting? Personally, I enjoy having as much data available as possible, both for academic and practical curiosity. You're free to decide whether such discussions are useful to you, and I admit this is a very theoretical one, but unless you're born with knowledge of which drugs are safe and which ones aren't, this question makes you sound like you think unanswerable questions about safety are somehow detrimental.

Personally, I doubt if Hup A will give anyone Alzheimer's, though again, there's an almost complete dearth of data available that's relevant to non-AD models, so it's really just a guess based on the concomitant lack of negative data. Perhaps in certain populations it would, we just have no way of knowing. If you read my post #15 above, I feel like the main concern is the strong inhibition of the body's regulatory mechanisms for one of its neurotransmitters for a long period of time. That is not handwavy; it is quite important. Also note the potency and efficacy of the inhibition...cherry-picking safety data from more common drugs which are probably an order of magnitude less effective (if clinically relevant at all, I don't have time to research that right now) is potentially indicative, but not a very strong argument about any characteristics of Hup A.

#23 reversible

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Posted 05 November 2012 - 07:07 PM

Hi Chronos,
Thanks for your response. Very thoughtful, and I agree with a lot of it. I plan to post a follow up when I have time. I don't disapprove of OPs highly conjectural discussion about the potential harms of this mode of therapy so much as I disagree with the propensity of subsequent users to cite this post sans interpretation as unequivocal demonstration that AChEis are liable to leave a smoking hole in your head. ("Thanks for saving us from the brain damage, I just flushed my bottle of huperzine," etc., and links in other threads to this one). Finer points to be discussed later.

#24 reversible

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Posted 06 November 2012 - 05:36 AM

I'd be shocked if chronic huperzine treatment didn't have adverse effects of some kind. I'm assuming that what most folks here are worried about are long-term detriments to cognitive faculities arising from on-mechanism toxicity of AChEi's, and from what I can tell, the experimental and clinical studies do not seem to validate these specific concerns.

Arguably, AChE is neither more 'important' nor more vulnerable than any of the other critical CNS targets we chronically modulate the bejesus out of in much of western medicine, e.g., DAT, SERT, adrenergic autoreceptors, MAOI, etc, often with miraculous results for the people expressing said proteins. I would find it highly surprising if an oppositional tolerance to HupA inhibition of AChEi didn't develop during chronic dosing - but I wouldn't impart catastrophic significance to such a finding.

Before delving into the primary literature, I should say something about comparisons of Huperzine to other reversible AChEi's: as a method of inferring likely adverse events associated with huperzine, it is obviously not preferred. However, what we are interested in here is precisely the "on-mechanism" toxicity associated with AChE inhibition. A hypothetical perfectly selective AChEi would exhibit only these tox features (by definition) and all drugs operating by this mechanism should also exhibit this toxicity (in addition to their own individual idiosyncratic toxicities) at dosages adjusted to provide comparable target-coverage, barring some major convoluting factor. Donepezil and Huperzine A are both highly selective, reversible, centrally-acting AChEi's, and both reassuringly show primarily cholinergic side effects in overdose. Moreover, that certain effects are on-mechanism seems to be corroborated by extensive characterization of numerous mechanistically-similar AChEi's. Qualitative extrapolations or predictions based on the presumptive on-mechanism effects of e.g., donepezil, may therefore be useful in cases where specific data for Hup A is lacking.

The dearth of data concerning the effects of chronic AChE-inhibition in non-AD animals isn't as severe as you might think.


Here is a highly relevant study on cognitive performance in healthy rats given chonic donepezil:
"Cognitive performance of healthy young rats following chronic donepezil administration," from Psychopharmacology, 2008.

http://www.springerl...50420m4356/. "The cognitive functions of healthy young rats treated chronically with the acetylcholinesterase inhibitor donepezil were evaluated using a wide behavioral test battery ... Chronic treatment with donepezil ameliorated memory functions and explorative strategies, speeded up the acquisition of localizing knowledge, augmented responsiveness to the context, and reduced anxiety levels. However, it did not affect spatial span, modify motivational levels, or influence associative learning."


Here is an excellent study of the effects of both acute and chronic Hup A in healthy rats:
"Acute and chronic studies with the anticholinesterase huperzine a: Effect on central nervous system cholinergic parameters," from Neuropharmacology, 1998.

"acute or chronic treatment with Huperzine A: did not alter ChAT; reduced high affinity choline transport in the hippocampus in a transient manner; and had a longer duration of action as an AChE inhibitor than physostigmine. Moreover, tolerance to low-toxicity doses of Huperazine A was minimal, contrary to what has been observed with other inhibitors of AChE."

(http://www.sciencedi...02839089190184D.)



Here we have another study on the long-term effects of chronic reversible AChE-inhibition (donepezil) in non-AD ederly rats; "Enhanced dendritic spine number of neurons of the prefrontal cortex, hippocampus, and nucleus accumbens in old rats after chronic donepezil administration," from Synapse, 2010, (http://onlinelibrary...enticated=false). "Our results suggest that Donepezil prevents the alterations of the neuronal dendrite morphology caused by aging."


Here we have a study illustrating enhanced long-term potentiation in the brains of non-AD elderly rats after chronic administration of either donepezil or galantamine:

"Chronic treatment of old rats with donepezil or galantamine: effects on memory, hippocampal plasticity and nicotinic receptors" from Neuroscience, 2000. (http://www.sciencedi...306452200001809). "There was no effect of drug treatment on baseline synaptic transmission or on the threshold or magnitude of long-term potentiation induction. Both drug treatment groups, however, showed significantly extended long-term potentiation decay times at the perforant path–granule cell synapse over the saline control animals, as measured during the week following induction. Both drugs also elevated the number of nicotinic receptors within the hippocampus and neocortex ...Furthermore, the durability of long-term potentiation was significantly, positively correlated with nicotinic receptor binding in the hippocampus ...These data suggest that the therapeutic doses of cholinesterase inhibitors used to treat patients with Alzheimer’s disease may have effects on neurophysiology and neurochemistry that are close to the threshold for producing detectable behavioral improvements."


Contained within these findings (the latter particularly) as well as at least one of the articles linked in my first post, is one probable mechanism for neuroprotective/nootropic effects of HupA and other AChEis in *Non-AD* animals (as well as AD animals): anti-inflammatory cholinergic signaling via the alpha-7 nicotinic acetylcholine receptor, which receptor we also now know to be upregulated by chronic treatment with reversible AChEi's. We know that donepezil exerts at least some of its neuroprotective effects via this mechanism (http://www.sciencedi...014299908006390). There is also unequivocal proof that HupA also exhibits nicotinic-receptor mediated neuroprotective effects (http://onlinelibrary...08.05504.x/full). It is probably signaling at the alpha 7 nicotinic receptor that prevents glutamate excitotoxicity, rather than HupA's ostensible direct NMDA-antagonism. We also know that anti-inflammatory signalling via this receptor confers neuroprotective effects in a number of other non-AD scenarios (e.g., the "Smokers Paradoxes," like the negative correlation of nicotine with degeneration of the dopaminergic neurons, cf. e.g, http://www.jneuroinf.../content/9/1/98 or http://www.ingentaco...00011/art00001.)

To my knowledge, none of the studies above report any particularly worrisome findings, and neither do the clinical studies of reversible AChEis in humans.

As for the allegation that I'd cherry-picked results of the long-term tolerability studies in the above post, this is just not so. Cf. also "Chronic Donepezil Treatment Is Associated with Slowed Cognitive Decline in Alzheimer’s Disease" from Dementia and Geriatric Cognitive Disorders, 2001. (http://content.karge...roduktNr=227769). "As expected, treated and untreated patients differed with respect to age, education, ethnicity, percentage of community dwelling and exact days of follow-up (ANOVA and χ2) in several comparisons, but did not differ on baseline MMSE score. These baseline variables were highly intercorrelated. MMSE scores declined significantly more slowly after 1 year of ChE-I treatment compared to untreated patients (p = 0.05) after controlling for baseline differences in age, education, ethnicity and percentage of community dwelling. Slowing of decline was significant in the donepezil-treated patients (p = 0.007) but not in the tacrine-treated group (p = 0.33). Conclusions: This study, utilizing concurrent, nonrandomized controls, suggests that donepezil continues to have efficacy over at least the first year of therapy." I agree that AD-animals are not equivalent to non-AD animals, but on the other hand, the AD population should be excruciatingly sensitive AChE-related toxcity.

As for inhibition of AChEi by tetrahydrocannabinol, Janda et al. in Molecular Pharmacology say "Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Abeta aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease." I.e., Janda et al. assert that THC inhibits AChE via a direct interaction with AChIE, NOT via downstream activation of CB1. (I don't really wish to make any arguments here about THC except that it appears to be an example of a commonly-used reversible AChE inhibitor that is devoid of any really scary tox upon chronic administration. The mechanism of THC's AChE inhibition may not be totally comparable to the standard noots - i need to look into this more when I can get a copy of Janda's paper).

Edited by reversible, 06 November 2012 - 06:34 AM.

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#25 reversible

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Posted 06 November 2012 - 05:43 AM

I'd also mention vis-a-vis THC that even if the intrinsic potency for AChIE were several orders of magnitude lower than that of HupA, the much larger doses of THC targeted ad libitum by many users could easily make up for that. Nevertheless, I don't have institutional access to Janda's papers and can't confirm offhand that the binding of THC at AChE occurs at the same site or in the same manner as observed with the more typical noot AChIEs.

Edited by reversible, 06 November 2012 - 05:48 AM.


#26 reversible

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Posted 06 November 2012 - 06:09 AM

All that said, there is a dearth of studies of AChEis in healthy animals (h. sapiens included) that take place over the course of years. But that's true of most substances for most indications - we currently lack truly long-term safety and efficacy data for many of the most heavily prescribed substances in the pharmacopeia.

Edited by reversible, 06 November 2012 - 06:13 AM.


#27 reversible

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Posted 06 November 2012 - 07:45 AM

Point taken that the existence of beneficial effects doesn't rule out the possibility of adverse findings. But many of these studies have entailed a pretty thorough-going analysis of cognitive performance and integrity of brain structure in both AD and non-AD animals and the results of the in vivo studies necessarily reflect the aggregate of these ACHiE's multifarious effects on the animal on the experimental observables. If something really bad was happening, I think we'd see some more compelling indication of it than we have.

"AChE is an important enzyme and complicated enzyme and inhibiting it for awhile might not have totally obvious and trivial effects" - that is precisely why all of these experiments have been done, it is hypothesis number zero in pretty much all of this. We'll probably never get the study we'd want: multi-year dosing of HupA in healthy humans with a total cognitive performance workup at regular intervals and post-mortem harvesting of brains, etc. At the end of the day, we have a lot of pretty rigorous evidence for meaningful clinical benefit and little or no evidence of serious harm.

#28 dear mrclock

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Posted 15 December 2012 - 09:32 PM

interested in this; Warnings about pharmaceutical grade versus health store/website Huperzine A:
http://64.233.169.10...-...;cd=6&gl=us

the url doesnt work. any re-urling and help on this one topic alone ?

#29 PuzzleSolver

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Posted 06 January 2013 - 11:12 AM

interested in this; Warnings about pharmaceutical grade versus health store/website Huperzine A:
http://64.233.169.10...-...;cd=6&gl=us

the url doesnt work. any re-urling and help on this one topic alone ?


This is the closest thing that I could find concerning Pharma & Healthstore comparison... all in all breakdown,
You don't know what your getting from the herbstore vs 99.44% purity through Pharma

http://news.usc.edu/...mer-s-treament/
Huperzine A study seeks alternative Alzheimer’s treament

By Monika Guttman
March 6, 2002
A clinical trial to test the Chinese herb Huperzia serrata—known commercially as huperzine A—as a treatment for early or mild Alzheimer’s disease is underway at USC, announced Lon Schneider, professor of psychiatry, neurology and gerontology at the Keck School of Medicine of USC.
Schneider, who is spearheading USC’s participation in the multi-center Phase II trial sponsored by the National Institute on Aging, noted that earlier trials suggested huperzine A works much like some of the main medications now prescribed to treat Alzheimer’s symptoms. “Aricept, Razadyne, Exelon—the current drugs used to ease Alzheimer’s symptoms—are expensive and have side effects,” he said. “What’s potentially attractive about huperzine is that it’s an herb that’s been chewed by people over the course of centuries because of its cholinergic effects. It’s very available and easy to extract from the plant, may have fewer side effects and would cost much less than the current drugs for Alzheimer’s disease.”
Current medications like Aricept inhibit acetylcholinesterase, an enzyme that deactivates the neurotransmitter acetylcholine. Acetylcholine is involved in memory and learning. By inhibiting the enzyme that breaks it down, more acetylcholine continues to be available to stimulate neurons. Medications that block acetylcholinesterase may improve symptoms in some patients but do not stop the progression of Alzheimer’s.
Huperzine A, a naturally occurring compound found in a moss from the tropical woodland regions of China, has long been used by traditional healers as a fever and inflammation remedy. The compound is extracted from a Chinese herbal plant named Huperzia serrata, Shuangyiping, or Qian Ceng Ta. Huperzine A has become the most commonly prescribed medication in China for Alzheimer’s disease and other memory disorders, and appears to be able to improve memory loss and possibly slow the emergence of some symptoms of Alzheimer’s, especially in the early stages.
Delaying onset of some symptoms may delay the onset of disability. Finding a treatment that could delay onset by even five years could reduce the number of individuals with Alzheimer’s disease by nearly 50 percent after 50 years, according to the Alzheimer’s Association. Currently 4.5 million Americans have Alzheimer’s, more than double the number in 1980.
The huperzine A study, said Schneider, is intended to show whether the herb improves cognitive function in those already diagnosed with Alzheimer’s. It will also show what dosage may be most effective, and whether there are significant adverse effects. “Most of the information we have so far is anecdotal—there just hasn’t been well-designed clinical trials of this herb,” he noted.
Yet huperzine A, which is available commercially in health food stores and on web sites, is already being used by some doctors and patients to treat Alzheimer’s. The danger with that approach, said Schneider, is that huperzine is not regulated by the Food and Drug Administration with regard to purity and amount of substance because it is an herb. “With most substances regulated as nutraceuticals or diet supplements you never know what you’re getting.
It can be a broad range of substances of differing quality. The trial huperzine A is derived through a pharmaceutical-grade extraction process so it’s more than ninety-nine and forty-four hundredths percent pure, and so we know what dosages we’re giving.”
That is important, he noted, because it is possible to overdose on drugs that block acetylcholinesterase. “If someone added huperzine to Aricept, for example, they risk nausea, vomiting, confusion, muscle cramping, respiratory difficulties and even seizures,” he said.
What makes huperzine more attractive than the current pharmacologic treatments is that “it may be a bit different, it may have certain benefits the current treatments do not,” said Schneider. Yet, he cautioned, “We don’t have unrealistic expectations. This cholinesterase inhibitor may have a more favorable side effect profile, so it may make a difference. We have expectations that it will help, but this is still in the very early stages.”

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#30 Endymion

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Posted 04 August 2013 - 08:00 AM

Who really knows the totality of what is occurring within the brain following AChE inhibition, but I agree with reversible that so far all studies relating to huperzine A have only shown changes within the brain that could be considered beneficial.
I think the AChE inhibition by caffeine is a good point too - you could apply the same logic and ditch all caffeine as a precautionary measure based on the speculation of those articles. However, real studies show caffeine to be protective of neuronal health over the long-term.

Sort of a tangent, but I just wanted to share this recent study (Brain Research, April 2013) suggesting a positive effect of huperzine A by promoting neurogenesis in the hippocampus. The in vitro part used very high concentrations that probably aren't applicable (1µM), given the low plasma concentrations cited by chrono. Regardless, neurogenesis was seen in vivo with a dose of 0.2mg/kg. Converting the dose it would be around 1mg for a 70kg human, which would be a fool-hardy dose, but it is interesting nonetheless.

Huperzine A promotes hippocampal neurogenesis in vitro and in vivo.

Ma T, Gong K, Yan Y, Zhang L, Tang P, Zhang X, Gong

Abstract

Huperzine A (Hup A) is a lycopodium alkaloid from Huperzia serrata, which has been used as a therapeutic agent in several neurological disorders. Despite the diverse pharmacological activities Hup A has, its role in hippocampal neurogenesis remains to be established. This study showed that Hup A not only promoted the proliferation of cultured mouse embryonic hippocampal neural stem cells (NSCs), but also increased the newly generated cells in the subgranular zone (SGZ) of the hippocampus in adult mice. Furthermore, the in vitro findings indicated that low concentrations of Hup A stimulated the proliferation of cultured NSCs, whereas extremely high concentration of it decreased the cell proliferation. Hup A activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which was a well-known regulator of biological processes including cell proliferation and differentiation. ERK inhibitor dramatically inhibited the proliferative effect of Hup A on NSCs. Administration of Hup A to adult mice significantly enhanced the cell proliferation in dentate gyrus of hippocampus, and increased the remaining newborn cells 4 weeks after the drug administration. Moreover, the newly generated BrdU(+)/NeuN(+) neurons were also increased by Hup A treatment. These findings suggest a novel role of Hup A in neurogenesis and provide a new insight into its therapeutic effects in neurological disorders via a neurogenesis-related mechanism.


Edited by Endymion, 04 August 2013 - 08:05 AM.

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