4019 replies to this topic

[bigyellowlemon]

 

https://en.wikipedia.org/wiki/Apigenin Apigenin induces autophagy. It is a benzo-site ligand at the GABA-A receptor, being a PAM. It also binds to the adenosine receptor, as well as being an NMDA antagonist. It is also neurogenic. The only negative I can think of is that it is anti-inflammatory, which might not be good for sleep.

 

I would strongly suggest not taking PDE4i at night time, from my understanding that would destroy circadian signaling and rhythm. Curcumin, though a wonderful substance, would not be good for sleep either. 

 

Spermidine seems good at night.

 

Maybe take PDE4i and curcumin in morning and spermidine and apigenin at night? Of course we could add more as well.

 

EDIT: Apigenin also actiavtes monoamine transporters so it can blunt drive and salience, good for sleep. 

Which mechanisms are you thinking of with PDE4i and circadian biology? Ibudilast (mainly PDE4i) is a bit non-selective and PDE5i is pretty bad before bed so it may not be the best idea...but I'm curious. Took it last night (10mg) without any problems or noticeable positive effects. I'll try it again a few times and see what happens. 

 

Curcumin/turmeric seems to enhance some people and inhibit others before sleep (anecdotally). What are your reasons for advising against it? Glial cell activity? 

 

Anecdotally it works pretty well for me. Wake up refreshed with a clear head. 

 

Spermidine is quite good before bed ime. Been taking it for about a month and half so we'll see how it works over time. 

 

I've only taken apigenin during the day. I'll look into the mechanisms (there are always many) and see how it looks overall. Have you tried it before bed?

 

 

cAMP is released at waking and resets your circadian rhythm. I could be wrong though, maybe PDE4i only works on a small subset of cAMP and allows you to escape the circadian rhythm resetting.

 

Curcumin is probably good for people who have high inflammation but for people who have low inflammation I just see it as stopping you from getting to sleep. What theory do you have about glial cells?

 

Hey if it works for you that's all that's important.

 

Apigenin has a long ass half-life, like 93 hours. I have eaten shitloads of parsely and have enjoyed chamomile quite a bit, both of which have lots of apigenin. It's good. Apparently supplementing it has low absorption but in it's natural form it's bioavailable.

 

Does autophagy hurt performance? I imagine it does but if not then we should do it all day and night... maybe

[bigyellowlemon]

Also, going back to the dlPFC, how do you think we can selectively inhibit cAMP in one area? Will we simply block HCN or find a way to block cAMP?

[lostfalco]

Also, going back to the dlPFC, how do you think we can selectively inhibit cAMP in one area? Will we simply block HCN or find a way to block cAMP?

Guanfacine is the most selective cAMP blocker that I'm aware of but it's hard to come by.

 

I think the ultimate goal we are after is enhancement of action potential firing. Inhibiting cAMP inhibits K+ signaling which has the end effect of enhancing Na+ signaling and therefore action potentials and therefore connectivity. It's just one means to an end. Sodium channel enhancement seems a bit more accessible with things readily available like ghrelin, insulin, igf-1, dihexa, etc.  

 

Of course, I am testing out clonidine (for a2 activation and cAMP inhibition) but it has had mixed results in the studies. I kinda doubt it will work but we'll see. 

 

http://www.ncbi.nlm....pubmed/10192826

 

Neuropsychopharmacology. 1999 May;20(5):460-70.

Guanfacine, but not clonidine, improves planning and working memory performance in humans.

Jäkälä P1, Riekkinen M, Sirviö J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen P Jr.

Author information

Abstract

The present study compares, using a double-blind, placebo controlled design the effects of two alpha 2-agonists, clonidine (0.5, 2, and 5 micrograms/kg) and guanfacine (7 and 29 micrograms/kg) on spatial working memory, planning and attentional set-shifting, functions thought to be dependent on the "central executive" of the prefrontal cortex. Blood pressure and the subjective feeling of sedation were affected equally by clonidine and guanfacine. The 0.5 microgram/kg and 5 micrograms/kg doses of clonidine disrupted spatial working memory, but the medium dose had no effect. The 0.5 and 2 micrograms/kg doses of clonidine increased impulsive responding in the planning test. The 5 micrograms/kg dose of clonidine slowed responding at effortful levels of planning and attentional set-shifting tests. The 29 micrograms/kg dose of guanfacine improved spatial working memory and planning. Guanfacine had no effect on attentional set-shifting. These data indicate that guanfacine improved planning and spatial working memory, but clonidine dose-dependently disrupted performance. It is possible that the greater selectivity of guanfacine for alpha 2A-adrenoceptor subtype may underlie its differences from clonidine.

 

http://www.ncbi.nlm....pubmed/20347876

 

Behav Brain Res. 2010 Aug 25;211(2):236-9. doi: 10.1016/j.bbr.2010.03.040. Epub 2010 Mar 27.

Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism.

Schneider JS1, Tinker JP, Decamp E.

Author information

Abstract

Cognitive deficits, including attention and working memory deficits, are often described in Parkinson's disease (PD) patients even during the early stages of the disease. However, cognitive deficits associated with PD have proven difficult to treat and often do not respond well to the dopaminergic therapies used to treat the motor symptoms of the disease. Chronic administration of low doses of the neurotoxin 1-methy,4-phenyl,1,2,3,6-tetrahydropyridine (MPTP) can induce cognitive dysfunction in non-human primates, including impaired performance on a variable delayed response (VDR) task with attentional and memory components. Since alpha-2 adrenergic receptor agonists have been suggested to improve attention and working memory in a variety of conditions, the present study assessed the extent to which the alpha-2 noradrenergic agonist clonidine might influence VDR performance in early Parkinsonian non-human primates. Clonidine (0.02-0.10 mg/kg) improved performance on both attentional and memory components of the task, performed in a modified Wisconsin General Test Apparatus, in a dose-dependent manner and the cognition enhancing effects of clonidine were blocked by co-administration of the alpha-2 noradrenergic antagonist idazoxan (0.10 mg/kg). These data suggest that clonidine or drugs of this class, perhaps with greater receptor subtype selectivity and low sedation liability, might be effective therapeutics for cognitive dysfunction associated with PD.

 

Edited by lostfalco, 11 February 2016 - 01:06 AM.

[abelard lindsay]

Of course, I am testing out clonidine (for a2 activation and cAMP inhibition) but it has had mixed results in the studies. I kinda doubt it will work but we'll see. 

 

http://www.ncbi.nlm....pubmed/10192826

 

Neuropsychopharmacology. 1999 May;20(5):460-70.

Guanfacine, but not clonidine, improves planning and working memory performance in humans.

Jäkälä P1, Riekkinen M, Sirviö J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen P Jr.

Author information

 

 

 

 

I have yet to see anecdotal reports of someone who takes Guanfacine and actually likes it for cognitive enhancement.   If you read all the patient reviews, it seems to be prescribed mostly for calming down children who are excessively hyperactive or aggressive.  Seems the reviews are mixed.

 

See: http://www.drugs.com...nts/guanfacine/

 

 

 

Edited by abelard lindsay, 12 February 2016 - 08:14 AM.

[Reformed-Redan]

I took guanfacine for a while and definitely liked its effects. One way to put it is that I felt much more rational and much less impulsive. I believe there is a study out there that it not only strengthens the PFC; but, also suppresses the amygdala. Only reason I'm not on it is because I can't find a source for it. I'm actually looking and having a pdoc prescribe it to me if possible. 

 

EDIT: I'd be interested in participating in a group buy if possible. (Don't really trust TLR much to be a supplier for it). There are plenty of legitimate suppliers from alibaba. Only thing is I would need the organizer to be able to create a solution, say 1 mg per 1 ml with a total amount of 100ml. Or 1 mg per .5ml, etc...

Edited by redan, 12 February 2016 - 01:26 PM.

[Reformed-Redan]

I'm wondering given my positive response to LLLT. Has anyone seen any studies on using strong magnets (think cheap neodymium magnets you can get off amazon) on specific areas of the brain? I'm specifically thinking about the DLPFC.

 

Any research on this would be awesome.

 

Thanks.

[Reformed-Redan]

I took guanfacine for a while and definitely liked its effects. One way to put it is that I felt much more rational and much less impulsive. I believe there is a study out there that it not only strengthens the PFC; but, also suppresses the amygdala. Only reason I'm not on it is because I can't find a source for it. I'm actually looking and having a pdoc prescribe it to me if possible. 

 

EDIT: I'd be interested in participating in a group buy if possible. (Don't really trust TLR much to be a supplier for it). There are plenty of legitimate suppliers from alibaba. Only thing is I would need the organizer to be able to create a solution, say 1 mg per 1 ml with a total amount of 100ml. Or 1 mg per .5ml, etc...

Here is the study:

 

http://www.ncbi.nlm....pubmed/25059532

 

Guanfacine modulates the emotional biasing of amygdala-prefrontal connectivity for cognitive control.

Schulz KP1, Clerkin SM2, Newcorn JH1, Halperin JM3, Fan J3.

Author information

 

Abstract

Functional interactions between amygdala and prefrontal cortex provide a cortical entry point for emotional cues to bias cognitive control. Stimulation of α2 adrenoceptors enhances the prefrontal control functions and blocks the amygdala-dependent encoding of emotional cues. However, the impact of this stimulation on amygdala-prefrontal interactions and the emotional biasing of cognitive control have not been established. We tested the effectof the α2 adrenoceptor agonist guanfacine on psychophysiological interactions of amygdala with prefrontal cortex for the emotional biasing of response execution and inhibition. Fifteen healthy adults were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task following administration of oral guanfacine (1mg) and placebo in a double-blind, counterbalanced design. Happy, sad, and neutral faces served as trial cues. Guanfacine moderated the effect of face emotion on the task-related functional connectivity of left and right amygdala with left inferior frontal gyrus compared to placebo, by selectively reversing the functional co-activation of the two regions for response execution cued by sad faces. This shift from positively to negatively correlated activation for guanfacine was associated with selective improvements in the relatively low accuracy of responses to sad faces seen for placebo. These results demonstrate the importance of functional interactions between amygdala and inferior frontal gyrus to both bottom-up biasing of cognitive control and top-down control of emotional processing, as well as for the α2 adrenoceptor-mediated modulation of these processes. These mechanisms offer a possibile method to address the emotional reactivity that is common to several psychiatric disorders.

 

Edited by redan, 12 February 2016 - 02:40 PM.

[cylack]

Found about this place called sci-hub where one can access pretty much any published paper: http://sci-hub.io

[lostfalco]

A quick reminder of MC4R (melanocortin) signaling in the brain. 

 

I think there are some serious possibilities here with intranasal MSH, melanotan ii, or PT-141. There are some blood pressure risks in certain individuals, so caution is warranted, but I've tested all three now and they really seem to work. Still working out dosing and exactly which product I like the best but this seems like an interesting (albeit risky) avenue for experimentation. 

 

http://www.antiaging...om/256-msh2-pro

http://www.superiorp...om/melanotan-ii

http://www.superiorpeptide.com/pt-141

 

 

 

 

In dopamine D1 receptor (D1R)-expressing neurons, melanocortin 4 receptor (MC4R) signalling is required for stress-induced anhedonia and anorexia³⁶ as well as for responses to drugs of abuse⁴⁴. In the nucleus accumbens, chronic stress increases α-melanocyte-stimulating hormone (α-MSH) levels and MC4R signalling, leading to changes in synaptic strength owing to endocytosis of AMPA receptors (AMPARs), which is associated with depressed glutamatergic transmission²⁰⁶. Stimulation of MC4R promotes cyclic AMP activity, which in turn activates exchange protein directly activated by cAMP 2 (EPAC2), a protein kinase A (PKA)-independent cAMP target²⁰⁷. EPAC2 enhances repressor/activator protein homologue·GTP (RAP·GTP) activity and promotes the endocytosis of GluA2-containing AMPARs. Changes in AMPAR stoichiometry are accompanied by depression of excitatory synaptic transmission, which includes alterations of long-term depression (LTD) and long-term potentiation during chronic stress. Conversely, the number of AMPARs on the cell surface is increased after cocaine exposure, and the convergence of MC4R and D1R signalling determines the behavioural effects of the drug⁴⁴. Specifically, after exposure to cocaine, dopamine- and cAMP-regulated phosphoprotein 32 (DARPP32) and GluA1 are phosphorylated via cAMP–PKA⁶² at Thr34 and Ser845, respectively, and this results in increased surface expression and opening of AMPARs within striatal neurons^{37, 44}. Further studies are needed to elucidate the activity of GluA1 versus GluA2 subunits during MC4R signalling in striatal neurons.

 

http://www.ncbi.nlm....pubmed/24588018

 

 

 

http://www.ncbi.nlm....pubmed/21803120

 

Mol Cell Endocrinol. 2012 Jan 2;348(1):47-54. doi: 10.1016/j.mce.2011.07.036. Epub 2011 Jul 22.

Melanocortin 4 receptor activation induces brain-derived neurotrophic factor expression in rat astrocytes through cyclic AMP-protein kinase A pathway.

Caruso C¹, Carniglia L, Durand D, Gonzalez PV, Scimonelli TN, Lasaga M.

Author information

Abstract

Melanocortin 4 receptors (MC4R) are mainly expressed in the brain. We previously showed that the anti-inflammatory action of α-melanocyte-stimulating hormone (α-MSH) in rat hypothalamus and in cultured astrocytes involved MC4R activation. However, MC4R mechanisms of action remain undetermined. Since brain-derived neurotrophic factor (BDNF) may be mediating MC4R hypothalamic anorexigenic actions, we determined melanocortin effects on BDNF expression in rat cultured astrocytes and certain mechanisms involved in MC4R signaling. α-MSH and its analogue NDP-MSH, induced production of cAMP in astrocytes. This effect was completely blocked by the MC4R antagonist, HS024. We found that NDP-MSH increased BDNF mRNA and protein levels in astrocytes. The effect of NDP-MSH on BDNF expression was abolished by the adenylate cyclase inhibitor SQ22536, and decreased by the PKA inhibitor Rp-cAMP. Since melanocortins are immunomodulators, we investigated their actions with bacterial lipopolysaccharide (LPS) and interferon-γ (IFN-γ) stimulus. Although both α-MSH and LPS+IFN-γ increased cAMP responding element binding protein (CREB) activation, LPS+IFN-γ did not modify BDNF expression. On the other hand, α-MSH did not modify basal or LPS+IFN-γ-induced nuclear factor-κB activation. Our results show for the first time that MC4R activation in astrocytes induces BDNF expression through cAMP-PKA-CREB pathway without involving NF-κB.

 

Edited by lostfalco, 14 February 2016 - 11:51 PM.

[lostfalco]

 

I have yet to see anecdotal reports of someone who takes Guanfacine and actually likes it for cognitive enhancement.   If you read all the patient reviews, it seems to be prescribed mostly for calming down children who are excessively hyperactive or aggressive.  Seems the reviews are mixed.

 

See: http://www.drugs.com...nts/guanfacine/

 

I'm with you, Abelard. The reviews are mixed but I like to see how things work in combo with other things. Occasionally you can get around some of the negatives (although most of the time you can't...at least 'I' can't. ha). Overall, I'm a bit more of a fan of increasing cAMP for LTP and using other methods to increase sodium channel activity in the dlpfc and therefore spatial working memory. I kind of doubt most of the other guanfacine users are taking intranasal insulin, MK-677, intranasal PT-141 and shooting a laser at their head every night in combination with an extensive supplement regimen to make sure they have no nutritional deficiencies. Guanfacine 'might' affect me a little differently (but it will most likely be similar). =)

Edited by lostfalco, 14 February 2016 - 11:46 PM.

[lostfalco]

I took guanfacine for a while and definitely liked its effects. One way to put it is that I felt much more rational and much less impulsive. I believe there is a study out there that it not only strengthens the PFC; but, also suppresses the amygdala. Only reason I'm not on it is because I can't find a source for it. I'm actually looking and having a pdoc prescribe it to me if possible. 

 

EDIT: I'd be interested in participating in a group buy if possible. (Don't really trust TLR much to be a supplier for it). There are plenty of legitimate suppliers from alibaba. Only thing is I would need the organizer to be able to create a solution, say 1 mg per 1 ml with a total amount of 100ml. Or 1 mg per .5ml, etc...

Hey yada, thanks for all the info on guanfacine! I would love to try it in a couple of months when I've saved up a bit. If you find a supplier or someone reliable to lead a group buy then let me know. 

[lostfalco]

Found about this place called sci-hub where one can access pretty much any published paper: http://sci-hub.io

Thanks, cylack! 

[alpal]

Im in on the Guanfacine groupby group buy as well, just let me know.

edit: sql

Edited by alpal, 15 February 2016 - 08:54 AM.

[Bluecheer]

Found about this place called sci-hub where one can access pretty much any published paper: http://sci-hub.io

Thanks, cylack!

Thanks!


Hey lostfalco, I know this is a bit of a pain. But I've been looking for a good laser to use as per LLLT but I haven't been able to find a good one that ships to Australia! Unfortunately most items on Amazon will not ship here (except things like books) anyway I was wondering if you knew of any other good source? Because I have been looking for quite some time with no success, cheers in advance!

P.s you've posted some interesting studies lately (: !

[lostfalco]

Hey lostfalco, I know this is a bit of a pain. But I've been looking for a good laser to use as per LLLT but I haven't been able to find a good one that ships to Australia! Unfortunately most items on Amazon will not ship here (except things like books) anyway I was wondering if you knew of any other good source? Because I have been looking for quite some time with no success, cheers in advance!

P.s you've posted some interesting studies lately (: !

 

Hey Bluecheer, something like this might work. =)  http://www.ebay.com.au/bhp/ir-light

[lostfalco]

Recent study on Natesto (nasal testosterone). It's not a great study due to the lack of controls/placebo but, it's still interesting imo. Of course, this shouldn't be taken unless and until one is ready to commit to exogenous testosterone supplementation for the long term (fertility issues are a legitimate concern). I'm interested in it because testosterone increases mitochondrial biogenesis and has major effects (along with DHT) on spinogenesis/synaptogenesis in the brain. Nasal testosterone significantly increases brain testosterone levels (in rodents) above the level of increase caused by comparable amounts of injectable testosterone. Just keeping this one in the back of my mind for the future. =)

 

Testosterone increases PGC-1a increases mitochondrial biogenesis. I probably get a little too excited thinking of the possibilities of intranasal testosterone + intranasal insulin + LLLT (high risk, of course =)). 

 

http://www.ncbi.nlm....pubmed/26695758

 

Andrology. 2016 Jan;4(1):46-54. doi: 10.1111/andr.12137. Epub 2015 Dec 22.

Natesto(™) , a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men.

Rogol AD1, Tkachenko N2, Bryson N2.

Author information

Abstract

Advantages of testosterone nasal gel include ease of administration, low dose, and no risk of secondary transference. The efficacy and safety of testosterone nasal gel was evaluated in hypogonadal males. The ninety-day, randomized, open-label, dose-ranging study, included potential dose titration and sequential safety extensions to 1 year. At 39 US outpatient sites, 306 men (mean age 54.4 years) with two fasting morning total serum testosterone levels <300 ng/dL were randomized (n = 228, b.i.d. dosing; n = 78, t.i.d. dosing). Natesto(™) Testosterone Nasal Gel was self-administered, using a multiple-dose dispenser, as two or three daily doses (5.5 mg per nostril, 11.0 mg single dose). Total daily doses were 22 mg or 33 mg. The primary endpoint was the Percentage of patients with Day-90 serum total testosterone average concentration (Cavg ) value within the eugonadal range (≥300 ng/dL, ≤1050 ng/dL). At Day 90, 200/273 subjects (73%; 95% CI 68, 79) in the intent-to-treat (ITT) population and 180/237 subjects (76%; 71, 81) in the per-protocol (PP) population were in the normal range. Also, in the normal range were 68% (61, 74) of ITT subjects and 70% (63, 77) of PP subjects in the titration arm, as well as, 90% (83, 97) of ITT subjects and 91% (84, 98) of PP subjects in the fixed-dose arm. Natesto(™) 11 mg b.i.d. or 11 mg t.i.d. restores normal serum total testosterone levels in most hypogonadal men. Erectile function, mood, body composition, and bone mineral density improved from baseline. Treatment was well tolerated; adverse event rates were low. Adverse event discontinuation rates were 2.1% (b.i.d.) and 3.7% (t.i.d.). This study lacked a placebo or an active comparator control which limited the ability to adequately assess some measures.

 

http://www.ncbi.nlm....pubmed/24005768

 

J Mol Neurosci. 2014 Apr;52(4):531-7. doi: 10.1007/s12031-013-0108-3. Epub 2013 Sep 5.

Brain testosterone deficiency leads to down-regulation of mitochondrial gene expression in rat hippocampus accompanied by a decline in peroxisome proliferator-activated receptor-γ coactivator 1α expression.

Hioki T1, Suzuki S, Morimoto M, Masaki T, Tozawa R, Morita S, Horiguchi T.

Author information

Abstract

Age-related decrease of testosterone levels in blood and brain is believed to be associated with neurodegenerative diseases such as Alzheimer's disease. However, the effect of testosterone on brain function is not well understood. Therefore, we investigated the impact of testosterone deprivation on mitochondrial gene expression in the brain of male gonadectomized (GDX) rats. We found that peripheral castration led to testosterone deficiency in the brain and caused a significant reduction in protein and mRNA expression of genes encoded by mitochondrial DNA, namely NADPH dehydrogenase subunit 1, subunit 4, cytochrome b, and cytochrome c oxidase subunit 1 and subunit 3 in the hippocampus. In addition, gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which is a master regulator of mitochondrial biogenesis, and its downstream transcriptional factors, nuclear respiratory factors 1 and 2 and mitochondrial transcription factors A and B2, were also decreased in the hippocampus of GDX rats. These reductions in the expression of mitochondrial gene and transcriptional coactivators and factors were recovered by androgen replacement. These findings indicate that androgen plays an important role in mitochondrial gene expression in the hippocampus.

 

http://www.ncbi.nlm....pubmed/25511993  (I've posted this study a few times before =))

 

Brain Res. 2015 Sep 24;1621:121-32. doi: 10.1016/j.brainres.2014.12.011. Epub 2014 Dec 13.

Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: Dependence on synaptic androgen receptor and kinase networks.

Hatanaka Y1, Hojo Y2, Mukai H2, Murakami G2, Komatsuzaki Y1, Kim J1, Ikeda M1, Hiragushi A1, Kimoto T1, Kawato S3.

Author information

Abstract

Rapid modulation of hippocampal synaptic plasticity by locally synthesized androgen is important in addition to circulating androgen. Here, we investigated the rapid changes of dendritic spines in response to the elevation of dihydrotestosterone (DHT) and testosterone (T), by using hippocampal slices from adult male rats, in order to clarify whether these signaling processes include synaptic/extranuclear androgen receptor (AR) and activation of kinases. We found that the application of 10nM DHT and 10nM T increased the total density of spines by approximately 1.3-fold within 2h, by imaging Lucifer Yellow-injected CA1 pyramidal neurons. Interestingly, DHT and T increased different head-sized spines. While DHT increased middle- and large-head spines, T increased small-head spines. Androgen-induced spinogenesis was suppressed by individually blocking Erk MAPK, PKA, PKC, p38 MAPK, LIMK or calcineurin. On the other hand, blocking CaMKII did not inhibit spinogenesis. Blocking PI3K altered the spine head diameter distribution, but did not change the total spine density. Blocking mRNA and protein synthesis did not suppress the enhancing effects induced by DHT or T. The enhanced spinogenesis by androgens was blocked by AR antagonist, which AR was localized postsynaptically. Taken together, these results imply that enhanced spinogenesis by DHT and T is mediated by synaptic/extranuclear AR which rapidly drives the kinase networks.

 

http://www.ncbi.nlm....pubmed/15591638

 

Pol J Pharmacol. 2004 Sep-Oct;56(5):509-18.

Neuroprotective role of testosterone in the nervous system.

Białek M1, Zaremba P, Borowicz KK, Czuczwar SJ.

Author information

Abstract

Testosterone -- the gonadal sex steroid hormone plays an important role in the central nervous system (CNS) development. One of the less known testosterone actions is neuroprotection. There are some evidences supporting the hypothesis that testosterone may act protectively in neurodegenerative disorders, e.g. Alzheimer's disease (AD), mild cognitive impairment (MCI) or depression. Androgens alter also the morphology, survival and axonal regeneration of motor neurons. These hormones accelerate the regeneration of hamster facial nerve and anterior tibialis sciatic nerve in rabbits following crush axotomy. Androgens exert trophic action in laryngeal motor nucleus of Xenopus laevis. Testosterone is linked to an increase in neuron somal size, neuritic growth, plasticity and synaptogenesis in both motoneurons of the spinal nucleus of the bulbocavernosus and several populations of pelvic autonomic neurons. The hormone reduced the extent of spinal cord damage in vitro. There are also evidences against the neuroprotective action of testosterone. Testosterone does not protect against methamphetamine-induced neurotoxicity of the dopaminergic system in mice and does not provide significant neuroprotection against glutamate-induced neurotoxicity. Androgens do not prevent striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Although the role of testosterone in the CNS is still poorly understood, accumulating evidence suggests that testosterone may create a future treatment for MCI and related cognitive diseases, including dementia and may influence motor neuron regeneration in adulthood. Androgen replacement therapy in selected male populations may hold therapeutic promise for the prevention and/or treatment of age-related disorders associated with neuronal injury.

 

Edited by lostfalco, 18 February 2016 - 03:30 PM.

[lostfalco]

A little stress is good, a lot is bad: the connection between mitochondria, synapses, and glucocorticoids. 

 

Have we talked about the importance of mitochondria and bioenergetics for brain function in this thread? =)

 

http://www.ncbi.nlm....pubmed/26885402

 

Neural Plast. 2016;2016:3985063. doi: 10.1155/2016/3985063. Epub 2016 Jan 14.

Linking Mitochondria to Synapses: New Insights for Stress-Related Neuropsychiatric Disorders.

Jeanneteau F1, Arango-Lievano M1.

Author information

Abstract

The brain evolved cellular mechanisms for adapting synaptic function to energy supply. This is particularly evident when homeostasis is challenged by stress. Signaling loops between the mitochondria and synapses scale neuronal connectivity with bioenergetics capacity. A biphasic "inverted U shape" response to the stress hormone glucocorticoids is demonstrated in mitochondria and at synapses, modulating neural plasticity and physiological responses. Low dose enhances neurotransmission, synaptic growth, mitochondrial functions, learning, and memory whereas chronic, higher doses produce inhibition of these functions. The range of physiological effects by stress and glucocorticoid depends on the dose, duration, and context at exposure. These criteria are met by neuronal activity and the circadian, stress-sensitive and ultradian, stress-insensitive modes of glucocorticoid secretion. A major hallmark of stress-related neuropsychiatric disorders is the disrupted glucocorticoid rhythms and tissue resistance to signaling with the glucocorticoid receptor (GR). GR resistance could result from the loss of context-dependent glucocorticoid signaling mediated by the downregulation of the activity-dependent neurotrophin BDNF. The coincidence of BDNF and GR signaling changes glucocorticoid signaling output with consequences on mitochondrial respiration efficiency, synaptic plasticity, and adaptive trajectories.

 

Edited by lostfalco, 18 February 2016 - 05:53 PM.

[Kalliste]

I've taking MitoQ 2 days a week or so, 10mg dosages. I've noticed it has a pretty profound effect on my personality in a strange way, it seems to make me a lot more talkative and outgoing. It took me a while to notice this.

 

Anyone else had this effect with MitoQ?

[lostfalco]

Hello my friends, I just have a quick question for everyone who is reading this. I'm currently thinking through career options and I'd really like to hear as many opinions as I can get. If I was to pursue nootropics/peak performance/learning and memory enhancement/etc. as a full time job...what do you think the best way to go about it would be? How could I contribute the most to people's lives through my research and experiments? How could I contribute the most to your life through my work?

 

I'd love to hear from as many people as possible so please chime in and share your thoughts. Thanks!

Edited by lostfalco, 19 February 2016 - 04:21 PM.

[Remington]

Hello my friends, I just have a quick question for everyone who is reading this. I'm currently thinking through career options and I'd really like to hear as many opinions as I can get. If I was to pursue nootropics/peak performance/learning and memory enhancement/etc. as a full time job...what do you think the best way to go about it would be? How could I contribute the most to people's lives through my research and experiments? How could I contribute the most to your life through my work?

I'd love to hear from as many people as possible so please chime in and share your thoughts. Thanks!

Lostfalco, are you talking about becoming a vendor and selling your own product?

[lostfalco]

 

Lostfalco, are you talking about becoming a vendor and selling your own product?

 

Hey Remington, possibly but not necessarily. For example, Joe Cohen does a lot of consulting where he makes tailored recommendations based on people's individual needs. He doesn't sell a product he sells a service. I could also write a book, make instructional YouTube videos (but then you'd have to see my ugly face), build a website, etc. Creating a product is only one option and might limit my ability to help people...but if the product didn't exist yet then it might be worthwhile. I'm still in the brainstorming phase. As of now, this is my hobby and I make money elsewhere. That limits my ability to help others because I just don't have time to research everyone's individual cases. I focus on what helps me and then attempt to share that. I can't tell you how many times people have messaged me asking for a depression protocol and I feel terrible that I have to tell them that I focus on learning and memory for healthy people (like me) and I don't feel comfortable making medical recommendations if I haven't delved into something deeply. 

Edited by lostfalco, 19 February 2016 - 05:35 PM.

[Remington]

Lostfalco, are you talking about becoming a vendor and selling your own product?

Hey Remington, possibly but not necessarily. For example, Joe Cohen does a lot of consulting where he makes tailored recommendations based on people's individual needs. He doesn't sell a product he sells a service. I could also write a book, make instructional YouTube videos (but then you'd have to see my ugly face), build a website, etc. Creating a product is only one option and might limit my ability to help people...but if the product didn't exist yet then it might be worthwhile. I'm still in the brainstorming phase. As of now, this is my hobby and I make money elsewhere. That limits my ability to help others because I just don't have time to research everyone's individual cases. I focus on what helps me and then attempt to share that. I can't tell you how many times people have messaged me asking for a depression protocol and I feel terrible that I have to tell them that I focus on learning and memory for healthy people (like me) and I don't feel comfortable making medical recommendations if I haven't delved into something deeply.

I see what you mean, I also follow Joe and like what he does. You know I really would like if you did the youtube thing, even though we'd see that ugly mug of yours

I think it would help. First the group of men and women that follow you on this forum would definitely follow you on YouTube, which would eventually make money for you on YouTube as well. Plus a lot of people are visual learners, seeing it on a video is much easier to grasp, which would cut down on you repeating the same answer to people who don't get it which I have been guilty of. Of course that's just apart of what I think.

[lostfalco]

 

I see what you mean, I also follow Joe and like what he does. You know I really would like if you did the youtube thing, even though we'd see that ugly mug of yours

I think it would help. First the group of men and women that follow you on this forum would definitely follow you on YouTube, which would eventually make money for you on YouTube as well. Plus a lot of people are visual learners, seeing it on a video is much easier to grasp, which would cut down on you repeating the same answer to people who don't get it which I have been guilty of. Of course that's just apart of what I think.

 

haha On your own head be it! 

 

Yeah, I think a LLLT video tutorial would probably be pretty helpful for a lot of people. I could also do some videos on making your own intranasal peptides...which are pretty powerful enhancements (though questionable legally). I do kind of like the idea of making ad revenue instead of charging people for things. One thing I've really tried to do with things like LLLT and intranasal insulin is find the cheapest methods possible so that everyone can try them. Thanks for the feedback!

Edited by lostfalco, 19 February 2016 - 10:15 PM.

[Nuke]

I hope that my LEDs and PQQ will arrive next week. The LEDs are the 830nm ones, I ordered 70 of them to be able to build a sizable array. Vanadium and Methylene blue will likely only arrive sometime in March. Before I start that I want to do a quick retest of my Cambridge Brain Sciences tests before I start with something new. I'm still taking the peptides, but I halved the dose.

 

Now my next issue is to make sure that I have a measurable effect from the nootropic substances I take. For one, all the supplements is getting expensive. Add to that the fact that drug to drug interactions become harder to anticipate the more things you take. I'll have to think on how to approach this.

 

I'll drop you a PM about some long term ideas I have.

[Thomlandia]

 joeCohen.JPG   17.08KB   18 downloads

 

Have you thought about moving to Cambria and joining the revolution?

 

 

 

[Nuke]

 

Delta sleep inducing peptide (DSIP): effect on respiration activity in rat brain mitochondria and stress protective potency under experimental hypoxia.

Khvatova EM1, Samartzev VN, Zagoskin PP, Prudchenko IA, Mikhaleva II.

Author information

 

Abstract

Neuromodulatory delta sleep inducing peptide (DSIP) seems to be implicated in the attenuation of stress-induced pathological metabolic disturbances in various animal species and human beings. Mitochondria, as cell organelles, are considered especially sensitive to stress conditions. In this work, the influence of DSIP and Deltaran(®)-a recently developed product based upon DSIP-on processes of oxidative phosphorylation and ATP production in rat brain mitochondria and rat brain homogenates was studied. A polarographic measurement of oxygen consumption was applied to evaluate the impact of DSIP on maximal rates of mitochondrial respiration and coupling of respiration to ATP production. We provide evidence that DSIP affected the efficiency of oxidative phosphorylation on isolated rat brain mitochondria. This peptide significantly increased the rate of phosphorylated respiration V3, while the rate of uncoupled respiration V(DNP) remaining unchanged. It enhanced the respiratory control ratio RCR and the rate of ADP phosphorylation. DSIP and Deltaran exhibited the same action in rat brain homogenates. We also examined the influence of DSIP under hypoxia when mitochondrial respiratory activity is altered. In rats subjected to hypoxia, we detected a significant stress-mediated reduction of V3 and ADP/t values. Pretreatment of rats with DSIP at the dose of 120 microgram/kg (i.p.) prior to their subjection to hypoxia completely inhibited hypoxia-induced reduction of mitochondrial respiratory activity. The revealed capacity of DSIP to enhance the efficiency of oxidative phosphorylation found in vitro experiments could contribute to understanding pronounced stress protective and antioxidant action of this peptide in vivo.

 

 

 

Talking about mitocondrial enhancement. From here. Use scihub to grab the full text.

 

[lostfalco]

Very informative 2008 article on various substances that can be targeted to the CNS through intranasal delivery:

insulin

IGF-1

fibroblast growth factor-2

nerve growth factor

deferoxamine

erythropoietin

NAP

epidermal growth factor

 

http://www.ncbi.nlm....les/PMC2604883/

 

BMC Neurosci. 2008 Dec 10;9 Suppl 3:S5. doi: 10.1186/1471-2202-9-S3-S5.

Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease.

Hanson LR1, Frey WH 2nd.

Author information

Abstract

Intranasal delivery provides a practical, non-invasive method of bypassing the blood-brain barrier (BBB) to deliver therapeutic agents to the brain and spinal cord. This technology allows drugs that do not cross the BBB to be delivered to the central nervous system within minutes. It also directly delivers drugs that do cross the BBB to the brain, eliminating the need for systemic administration and its potential side effects. This is possible because of the unique connections that the olfactory and trigeminal nerves provide between the brain and external environment. Intranasaldelivery does not necessarily require any modification to therapeutic agents. A wide variety of therapeutics, including both small molecules and macromolecules, can be targeted to the olfactory system and connected memory areas affected by Alzheimer's disease. Using the intranasaldelivery system, researchers have reversed neurodegeneration and rescued memory in a transgenic mouse model of Alzheimer's disease. Intranasal insulin-like growth factor-I, deferoxamine, and erythropoietin have been shown to protect the brain against stroke in animal models. Intranasal delivery has been used to target the neuroprotective peptide NAP to the brain to treat neurodegeneration. Intranasal fibroblast growth factor-2 and epidermal growth factor have been shown to stimulate neurogenesis in adult animals. Intranasal insulin improves memory, attention, and functioning in patients with Alzheimer's disease or mild cognitive impairment, and even improves memory and mood in normal adult humans. This new method of delivery can revolutionize the treatment of Alzheimer's disease, stroke, and other brain disorders.

 

 

Edited by lostfalco, 21 February 2016 - 08:10 PM.

[Bluecheer]

Hey Falco, I'm sure you have covered this before so I'm sorry.. But I was wondering I read somewhere that targeting the back of your brain with lllt can alter your cercadian rhythm, do you have any comments on this and do you still target your whole brain?
Hey Falco, I'm sure you have covered this before so I'm sorry.. But I was wondering I read somewhere that targeting the back of your brain with lllt can alter your cercadian rhythm, do you have any comments on this and do you still target your whole brain?

[Reformed-Redan]

Hello my friends, I just have a quick question for everyone who is reading this. I'm currently thinking through career options and I'd really like to hear as many opinions as I can get. If I was to pursue nootropics/peak performance/learning and memory enhancement/etc. as a full time job...what do you think the best way to go about it would be? How could I contribute the most to people's lives through my research and experiments? How could I contribute the most to your life through my work?

 

I'd love to hear from as many people as possible so please chime in and share your thoughts. Thanks!

I really think a store for unique products like JDTiC, guanfacine, and other worthwhile nootropics are a great thing to start. You make money and at the same time continue your research into the nootropics area. Since I've been a member of Longecity I've spent all my time in this sub-forum, and the administrators have noticed that in terms of increased traffic and ad revenue. There is still quite a huge unserved chunk of the nootropics area that can be served. 

 

As for your latter post on helping people with depression. First things you should say is that your not a doctor and do not have the credentials to give such advice. After that you can point them to papers of... for example 7,8-Dihydroxyflavone or Semax. Those are the two compounds I am aware of that actually help with depression. Obviously I'm no doctor either; but, what were doing here is citizen science at its best. No reason why people couldn't benefit from it. This is why I am really trying hard to get NRX-1074. It shows robust positive effects on depressed patients as well as very potent nootropic activity. 

 

So, if it were me I'd say try Semax for depression from Ceretropic or any other legitimate vendor. If that doesnt raise BDNF levels sufficiently, then give intranasal 7,8-DHF a try. It really works from my experience with it. There are other methods of treating depression, such as LLLT focused on the DLPFC (which by my n=1 works well). There's also CBT, which takes a while to work; but, when it does it will have a lasting and profound effect on anyone's state of mind. Mindfulness meditation is another option. Which brings me to also mention that there is essentially no silver bullet supplement (as many people think there is) that will completely treat your depression. The closest thing that comes to my mind is ketamine (derivatives of which can be easily found online; but, don't ask me for sources as I won't tell). 

 

For the time being I'm betting my last bet on NRX-1074 after my extensive research in the area of nootropics/depression treatment and cognitive enhancement. Hope this helps in some small way.

 

Cheers.

 

DERP, I totally forgot NSI-189. Lasting positive effects on depression from most of the research I've seen on the topic. Kudos

Edited by redan, 22 February 2016 - 09:23 AM.

[lostfalco]

 

I hope that my LEDs and PQQ will arrive next week. The LEDs are the 830nm ones, I ordered 70 of them to be able to build a sizable array. Vanadium and Methylene blue will likely only arrive sometime in March. Before I start that I want to do a quick retest of my Cambridge Brain Sciences tests before I start with something new. I'm still taking the peptides, but I halved the dose.

 

Now my next issue is to make sure that I have a measurable effect from the nootropic substances I take. For one, all the supplements is getting expensive. Add to that the fact that drug to drug interactions become harder to anticipate the more things you take. I'll have to think on how to approach this.

 

I'll drop you a PM about some long term ideas I have.

 

Sounds good, Nuke! Look forward to hearing your ideas.