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Quinolinic Acid's Relationship with Lyme, Neurodegenerative and Infammatory Disorders

quinolinc acid lyme disease spirochete stress neurodegenerative infammatory disorders

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#1 birthdaysuit

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Posted 02 June 2016 - 04:08 AM

Quinolinic Acid


Quinolinic acid levels are increased in the brains of children infected with a range of bacterial infections of the central nervous system (CNS),[17][19] of poliovirus patients,[19] and of Lyme disease with CNS involvement patients.[13][19] In addition, raised quinolinic acid levels have been found in traumatic CNS injury patients, patients suffering from cognitive decline with ageing, hyperammonaemia patients, hypoglycaemia patients, and systemic lupus erythematosus patients. Also, it has been found that people suffering from malaria and patients with olivopontocerebellar atrophy have raised quinolinic acid metabolism. Levels of quinolinic acid in the CSF of AIDS patients suffering from AIDS- dementia can be up to twenty times higher than normal. Similar to HIV patients, this increased quinolinic acid concentration correlates with cognitive and motor dysfunction. When patients were treated with zidovudine to decrease quinolinic acid levels, the amount of neurological improvement was related to the amount of quinolinic acid decreased.


It should be noted that quinolinic acid is essential for production of NAD+. Quinolinic acid is converted to nicotinic acid mononucleotide (NaMN) by transfer of a phosphoribose moiety. An adenylate moiety is then transferred to form nicotinic acid adenine dinucleotide (NaAD). Finally, the nicotinic acid moiety in NaAD is amidated to a nicotinamide (Nam) moiety, forming nicotinamide adenine dinucleotide.


However, in the case of Lyme infection and Neurodegenerative Disorders, we are talking about abnormally high levels of quinolinic acid in specific regions of the brain and serum and in many cases too little Kynurenic acid (Acts as NMDA receptor antagonist).


Lyme Disease


Usually in severe cases, the symptoms are due to toxin build-up; please note the methylation defect does not cause Lyme, which is a tick-borne illness. But the infection causes ammonia, quinolinic acid, acetylaldehyde, etc… and methylation defects reduce the person’s ability from properly detoxifying, repairing the damage and fighting the infection and co-infections.


It has widely been known that the Borrelia burgdorferi spirochete depletes a hosts magnesium levels to make biofilms. Low mag reduces your ability to methylate and can lead to a host of problems, including but not limited to an inability to modulate NMDA receptors.


Borrelia Burgdorferi, the Lyme bacteria, releases ammonia as an exotoxin within the body. Wherever the bacteria resides within the body, this can occur, and if it's in the brain, there is potential for damage to occur to neurotransmitter receptors, including but not limited to the NMDA receptor. This opens up the door to Lyme induced depersonalization and other discrepancies of the brain. Not only are we unable to detoxify these exotoxins but sufferers are unable to effectively modulate the NMDA receptor; excessive ammonia and quinolinic acid lead to excitoxicity.


NMDA receptors are also over-stimulated by the immune system itself, whenever there is an infection within the brain. A part of the brains own immune system, the microglia, rather unfortunately secrete both glutamate and quinolinic acid - both powerful NMDA activators - as a byproduct of their operation. (Not a very clever design). Thus, in as far as CFS is a central nervous system infection, there may already be some NMDA over-stimulation going on, just from the the microglia, even before ammonia might contribute to the act.) Therefore, if there’s chronic inflammation, your tryptophan is going to be robbed down the inflammatory pathway instead of going down the serotonin/melatonin pathway, and that’s why you develop the deficiency and in many cases excess quinolinic acid.



If you can’t methylate properly, you cannot produce CoQ10, carnitine, creatine or ATP (energy). You will also have nerve pain termed “neuropathy.” That’s because the methylation process helps make the protective wrapping around your nerves. This is one of a few reasons why people with CFS infections suffer from chronic fatigue and peripheral neuropathy.


Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease.

Heyes MP1, Saito K, Crowley JS, Davis LE, Demitrack MA, Der M, Dilling LA, Elia J, Kruesi MJ, Lackner A, et al.

Author information



Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly


increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia)


independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation. We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.




Brain. 1992 Oct;115 ( Pt 5):1249-73.



Nervous system Lyme disease

JJ Halperin
Medical Director, Atlantic Neuroscience Institute, Summit, New Jersey, and Professor of Neurology, Mount Sinai School of Medicine,

New York, USA

Snippet from page 253:

Although the mechanism of this encephalopathy – in Lyme or in other disorders – remains to be determined, several interesting observations may be relevant. A reasonable supposition would be that one or more soluble factors exist peripherally as part of the inflammatory response, are able to cross the blood–brain barrier, and then affect nervous system function. One such candidate molecule has been identified – quinolinic acid – which has been shown to be present in the serum and CSF of patients with a number of infectious disorders, (51,52) including Lyme disease. What makes this molecule of particular interest is that it is known to activate the N-methyl-D-aspartic acid (NMDA) receptor in the brain. The activation of this receptor can not only affect behaviour but, if excessive, can lead to neuronal death.



Review Article


Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets


Rafael Lugo-Huitrón,1 Perla Ugalde Muñiz,1 Benjamin Pineda,2 José Pedraza-Chaverrí,3 Camilo Ríos,1 and Verónica Pérez-de la Cruz1


Quinolinic acid (QUIN), a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF) and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA) receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity, which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death.


9. Conclusion


According to the information that has been reviewed, the mechanisms by which QUIN produces neurotoxicity include overactivation of the NMDA receptor, energy deficit, oxidative stress, and cell death. A sequence of these events is described in Figure 2. Far from being excluding, all these factors are somehow closely related and also act synergistically to induce neurodegeneration. Taking into account that QUIN has been implicated in neurodegenerative diseases and some of their toxic mechanisms are still unknown, the challenges for the future research should be directed to clarify all the possible routes that can promote or contribute to the damage induced by this metabolite. This may help to explain the physiopathological events occurring in several neurodegenerative diseases in which the levels of QUIN are increased.






Neurobiology of ammonia.


Felipo V1, Butterworth RF.

Author information




Hyperammonemia resulting from inherited urea cycle enzyme deficiencies or liver failure results in severe central nervous system dysfunction including brain edema, convulsions and coma. Neuropathologic evaluation in these disorders reveals characteristic alterations of astrocyte morphology ranging from cell swelling (acute hyperammonemia) to Alzheimer Type II astrocytosis (chronic hyperammonemia). Having no effective urea cycle, brain relies on glutamine synthesis for the removal of excess ammonia and the enzyme responsible, glutamine synthetase, has a predominantly astrocytic localization. Accumulation of ammonia in brain results in a redistribution of cerebral blood flow and metabolism from cortical to sub-cortical structures. In addition to changes in astrocyte morphology, increased brain ammonia concentrations result in alterations in expression of key astrocyte proteins including glial fibrillary acidic protein, glutamate and glycine transporters and "peripheral-type" (mitochondrial) benzodiazepine receptors. Such changes result in alterations of astrocytic volume and increased extracellular concentrations of excitatory and inhibitory substances. In addition, the ammonium ion has direct effects on excitatory-inhibitory transmission via distinct mechanisms involving cellular chloride extrusion and postsynaptic receptor function. Acute ammonia exposure leads to activation of NMDA receptors and their signal transduction pathways. Chronic hyperammonemia also results in increased concentrations of neuroactive L-tryptophan metabolites including serotonin and quinolinic acid. Therapy in hyperammonemic syndromes continues to rely on ammonia-lowering strategies via peripheral mechanisms (reduction of ammonia production in the gastrointestinal tract, increased ammonia removal by muscle).






At high concentrations, quinolinic acid inhibits glutamine synthetase, a critical enzyme in the glutamate-glutamine cycle. In addition, It can also promote glutamate release and block its reuptake by astrocytes. All three of these actions result in increased levels of glutamate activity that could be neurotoxic.[10]




Excess Glutamate, Lyme Disease and Multiple Sclerosis:


In the Mayo Clinic Study published in October 2008, Dr. Vanna Lennon and her team have demonstrated that glutamate accumulates in the brain of patients with neuromyelitis optica. They propose that this is a result of NMO antiboides leading to glutamate excess. Dr. Lennon's study suggests that glutamate is responsible for the myelin destruction in this disorder.

Dr. Hong has previously shown the destructive role of glutamate in Parkinson’s disease. Dr. Yash Agrawal has explained how glutamate toxicity causes symptoms in both Lyme disease and multiple sclerosis. Dr. Agrawal explains that the ability of the beta-lactam antibiotic cefrixatone to reduce glutamate accumulations accounts for its effectiveness in Lyme disease. He proposes that both cefrixatone and low dose naltrexone, by having the potential to reduce glutamate accumulations, have therapeutic value in Lyme disease, MS, and other neurological disorders.

Thus, while the Mayo researchers propose finding ways to block glutamate, the benefits of low dose naltrexone and beta lactam antibiotics lie in their ability to reduce glutamate excess.


Possible relationship with Quinolinic Acid?




Quinolinic acid in children with congenital hyperammonemia.


Batshaw ML1, Robinson MB, Hyland K, Djali S, Heyes MP.

Author information




Levels of the excitotoxin quinolinic acid (QUIN) were measured in the cerebrospinal fluid of infants and children with congenital hyperammonemia. Twofold to tenfold elevations of QUIN were found in 4 neonates in hyperammonemic coma (QUIN range, 250-990 nM; control mean, 110 +/- 90 nM; p < 0.005). Similar elevations of neopterin were found (range, 24-75 nM; control mean, 9.0 +/- 4.9 nM; p < 0.005). In addition, significant elevations of QUIN were found in 14 older children with congenital hyperammonemia (mean, 50 +/- 20 vs 17 +/- 6 nM; p < 0.05). Neopterin levels were not elevated in these children. The QUIN may originate from an increase in tryptophan transport across the blood-brain barrier or from induction of indolamine-2,3-dioxygenase activity. These findings support a role for QUIN in the neuropathology of congenital hyperammonemia. They also suggest the potential utility of N-methyl-D-aspartate receptor-blocking agents or inhibitors of QUIN synthesis in the treatment of hyperammonemic coma.







An Antimetabolic Action of Vitamin K



Institute of Biochemistry, University of Naples. June 22.


IN recent studies in vivo and in vitro, we have shown that the K vitamins (K1, K2, phthiocol, menadione and ‘Synkavit’) inhibit the synthesis of nicotinic acid at the stage 3-hydroxyanthranilic acidquinolinic acid.


We suggested that the mechanism of inhibition is competition between vitamin K and 3-hydroxyanthranilic acid, that is, the K vitamins exert antimetabolitic action on the substrate of the reaction catalysed by 3-hydroxyanthranilic acid oxidase. On the basis of this hypothesis, investigations were undertaken to determine if the inhibition of 3-hydroxyanthranilic acid oxidase produced in vivo by administration of menadione or ‘Synkavit’ could be reversed by subsequent administration of 3-hydroxyanthranilic acid. The results of these experiments demonstrated the capacity of 3-hydroxyanthranilic acid to overcome the inhibitory effect of vitamin K.







Natural inhibitors of indoleamine 3,5-dioxygenase induced by interferon-gamma in human neural stem cells.Chen S1, Corteling R, Stevanato L, Sinden J.


Author information Abstract


Indoleamine dioxygenase (IDO) is a heme- containing enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine, kynurenine and the downstream quinolinic acid. Though IDO is physiologically important in maintaining tissue integrity, aberrant IDO expression represses T cell function and promotes regulatory T cells (Treg) in cancer. It additionally exacerbates Alzheimer, depression, Huntington and Parkinson diseases via quinolinic acid. Inhibition of IDO has thus been recently proposed as a strategy for treating cancer and neuronal disorders. In the present study, we have developed a cell-based assay to evaluate the suppressive effect of anti-inflammatory phytochemicals on the enzyme. When stimulated by INF-γ, profound high expressions of IDO-1 mRNA as well as the protein were detected in human neural stem cells (hNSC) and verified by real-time retro-transcribed PCR and western blot analysis, respectively. The protein activity was measured by kynurenine concentration and the assay was validated by dose-responsive inhibition of IDO-1 antagonists including 1-methyltryptaphan, indomethacin and acetylsalicylic acid. Among the tested compounds, apigenin, baicalein, chrysin, and wogonin exhibit a potent repressive activity with IC(50s) comparable to that of indomethacin. The inhibition was further found to be independent of gene expression and protein translation because of the unaltered levels of mRNA and protein expression. Although curcumin displayed a potent inhibitory activity to the enzyme, it appeared to be cytotoxic to hNSCs. Morphological examination of hNSC revealed that baicalein and wogonin at the inhibitory concentrations induced neurite outgrowth. In conclusion, our data shows that certain phytochemicals with 2-phenyl-1-benzopyran-4-one backbone (flavones) attenuate significantly the IDO-1 protein activity without harming hNSCs. The inhibitory activity might have partially contributed to the anti-cancer and neuro-protective property of the compounds.






IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity.Wichers MC1, Koek GH, Robaeys G, Verkerk R, Scharpé S, Maes M.


Author information Abstract Th1 Response Increased IFN-γ Increased IDO Reduced Tryptophan Reduced Serotonin Depression

Studies show that administration of interferon (IFN)-alpha causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-alpha-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-alpha treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood-brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-alpha treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-alpha-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.





Novel Ways to Inhibit IDO


Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC is a heme-containing enzyme that in humans is encoded by the IDO1 gene.[1][2] This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine[3] using the superoxide anion as an oxygen donor. Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through kynurenine pathway, thus causing depletion of tryptophan which can cause halted growth of microbes as well as T cells.[4]



Norharmane, via inhibition of indoleamine 2,3-dioxygenase exerts neuroprotective properties by suppressing kynurenine neurotoxic metabolites such as quinolinic acid, 3-hydroxy-kynurenine and nitric oxide synthase.[8]


Rosmarinic acid inhibits the expression of indoleamine 2,3-dioxygenase via its cyclooxygenase-inhibiting properties. This Acid can be found in LEMON BALM.

Holy basil - COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.[10] 




Theanine inhibits the kynurenine pathway


Tryptophan can also be converted to Kynurenine -> quinolinic acid, an excess of which is one of the things found in people with mood-related problem. Here is a study that shows that Theanine actually blocks this conversion. This could explain the reason behind the mood elevating effects of this substance:





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#2 birthdaysuit

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Posted 02 June 2016 - 04:22 AM

I understand how anecdotal this is but my friend and I ate foods high in potassium over several days; beets, bananas, parsnips and lots of potatoes. I was diagnosed with CNS Lyme and each and every time I ate anything with potassium my brain zapped and I felt hyper excitable and overstimulated. Whereas, my friend felt completely fine. I was unable to even have a coherent conversation after eating three bananas. It should be noted I experienced many of these symptoms when herxing and using antibiotics to kill the spirochetes.  


If anyone has anymore INPUT on novel approaches to inhibit ammonia, enhance detoxification processes and inhibit excessive quinolinic acid that would be awesome!

Edited by birthdaysuit, 02 June 2016 - 04:44 AM.

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#3 birthdaysuit

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Posted 02 June 2016 - 06:23 PM

Possible inhibition of Cyclooxygenase could inhibit indoleamine 3,5-dioxygenase enzyme. Might reduce or prevent build up of quinolinic acid.


Also tagged with one or more of these keywords: quinolinc acid, lyme disease, spirochete, stress, neurodegenerative, infammatory disorders

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