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'''Quinolinic acid''' (abbreviated '''QUIN''' or '''QA''') is a di[[carboxylic acid]]. It may be prepared by the [[oxidation]] of [[quinoline]], either [[electrochemistry|electrochemically]],<ref>{{Ref patent|country=EP|number=0159769|status=|title=Electrochemical oxidation of pyridine bases|pubdate=|gdate=|fdate=|pridate=|invent1=Toomey Jr., Joseph E.|invent2=|assign1=Reilly Industries, Inc.|assign2=|class=}}</ref> or with acidic [[hydrogen peroxide]].<ref>{{Ref patent|country=US|number=4420616|status=Patent|title= Oxidative process for the preparation of copper quinolinate|pubdate=|gdate=|fdate=|pridate=|invent1= Ikegami, Seishi |invent2= Hatano, Yoshihiro |assign1=Yamamoto Kagaku Gosei KK|assign2=|class=}}</ref>
'''Quinolinic acid''' (abbreviated '''QUIN''' or '''QA''') is a di[[carboxylic acid]]. It may be prepared by the [[oxidation]] of [[quinoline]], either [[electrochemistry|electrochemically]],<ref>{{Ref patent|country=EP|number=0159769|status=|title=Electrochemical oxidation of pyridine bases|pubdate=|gdate=|fdate=|pridate=|invent1=Toomey Jr., Joseph E.|invent2=|assign1=Reilly Industries, Inc.|assign2=|class=}}</ref> or with acidic [[hydrogen peroxide]].<ref>{{Ref patent|country=US|number=4420616|status=Patent|title= Oxidative process for the preparation of copper quinolinate|pubdate=|gdate=|fdate=|pridate=|invent1= Ikegami, Seishi |invent2= Hatano, Yoshihiro |assign1=Yamamoto Kagaku Gosei KK|assign2=|class=}}</ref>


Quinolinic acid is a downstream [[kynurenine pathway]] metabolite of [[tryptophan]]. It acts as an [[NMDA receptor]] [[agonist]].<ref name="pmid8720470">{{cite journal |author=Misztal M, Frankiewicz T, Parsons CG, Danysz W |title=Learning deficits induced by chronic intraventricular infusion of quinolinic acid--protection by MK-801 and memantine |journal=Eur. J. Pharmacol. |volume=296 |issue=1 |pages=1–8 |year=1996 |month=January |pmid=8720470 |doi= 10.1016/0014-2999(95)00682-6|url=}}</ref> Quinolinic acid has a potent neurotoxic effect. Studies have demonstrated that quinolinic acid may be involved in many mood disorders, neurodegenerative processes in the brain, as well as other disorders. Within the brain, quinolinic acid is only produced by activated [[ microglia]] and [[macrophages]].<ref>{{cite journal | author = Guillemin, G. | year = 2003 | title = Expression of the kynurenine pathway enzymes in human microglia and macrophages | journal = Adv Exp Med Biol | volume = 527}}</ref>
Quinolinic acid is a downstream [[kynurenine pathway]] metabolite of [[tryptophan]]. It acts as an [[NMDA receptor]] [[agonist]].<ref name="pmid8720470">{{cite journal |author=Misztal M, Frankiewicz T, Parsons CG, Danysz W |title=Learning deficits induced by chronic intraventricular infusion of quinolinic acid--protection by MK-801 and memantine |journal=Eur. J. Pharmacol. |volume=296 |issue=1 |pages=1–8 |year=1996 |month=January |pmid=8720470 |doi= 10.1016/0014-2999(95)00682-6|url=}}</ref> Quinolinic acid has a potent neurotoxic effect. Studies have demonstrated that quinolinic acid may be involved in many mood disorders, neurodegenerative processes in the brain, as well as other disorders. Within the brain, quinolinic acid is only produced by activated [[ microglia]] and [[macrophages]].<ref>{{cite journal | author = Guillemin, G. | year = 2003 | title = Expression of the kynurenine pathway enzymes in human microglia and macrophages | journal = Adv Exp Med Biol | volume = 527 | doi = 10.1007/978-1-4615-0135-0_12 | series = Advances in Experimental Medicine and Biology | last2 = Smith | first2 = Danielle G. | last3 = Smythe | first3 = George A. | last4 = Armati | first4 = Patricia J. | last5 = Brew | first5 = George J. | isbn = 978-0-306-47755-3 | pages = 105–12 | pmid = 15206722}}</ref>


[[Norharmane]], suppresses the production of quinolinic acid, [[3-hydroxykynurenine]] and [[nitric oxide synthase]], thereby acting as a neuroprotectant.<ref name="pmid10947071">{{cite journal |author=Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F |title=Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages |url=http://www.jleukbio.org/content/68/2/260.long |journal=J. Leukoc. Biol. |volume=68 |issue=2 |pages=260–6 |year=2000 |month=August |pmid=10947071 }}</ref> [[Natural phenol]]s such as [[catechin hydrate]], [[curcumin]] and [[epigallocatechin gallate]] reduce the neurotoxicity of quinolinic acid, via anti-oxidant and possibly calcium influx mechanisms.<ref name="pmid20015232">{{cite journal |author=Braidy N, Grant R, Adams S, Guillemin GJ |title=Neuroprotective effects of naturally occurring polyphenols on quinolinic acid-induced excitotoxicity in human neurons |journal=FEBS J. |volume=277 |issue=2 |pages=368–82 |year=2010 |month=January |pmid=20015232 |doi=10.1111/j.1742-4658.2009.07487.x }}</ref> [[COX-2 inhibitors]] have also demonstrated protective properties against the neurotoxic properties of quinolinic acid,<ref name="pmid20043943">{{cite journal |author=Kalonia H, Kumar P, Kumar A, Nehru B |title=Protective effect of rofecoxib and nimesulide against intra-striatal quinolinic acid-induced behavioral, oxidative stress and mitochondrial dysfunctions in rats |journal=Neurotoxicology |volume=31 |issue=2 |pages=195–203 |year=2010 |month=March |pmid=20043943 |doi=10.1016/j.neuro.2009.12.008 }}</ref> and these COX-2 inhibitors have demonstrated some evidence of efficacy in mental health disorders such as [[major depressive disorder]] as well as [[schizophrenia]].<ref name="pmid20047157">{{cite journal |author=Müller N |title=COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence |journal=Curr Opin Investig Drugs |volume=11 |issue=1 |pages=31–42 |year=2010 |month=January |pmid=20047157 }}</ref>
[[Norharmane]], suppresses the production of quinolinic acid, [[3-hydroxykynurenine]] and [[nitric oxide synthase]], thereby acting as a neuroprotectant.<ref name="pmid10947071">{{cite journal |author=Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F |title=Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages |url=http://www.jleukbio.org/content/68/2/260.long |journal=J. Leukoc. Biol. |volume=68 |issue=2 |pages=260–6 |year=2000 |month=August |pmid=10947071 }}</ref> [[Natural phenol]]s such as [[catechin hydrate]], [[curcumin]] and [[epigallocatechin gallate]] reduce the neurotoxicity of quinolinic acid, via anti-oxidant and possibly calcium influx mechanisms.<ref name="pmid20015232">{{cite journal |author=Braidy N, Grant R, Adams S, Guillemin GJ |title=Neuroprotective effects of naturally occurring polyphenols on quinolinic acid-induced excitotoxicity in human neurons |journal=FEBS J. |volume=277 |issue=2 |pages=368–82 |year=2010 |month=January |pmid=20015232 |doi=10.1111/j.1742-4658.2009.07487.x }}</ref> [[COX-2 inhibitors]] have also demonstrated protective properties against the neurotoxic properties of quinolinic acid,<ref name="pmid20043943">{{cite journal |author=Kalonia H, Kumar P, Kumar A, Nehru B |title=Protective effect of rofecoxib and nimesulide against intra-striatal quinolinic acid-induced behavioral, oxidative stress and mitochondrial dysfunctions in rats |journal=Neurotoxicology |volume=31 |issue=2 |pages=195–203 |year=2010 |month=March |pmid=20043943 |doi=10.1016/j.neuro.2009.12.008 }}</ref> and these COX-2 inhibitors have demonstrated some evidence of efficacy in mental health disorders such as [[major depressive disorder]] as well as [[schizophrenia]].<ref name="pmid20047157">{{cite journal |author=Müller N |title=COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence |journal=Curr Opin Investig Drugs |volume=11 |issue=1 |pages=31–42 |year=2010 |month=January |pmid=20047157 }}</ref>
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==Synthesis==
==Synthesis==
One of the earliest reported syntheses of this quinolinic acid was by [[Zdenko Hans Skraup]], who found that methyl-substituted quinolines could be oxidized to quinolinic acid by potassium permanganate.<ref>{{cite journal | doi = 10.1007/BF01516502 | journal = Monatshefte f&uuml; Chemie | title = Synthetische Versuche in der Chinolinreihe | author = Zd. H. Skraup | volume = 2 | issue = 1 | year = 1881 | pages = =139-170}}</ref>
One of the earliest reported syntheses of this quinolinic acid was by [[Zdenko Hans Skraup]], who found that methyl-substituted quinolines could be oxidized to quinolinic acid by potassium permanganate.<ref>{{cite journal | doi = 10.1007/BF01516502 | journal = Monatshefte f&uuml; Chemie | title = Synthetische Versuche in der Chinolinreihe | year = 1881 | last1 = Skraup | first1 = Zd. H. | volume = 2 | pages = 139}}</ref>


This compound is commercially available. It is generally obtained by the oxidation of quinoline. Oxidants such as [[ozone]]<ref>{{cite patent | country = WO | number = 2010011134 | title = Ozonolysis of Aromatics and/or Olefins | invent1 = H. bruno }}</ref> and [[potassium permanganate]] have been used. Electrolysis is able to perform the transformation as well.<ref>{{cite journal | doi = 10.1021/ja01216a008 | journal = J. Am. Chem. Soc. | title = Electrolytic Oxidation of Quinoline and 3-Picoline | author =Marshall Kulka | year = 1946 | volume = 68 | issue = 12 | pages = 2472–2473}}</ref>
This compound is commercially available. It is generally obtained by the oxidation of quinoline. Oxidants such as [[ozone]],<ref>{{cite patent | country = WO | number = 2010011134 | title = Ozonolysis of Aromatics and/or Olefins | invent1 = H. bruno }}</ref> and [[potassium permanganate]] have been used. Electrolysis is able to perform the transformation as well.<ref>{{cite journal | doi = 10.1021/ja01216a008 | journal = J. Am. Chem. Soc. | title = Electrolytic Oxidation of Quinoline and 3-Picoline | author =Marshall Kulka | year = 1946 | volume = 68 | issue = 12 | pages = 2472 | pmid = 20282382}}</ref>


Quinolinic acid may undergo further decarboxylation to nicotinic acid (niacin):
Quinoline may undergo further decarboxylation to nicotinic acid (niacin):
:[[File:Synthesis_Niacin_I.svg|400px]]
:[[File:Synthesis_Niacin_I.svg|400px]]


==Production In Vivo==
==Production In Vivo==
Quinolinic acid is a byproduct of the [[kynurenine pathway]] which is responsible for catabolism of tryptophan in mammals. This pathway is important for its production of the coenzyme [[nicotinamide adenine dinucleotide]] (NAD+) and produces several neuroactive intermediates including quinolinic acid, [[kynurenine]] (KYN), [[kynurenic acid]] (KYNA), [[3-hydroxykynurenine]] (3-HK), and [[3-Hydroxyanthranilic acid|3-hydroxyanthranilic acid]] (3-HANA).<ref name=Guillemin>{{cite journal|last=Guillemin|first=Giles|title=Quinolinic acid, the inescapable neurotoxin|journal=FEBS Journal|year=2012|month=April|volume=279|issue=8|pages=1356-1365|doi=10.1111/j.1742-4658.2012.08485.x|url=http://onlinelibrary.wiley.com.proxy.bc.edu/doi/10.1111/j.1742-4658.2012.08485.x/abstract;jsessionid=5823C24FF2ABDCC4A941E609471599B2.d03t01|accessdate=4 November 2012}}</ref><ref name=Schwarcz>{{cite journal|last=Schwarcz|first=Robert|coauthors=John P. Bruno, Paul J. Muchowski, Hui-Qiu Wu|title=Kynurenines in the mammalian brain: when physiology meets pathology|journal=Nature Reviews Neuroscience|year=2012|month=July|volume=13|pages=465-477|doi=10.1038/nrn3257|accessdate=4 November 2012}}</ref> quinolinic acid is a neuroactive molecule with excitatory properties and acts as an agonist to [[NMDA receptor|NMDA receptors]] in the brain.<ref name=Schwarcz /> Furthermore, quinolinic acid acts as a [[neurotoxin]], gliotoxin, proinflammatory mediator, and pro-oxidant molecule.<ref name=Guillemin />
Quinolinic acid is a byproduct of the [[kynurenine pathway]] which is responsible for catabolism of tryptophan in mammals. This pathway is important for its production of the coenzyme [[nicotinamide adenine dinucleotide]] (NAD+) and produces several neuroactive intermediates including quinolinic acid, [[kynurenine]] (KYN), [[kynurenic acid]] (KYNA), [[3-hydroxykynurenine]] (3-HK), and [[3-Hydroxyanthranilic acid|3-hydroxyanthranilic acid]] (3-HANA).<ref name=Guillemin>{{cite journal|last=Guillemin|first=Giles|title=Quinolinic acid, the inescapable neurotoxin|journal=FEBS Journal|year=2012|month=April|volume=279|issue=8|pages=1356–1365|doi=10.1111/j.1742-4658.2012.08485.x|url=http://onlinelibrary.wiley.com.proxy.bc.edu/doi/10.1111/j.1742-4658.2012.08485.x/abstract;jsessionid=5823C24FF2ABDCC4A941E609471599B2.d03t01|accessdate=4 November 2012|pmid=22248144}}</ref><ref name=Schwarcz>{{cite journal|last=Schwarcz|first=Robert|coauthors=John P. Bruno, Paul J. Muchowski, Hui-Qiu Wu|title=Kynurenines in the mammalian brain: when physiology meets pathology|journal=Nature Reviews Neuroscience|year=2012|month=July|volume=13|pages=465–477|doi=10.1038/nrn3257|issue=7|pmid=22678511}}</ref> quinolinic acid is a neuroactive molecule with excitatory properties and acts as an agonist to [[NMDA receptor|NMDA receptors]] in the brain.<ref name=Schwarcz /> Furthermore, quinolinic acid acts as a [[neurotoxin]], gliotoxin, proinflammatory mediator, and pro-oxidant molecule.<ref name=Guillemin />


Quinolinic acid is unable to pass through the [[blood-brain barrier]] (BBB) and must be produced within the brain microglial cells or macrophages which have passed the BBB.<ref name=Guillemin /> While quinolinic acid cannot pass the BBB, kyurenic acid, tryptophan and 3-hydroxykynurenine will and subsequently act as precursors to the production of quinolinic acid in the brain. The quinolinic acid produced in [[microglia]] is then released and acts as an excitatory neurotoxin through stimulation of [[NMDA receptor|NMDA receptors]].<ref name=Schwarcz /> While [[astrocytes]] are not able to produce quinolinic acid directly, they are capable of producing KYNA, which when released from the astrocytes can be taken in by migroglia which can in turn increase quinolinic acid production.<ref name=Schwarcz /><ref name=Guillemin />
Quinolinic acid is unable to pass through the [[blood-brain barrier]] (BBB) and must be produced within the brain microglial cells or macrophages which have passed the BBB.<ref name=Guillemin /> While quinolinic acid cannot pass the BBB, kyurenic acid, tryptophan and 3-hydroxykynurenine will and subsequently act as precursors to the production of quinolinic acid in the brain. The quinolinic acid produced in [[microglia]] is then released and acts as an excitatory neurotoxin through stimulation of [[NMDA receptor|NMDA receptors]].<ref name=Schwarcz /> While [[astrocytes]] are not able to produce quinolinic acid directly, they are capable of producing KYNA, which when released from the astrocytes can be taken in by migroglia which can in turn increase quinolinic acid production.<ref name=Schwarcz /><ref name=Guillemin />


Microglia and macrophages produce the vast majority of quinolinic acid present in the body. This production is increased during an immune response. It is suspected that this is a result of cytokine activation of [[Indoleamine 2,3-dioxygenase|indoleamine dioxygenases]] (specifically IDO-1 and IDO-2) as well as [[tryptophan 2,3-dioxygenase]] (TDO) stimulation by inflammatory cytokines (mainly [[IFN]]-gamma, but also IFN-beta and IFN-alpha).<ref name=Guillemin /> IDO-1, IDO-2 and TDO are present in microglia and macrophages. Under inflammatory conditions and conditions of [[T cell]] activation, [[leukocyte|leukocytes]] are retained in the brain by cytokine and chemokine production which can lead to the breakdown of the BBB thus increasing the quinolinic acid which enters the brain. Furthermore, quinolinic acid has been shown to play a role in destabilization of the cytoskeleton within astrocytes and brain endothelial cells contributing to the degredation of the BBB which results in higher concentrations of quinolinic acid in the brain.<ref name=Combes>{{cite journal|last=Combes|first=Valery|coauthors=Gilles J. Guillemin, Tailoi Chan-Ling, Nicholas H. Hunt, Georges E.R. Grau|title=The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes|journal=Trends in Parasitology|year=2012|month=August|volume=28|issue=8|pages=311-319|doi=10.1016/j.pt.2012.05.008|url=http://www.sciencedirect.com.proxy.bc.edu/science/article/pii/S1471492212000918|accessdate=5 November 2012}}</ref>
Microglia and macrophages produce the vast majority of quinolinic acid present in the body. This production is increased during an immune response. It is suspected that this is a result of cytokine activation of [[Indoleamine 2,3-dioxygenase|indoleamine dioxygenases]] (specifically IDO-1 and IDO-2) as well as [[tryptophan 2,3-dioxygenase]] (TDO) stimulation by inflammatory cytokines (mainly [[IFN]]-gamma, but also IFN-beta and IFN-alpha).<ref name=Guillemin /> IDO-1, IDO-2 and TDO are present in microglia and macrophages. Under inflammatory conditions and conditions of [[T cell]] activation, [[leukocyte|leukocytes]] are retained in the brain by cytokine and chemokine production which can lead to the breakdown of the BBB thus increasing the quinolinic acid which enters the brain. Furthermore, quinolinic acid has been shown to play a role in destabilization of the cytoskeleton within astrocytes and brain endothelial cells contributing to the degredation of the BBB which results in higher concentrations of quinolinic acid in the brain.<ref name=Combes>{{cite journal|last=Combes|first=Valery|coauthors=Gilles J. Guillemin, Tailoi Chan-Ling, Nicholas H. Hunt, Georges E.R. Grau|title=The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes|journal=Trends in Parasitology|year=2012|month=August|volume=28|issue=8|pages=311–319|doi=10.1016/j.pt.2012.05.008|url=http://www.sciencedirect.com.proxy.bc.edu/science/article/pii/S1471492212000918|accessdate=5 November 2012|pmid=22727810}}</ref>


==Toxicity==
==Toxicity==
Quinolinic acid is an [[excitotoxicity|excitotoxin]] in the [[central nervous system|CNS]] that reaches pathological levels in response to inflammation which activates resident microglia and macrophages in the brain. High levels of quinolinic acid can lead to hindered neuronal function or even [[apoptosis|apoptotic]] death.<ref name=Guillemin /> Quinolinic acid produces its toxic effect through several mechanisms; primarily as its function as an N-methyl-D-aspartate (NMDA) receptor agonist, which triggers a chain of deleterious effects, but also through [[lipid peroxidation]], and cytoskeletal destabilization. <ref name=Guillemin /> Quinolinic acid is also gliotoxic, which as a result further amplifies the inflammation response. The main neurons quinolinic acid effects are located in the [[hippocampus]], [[striatum]], and [[neocortex]], due to the selectivity towards quinolinic acid by the specific NMDAr residing in those regions.<ref name=Guillemin />
Quinolinic acid is an [[excitotoxicity|excitotoxin]] in the [[central nervous system|CNS]] that reaches pathological levels in response to inflammation which activates resident microglia and macrophages in the brain. High levels of quinolinic acid can lead to hindered neuronal function or even [[apoptosis|apoptotic]] death.<ref name=Guillemin /> Quinolinic acid produces its toxic effect through several mechanisms; primarily as its function as an N-methyl-D-aspartate (NMDA) receptor agonist, which triggers a chain of deleterious effects, but also through [[lipid peroxidation]], and cytoskeletal destabilization. <ref name=Guillemin /> Quinolinic acid is also gliotoxic, which as a result further amplifies the inflammation response. The main neurons quinolinic acid effects are located in the [[hippocampus]], [[striatum]], and [[neocortex]], due to the selectivity towards quinolinic acid by the specific NMDAr residing in those regions.<ref name=Guillemin />


When inflammation occurs, quinolinic acid is produced in excessive levels through the Kyurinene pathway. This leads to over excitation of the NMDA receptor, which leads to an influx of Ca<sup>2+</sup> into the neuron. High levels of Ca<sup>2+</sup> in the neuron trigger an activation of destructive enzymatic pathways including [[protein kinase|protein kinases]], [[phospholipase|phospholipases]], [[nitric oxide synthase|NO synthase]], and [[protease|proteases]].<ref name=Perez>{{cite journal|last=Pérez-De La Cruz|first=V.|coauthors=P.Carrillo-Mora, A. Santamaría|title=Quinolinic acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms|journal=International Journal of Tryptophan Research|year=2012|issue=5|pages=1-8|doi=10.4137/IJTR.S8158|url=http://www.la-press.com/quinolinic-acid-an-endogenous-molecule-combining-excitotoxicity-oxidat-article-a3068|accessdate=4 November 2012}}</ref> These enzymes will degenerate crucial proteins in the cell and increase NO levels, leading to an apoptotic response by the cell, resulting in cell death.
When inflammation occurs, quinolinic acid is produced in excessive levels through the Kyurinene pathway. This leads to over excitation of the NMDA receptor, which leads to an influx of Ca<sup>2+</sup> into the neuron. High levels of Ca<sup>2+</sup> in the neuron trigger an activation of destructive enzymatic pathways including [[protein kinase|protein kinases]], [[phospholipase|phospholipases]], [[nitric oxide synthase|NO synthase]], and [[protease|proteases]].<ref name=Perez>{{cite journal|last=Pérez-De La Cruz|first=V.|coauthors=P.Carrillo-Mora, A. Santamaría|title=Quinolinic acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms|journal=International Journal of Tryptophan Research|year=2012|issue=5|pages=1–8|doi=10.4137/IJTR.S8158|url=http://www.la-press.com/quinolinic-acid-an-endogenous-molecule-combining-excitotoxicity-oxidat-article-a3068|accessdate=4 November 2012}}</ref> These enzymes will degenerate crucial proteins in the cell and increase NO levels, leading to an apoptotic response by the cell, resulting in cell death.


In normal cell conditions, astrocytes in the neuron will provide a [[glutamate-glutamine cycle]] which results in reuptake of glutamate from the synapse into the pre-synaptic cell to be used again, to keep glutamate from accumulating to lethal levels inside the synapse. When quinolinic acid is in pathological concentrations, a reduction of [[glutamine synthetase]], a critical enzyme in the glutamate-glutamine cycle occurs.<ref name=Guillemin /> This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity.<ref name=Guillemin /> Furthermore, quinolinic acid results in changes of the biochemistry and structure of the astrocytes themselves, resulting in an apoptotic response. A loss of astrocytes results in a pro-inflammatory effect, further increasing the initial inflammatory response the quinolinic acid was produced by.<ref name=Guillemin />
In normal cell conditions, astrocytes in the neuron will provide a [[glutamate-glutamine cycle]] which results in reuptake of glutamate from the synapse into the pre-synaptic cell to be used again, to keep glutamate from accumulating to lethal levels inside the synapse. When quinolinic acid is in pathological concentrations, a reduction of [[glutamine synthetase]], a critical enzyme in the glutamate-glutamine cycle occurs.<ref name=Guillemin /> This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity.<ref name=Guillemin /> Furthermore, quinolinic acid results in changes of the biochemistry and structure of the astrocytes themselves, resulting in an apoptotic response. A loss of astrocytes results in a pro-inflammatory effect, further increasing the initial inflammatory response the quinolinic acid was produced by.<ref name=Guillemin />
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===Mood Disorders===
===Mood Disorders===
The [[prefrontal cortex]]es in the [[postmortem studies|post-mortem brains]] of patients with [[major depression]] and [[bipolar depression]] contain increased levels quinolinic acid [[immunoreactivity]] compared to the brains of patients who never suffered from depression. There is also evidence that increased concentrations of quinolinic acid can play a role in [[Depression in childhood and adolescence|adolescent depression]] and that quinolinic acid may be involved in [[schizophrenia]].<ref name=Myint>{{cite journal|last=Myint|first=Aye M.|title=Kynurenines: from the perspective of major psychiatric disorders|journal=FEBS Journal|year=2012|month=April|volume=279|issue=8|pages=1375-1385|doi=10.1111/j.1742-4658.2012.08551.x|pmid=22404766|url=http://onlinelibrary.wiley.com.proxy.bc.edu/doi/10.1111/j.1742-4658.2012.08551.x/abstract;jsessionid=7CB09DDF464FE7D4B7D5F400668C8414.d03t02|accessdate=5 November 2012}}</ref>
The [[prefrontal cortex]]es in the [[postmortem studies|post-mortem brains]] of patients with [[major depression]] and [[bipolar depression]] contain increased levels quinolinic acid [[immunoreactivity]] compared to the brains of patients who never suffered from depression. There is also evidence that increased concentrations of quinolinic acid can play a role in [[Depression in childhood and adolescence|adolescent depression]] and that quinolinic acid may be involved in [[schizophrenia]].<ref name=Myint>{{cite journal|last=Myint|first=Aye M.|title=Kynurenines: from the perspective of major psychiatric disorders|journal=FEBS Journal|year=2012|month=April|volume=279|issue=8|pages=1375–1385|doi=10.1111/j.1742-4658.2012.08551.x|pmid=22404766|url=http://onlinelibrary.wiley.com.proxy.bc.edu/doi/10.1111/j.1742-4658.2012.08551.x/abstract;jsessionid=7CB09DDF464FE7D4B7D5F400668C8414.d03t02|accessdate=5 November 2012}}</ref>


===Conditions Related to Neuronal Death===
===Conditions Related to Neuronal Death===
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====Alzheimer’s Disease====
====Alzheimer’s Disease====
Researchers have found a correlation between quinolinic acid and [[Alzheimer’s disease]]. For example, studies have found in the post-mortem brains of Alzheimer’s disease patients higher neuronal quinolinic acid levels and that quinolinic acid can associate with [[tau protein]]. Furthermore, researchers have demonstrated that quinolinic acid increases tau [[phosphorylation]] in vitro in human [[fetus|fetal]] neurons and induces ten neuronal [[gene]]s including some known to correlate with Alzheimer’s disease.<ref name=Severino>{{cite journal|last=Severino|first=Patricia Cardoso|coauthors=Muller, GDS, Vandresen-Filho, S, Tasca, CI|title=Cell signaling in NMDA preconditioning and neuroprotection in convulsions induced by quinolinic acid|journal=Life Sciences|date=10|year=2011|month=October|volume=89|issue=15-16|pages=570-576|doi=10.1016/j.lfs.2011.05.014|pmid=21683718|url=http://www.sciencedirect.com.proxy.bc.edu/science/article/pii/S0024320511002608|accessdate=5 November 2012}}</ref>
Researchers have found a correlation between quinolinic acid and [[Alzheimer’s disease]]. For example, studies have found in the post-mortem brains of Alzheimer’s disease patients higher neuronal quinolinic acid levels and that quinolinic acid can associate with [[tau protein]]. Furthermore, researchers have demonstrated that quinolinic acid increases tau [[phosphorylation]] in vitro in human [[fetus|fetal]] neurons and induces ten neuronal [[gene]]s including some known to correlate with Alzheimer’s disease.<ref name=Severino>{{cite journal|last=Severino|first=Patricia Cardoso|coauthors=Muller, GDS, Vandresen-Filho, S, Tasca, CI|title=Cell signaling in NMDA preconditioning and neuroprotection in convulsions induced by quinolinic acid|journal=Life Sciences|date=10|year=2011|month=October|volume=89|issue=15–16|pages=570–576|doi=10.1016/j.lfs.2011.05.014|pmid=21683718|url=http://www.sciencedirect.com.proxy.bc.edu/science/article/pii/S0024320511002608|accessdate=5 November 2012}}</ref>


====Brain Ischemia====
====Brain Ischemia====
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====Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)====
====Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)====
Studies have found that there is a correlation between levels of quinolinic acid in CSF and [[HIV associated neurocognitive disorder]] (HAND) severity. About 20% of [[human immunodeficiency virus|HIV]] patients suffer from this disorder. Concentrations of quinolinic acid in the CSF are associated to different stages of HAND. For example, raised levels of quinolinic acid after infection are correlated to perceptual-motor slowing in patients. Then, in later stages of HIV, increased concentrations of quinolinic acid in the of HAND patients CSF correlates with HIV [[encephalitis]] and [[cerebral atrophy]].<ref name=Kandanearatchi>{{cite journal|last=Kandanearatchi|first=Apsara|coauthors=Brew, Bruce J.|title=The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders|journal=FEBS Journal|year=2012|month=April|volume=279|issue=8|pages=1366-1374|doi=10.1111/j.1742-4658.2012.08500.x|pmid=22260426|url=http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08500.x/abstract|accessdate=5 November 2012}}</ref>
Studies have found that there is a correlation between levels of quinolinic acid in CSF and [[HIV associated neurocognitive disorder]] (HAND) severity. About 20% of [[human immunodeficiency virus|HIV]] patients suffer from this disorder. Concentrations of quinolinic acid in the CSF are associated to different stages of HAND. For example, raised levels of quinolinic acid after infection are correlated to perceptual-motor slowing in patients. Then, in later stages of HIV, increased concentrations of quinolinic acid in the of HAND patients CSF correlates with HIV [[encephalitis]] and [[cerebral atrophy]].<ref name=Kandanearatchi>{{cite journal|last=Kandanearatchi|first=Apsara|coauthors=Brew, Bruce J.|title=The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders|journal=FEBS Journal|year=2012|month=April|volume=279|issue=8|pages=1366–1374|doi=10.1111/j.1742-4658.2012.08500.x|pmid=22260426|url=http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08500.x/abstract|accessdate=5 November 2012}}</ref>


Quinolinic acid has also been found in HAND patients’ brains. In fact, the amount of quinolinic acid found in the brain of HAND patients can be up to 300 times greater than that found in the CSF.<ref name=Stone-Endo>{{cite journal|last=Stone|first=Trevor W.|title=Endogenous neurotoxins from tryptophan|journal=Toxicon|year=2001|month=January|volume=39|issue=1|pages=61-73|doi=10.1016/S0041-0101(00)00156-2|pmid=10936623|url=http://www.sciencedirect.com.proxy.bc.edu/science/article/pii/S0041010100001562|accessdate=5 November 2012}}</ref> Neurons exposed to quinolinic acid for long periods of time can develop [[cytoskeleton|cytoskeletal]] abnormalities, [[vacuole|vacuolization]], and [[cell]] death. HAND patients’ brains contain many of these defects. Furthermore, studies in rats have demonstrated that quinolinic acid can lead to [[neuron]]al death in brains structures that are affected by HAND, including the [[striatum]], [[hippocampus]], the [[substantia nigra]], and non-limbic [[cortex]].<ref name=Kandanearatchi />
Quinolinic acid has also been found in HAND patients’ brains. In fact, the amount of quinolinic acid found in the brain of HAND patients can be up to 300 times greater than that found in the CSF.<ref name=Stone-Endo>{{cite journal|last=Stone|first=Trevor W.|title=Endogenous neurotoxins from tryptophan|journal=Toxicon|year=2001|month=January|volume=39|issue=1|pages=61–73|doi=10.1016/S0041-0101(00)00156-2|pmid=10936623|url=http://www.sciencedirect.com.proxy.bc.edu/science/article/pii/S0041010100001562|accessdate=5 November 2012}}</ref> Neurons exposed to quinolinic acid for long periods of time can develop [[cytoskeleton|cytoskeletal]] abnormalities, [[vacuole|vacuolization]], and [[cell]] death. HAND patients’ brains contain many of these defects. Furthermore, studies in rats have demonstrated that quinolinic acid can lead to [[neuron]]al death in brains structures that are affected by HAND, including the [[striatum]], [[hippocampus]], the [[substantia nigra]], and non-limbic [[cortex]].<ref name=Kandanearatchi />


Levels of quinolinic acid in the CSF of [[acquired immunodeficiency syndrome|AIDS]] patients suffering from [[HIV associated neurocognitive disorder|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.<ref name=Stone-Endo />
Levels of quinolinic acid in the CSF of [[acquired immunodeficiency syndrome|AIDS]] patients suffering from [[HIV associated neurocognitive disorder|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.<ref name=Stone-Endo />
Line 95: Line 95:


====Parkinson's Disease====
====Parkinson's Disease====
Studies show that quinolinic acid is involved in the degeneration of the [[dopaminergic neuron]]s in the [[substantia nigra]] (SN) of [[Parkinson's disease]] patients. Substantia nigra degeneration is one of the key characteristics of Parkinson's disease. Microglia associated with dopaminergic cells in the SN produce quinolinic acid at this location when scientists induce Parkinson's disease symptoms in [[macaques]]. quinolinic acid levels are too high at these sites to be controlled by KYNA, causing neurotoxicity to occur. <ref name=Tan>{{cite journal|last=Tan|first=Lin|coauthors=Yu, JT, Tan, L|title=The kynurenine pathway in neurodegenerative diseases: Mechanistic and therapeutic considerations|journal=Journal of the Neurological Sciences|date=15|year=2012|month=December|volume=323|issue=1-2|pages=1-8|doi=10.1016/j.jns.2012.08.005|pmid=22939820|url=http://www.sciencedirect.com/science/article/pii/S0022510X12004340|accessdate=5 November 2012}}</ref>
Studies show that quinolinic acid is involved in the degeneration of the [[dopaminergic neuron]]s in the [[substantia nigra]] (SN) of [[Parkinson's disease]] patients. Substantia nigra degeneration is one of the key characteristics of Parkinson's disease. Microglia associated with dopaminergic cells in the SN produce quinolinic acid at this location when scientists induce Parkinson's disease symptoms in [[macaques]]. quinolinic acid levels are too high at these sites to be controlled by KYNA, causing neurotoxicity to occur. <ref name=Tan>{{cite journal|last=Tan|first=Lin|coauthors=Yu, JT, Tan, L|title=The kynurenine pathway in neurodegenerative diseases: Mechanistic and therapeutic considerations|journal=Journal of the Neurological Sciences|date=15|year=2012|month=December|volume=323|issue=1–2|pages=1–8|doi=10.1016/j.jns.2012.08.005|pmid=22939820|url=http://www.sciencedirect.com/science/article/pii/S0022510X12004340|accessdate=5 November 2012}}</ref>


===Other===
===Other===
Line 101: Line 101:


==Treatment Focus==
==Treatment Focus==
Reduction of the excitotoxic effects of quinolinic acid is the subject of on-going research. NMDAr antagonists have been shown to provide protection to motor neurons from excitotoxicity resulting from quinolinic acid production.<ref name=Guillemin /> Kyurenic acid (KYA), another product of the Kyurenine pathway in which quinolinic acid is also produced, provides the ability to block receptors for glutamate.<ref name=Kalonia>{{cite journal|last=Kalonia|first=H.|coauthors=P. Kumar, A. Kumar|title=Licofelone attenuates quinolinic acid induced huntington like symptoms: Possible behavioral, biochemical and cellular alterations|journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry|year=2011|issue=35(2)|pages=607-615}}</ref> Kyurenic acid in this way acts as a neuroprotectant, by reducing the dangerous overactivation of the NMDAr. Manipulation of the KP away from quinolinic acid and towards kyurenic acid is therefore a major therapeutic focus. Nicotinylalanine has been shown to be an inhibitor of kynurenine hydroxylase which results in a decreased production of quinolinic acid, thus favoring kyurenic acid production.<ref name=Kalonia /> This change in balance has the potential to reduce hyperexcitability, and thus excitotoxic damage produced from elevated levels of quinolinic acid.<ref name=Kalonia />
Reduction of the excitotoxic effects of quinolinic acid is the subject of on-going research. NMDAr antagonists have been shown to provide protection to motor neurons from excitotoxicity resulting from quinolinic acid production.<ref name=Guillemin /> Kyurenic acid (KYA), another product of the Kyurenine pathway in which quinolinic acid is also produced, provides the ability to block receptors for glutamate.<ref name=Kalonia>{{cite journal|last=Kalonia|first=H.|coauthors=P. Kumar, A. Kumar|title=Licofelone attenuates quinolinic acid induced huntington like symptoms: Possible behavioral, biochemical and cellular alterations|journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry|year=2011|issue=35(2)|pages=607–615|doi=10.1016/j.pnpbp.2011.01.003|volume=35}}</ref> Kyurenic acid in this way acts as a neuroprotectant, by reducing the dangerous overactivation of the NMDAr. Manipulation of the KP away from quinolinic acid and towards kyurenic acid is therefore a major therapeutic focus. Nicotinylalanine has been shown to be an inhibitor of kynurenine hydroxylase which results in a decreased production of quinolinic acid, thus favoring kyurenic acid production.<ref name=Kalonia /> This change in balance has the potential to reduce hyperexcitability, and thus excitotoxic damage produced from elevated levels of quinolinic acid.<ref name=Kalonia />
Therapeutic efforts are also focusing on antioxidants which have shown to provide protection against the pro-oxidant properties of quinolinic acid.<ref name=Guillemin />
Therapeutic efforts are also focusing on antioxidants which have shown to provide protection against the pro-oxidant properties of quinolinic acid.<ref name=Guillemin />


Revision as of 00:51, 19 November 2012

Quinolinic acid
Names
IUPAC name
Pyridine-2,3-dicarboxylic acid
Identifiers
3D model (JSmol)
ChEMBL
ECHA InfoCard 100.001.704 Edit this at Wikidata
  • InChI=1/C7H5NO4/c9-6(10)4-2-1-3-8-5(4)7(11)12/h1-3H,(H,9,10)(H,11,12)
  • O=C(O)c1ncccc1C(O)=O
Properties
C7H5NO4
Molar mass 167.12 g/mol
Melting point 185–190 °C (dec.)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Quinolinic acid (abbreviated QUIN or QA) is a dicarboxylic acid. It may be prepared by the oxidation of quinoline, either electrochemically,[1] or with acidic hydrogen peroxide.[2]

Quinolinic acid is a downstream kynurenine pathway metabolite of tryptophan. It acts as an NMDA receptor agonist.[3] Quinolinic acid has a potent neurotoxic effect. Studies have demonstrated that quinolinic acid may be involved in many mood disorders, neurodegenerative processes in the brain, as well as other disorders. Within the brain, quinolinic acid is only produced by activated microglia and macrophages.[4]

Norharmane, suppresses the production of quinolinic acid, 3-hydroxykynurenine and nitric oxide synthase, thereby acting as a neuroprotectant.[5] Natural phenols such as catechin hydrate, curcumin and epigallocatechin gallate reduce the neurotoxicity of quinolinic acid, via anti-oxidant and possibly calcium influx mechanisms.[6] COX-2 inhibitors have also demonstrated protective properties against the neurotoxic properties of quinolinic acid,[7] and these COX-2 inhibitors have demonstrated some evidence of efficacy in mental health disorders such as major depressive disorder as well as schizophrenia.[8]

History

In 1949 L. Henderson was one of the earliest to describe quinolinic acid. Lapin followed up this research by demonstrating that quinolinic acid could induce convulsions when injected into mice brain ventricles. However, it was not until 1981 that Stone and Perkins showed that quinolinic acid activates the N-methyl-d-aspartate receptor (NMDAR). Schwarcz later demonstrated that elevated quinolinic acid levels could lead to axonal neurodegeneration.[9]

Synthesis

One of the earliest reported syntheses of this quinolinic acid was by Zdenko Hans Skraup, who found that methyl-substituted quinolines could be oxidized to quinolinic acid by potassium permanganate.[10]

This compound is commercially available. It is generally obtained by the oxidation of quinoline. Oxidants such as ozone,[11] and potassium permanganate have been used. Electrolysis is able to perform the transformation as well.[12]

Quinoline may undergo further decarboxylation to nicotinic acid (niacin):

Production In Vivo

Quinolinic acid is a byproduct of the kynurenine pathway which is responsible for catabolism of tryptophan in mammals. This pathway is important for its production of the coenzyme nicotinamide adenine dinucleotide (NAD+) and produces several neuroactive intermediates including quinolinic acid, kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HANA).[13][14] quinolinic acid is a neuroactive molecule with excitatory properties and acts as an agonist to NMDA receptors in the brain.[14] Furthermore, quinolinic acid acts as a neurotoxin, gliotoxin, proinflammatory mediator, and pro-oxidant molecule.[13]

Quinolinic acid is unable to pass through the blood-brain barrier (BBB) and must be produced within the brain microglial cells or macrophages which have passed the BBB.[13] While quinolinic acid cannot pass the BBB, kyurenic acid, tryptophan and 3-hydroxykynurenine will and subsequently act as precursors to the production of quinolinic acid in the brain. The quinolinic acid produced in microglia is then released and acts as an excitatory neurotoxin through stimulation of NMDA receptors.[14] While astrocytes are not able to produce quinolinic acid directly, they are capable of producing KYNA, which when released from the astrocytes can be taken in by migroglia which can in turn increase quinolinic acid production.[14][13]

Microglia and macrophages produce the vast majority of quinolinic acid present in the body. This production is increased during an immune response. It is suspected that this is a result of cytokine activation of indoleamine dioxygenases (specifically IDO-1 and IDO-2) as well as tryptophan 2,3-dioxygenase (TDO) stimulation by inflammatory cytokines (mainly IFN-gamma, but also IFN-beta and IFN-alpha).[13] IDO-1, IDO-2 and TDO are present in microglia and macrophages. Under inflammatory conditions and conditions of T cell activation, leukocytes are retained in the brain by cytokine and chemokine production which can lead to the breakdown of the BBB thus increasing the quinolinic acid which enters the brain. Furthermore, quinolinic acid has been shown to play a role in destabilization of the cytoskeleton within astrocytes and brain endothelial cells contributing to the degredation of the BBB which results in higher concentrations of quinolinic acid in the brain.[15]

Toxicity

Quinolinic acid is an excitotoxin in the CNS that reaches pathological levels in response to inflammation which activates resident microglia and macrophages in the brain. High levels of quinolinic acid can lead to hindered neuronal function or even apoptotic death.[13] Quinolinic acid produces its toxic effect through several mechanisms; primarily as its function as an N-methyl-D-aspartate (NMDA) receptor agonist, which triggers a chain of deleterious effects, but also through lipid peroxidation, and cytoskeletal destabilization. [13] Quinolinic acid is also gliotoxic, which as a result further amplifies the inflammation response. The main neurons quinolinic acid effects are located in the hippocampus, striatum, and neocortex, due to the selectivity towards quinolinic acid by the specific NMDAr residing in those regions.[13]

When inflammation occurs, quinolinic acid is produced in excessive levels through the Kyurinene pathway. This leads to over excitation of the NMDA receptor, which leads to an influx of Ca2+ into the neuron. High levels of Ca2+ in the neuron trigger an activation of destructive enzymatic pathways including protein kinases, phospholipases, NO synthase, and proteases.[16] These enzymes will degenerate crucial proteins in the cell and increase NO levels, leading to an apoptotic response by the cell, resulting in cell death.

In normal cell conditions, astrocytes in the neuron will provide a glutamate-glutamine cycle which results in reuptake of glutamate from the synapse into the pre-synaptic cell to be used again, to keep glutamate from accumulating to lethal levels inside the synapse. When quinolinic acid is in pathological concentrations, a reduction of glutamine synthetase, a critical enzyme in the glutamate-glutamine cycle occurs.[13] This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity.[13] Furthermore, quinolinic acid results in changes of the biochemistry and structure of the astrocytes themselves, resulting in an apoptotic response. A loss of astrocytes results in a pro-inflammatory effect, further increasing the initial inflammatory response the quinolinic acid was produced by.[13]

Quinolinic acid can also exert neurotoxicity through lipid peroxidation, as a result of its pro-oxidant properties. quinolinic acid can interact with Fe(II) to form a complex which induces a reactive oxygen and nitrogen species (ROS/RNS), notably the hydroxyl radical •OH. This free radical causes oxidative stress by further increasing glutamate release and inhibiting its reuptake, and results in the breakdown of DNA and lipid peroxidation.[16] quinolinic acid has also been noted to increase phosphorylation of proteins involved in cell structure, leading to destabilization of the cytoskeleton.[13]

Clinical Implications

Mood Disorders

The prefrontal cortexes in the post-mortem brains of patients with major depression and bipolar depression contain increased levels quinolinic acid immunoreactivity compared to the brains of patients who never suffered from depression. There is also evidence that increased concentrations of quinolinic acid can play a role in adolescent depression and that quinolinic acid may be involved in schizophrenia.[17]

Conditions Related to Neuronal Death

Inflammation occurs at the sites of cell death which can lead to further neuronal damage. The inflammation response includes the generation of quinolinic acid, and this quinolinic acid contributes to the process of delayed degeneration of the neurons at the initial site of cell death.[17]

Amyotrophic Lateral Sclerosis (ALS)

Quinolinic acid may contribute to the causes of amyotrophic lateral sclerosis ALS. Researchers have found elevated levels of quinolinic acid in the cerebral spinal fluid (CSF), motor cortex, and spinal cord in ALS patients. These increased concentrations of quinolinic acid could lead to neurotoxicity. In addition, quinolinic acid is associated with overstimulating NMDA receptors on motor neurons. Studies have demonstrated that quinolinic acid leads to depolarization of spinal motor neurons by interacting with the NMDA receptors on those cells in rats. Lastly, quinolinic acid plays a role in mitochondrial dysfunction in neurons. All of these effects could contribute to ALS symptoms.[18]

Alzheimer’s Disease

Researchers have found a correlation between quinolinic acid and Alzheimer’s disease. For example, studies have found in the post-mortem brains of Alzheimer’s disease patients higher neuronal quinolinic acid levels and that quinolinic acid can associate with tau protein. Furthermore, researchers have demonstrated that quinolinic acid increases tau phosphorylation in vitro in human fetal neurons and induces ten neuronal genes including some known to correlate with Alzheimer’s disease.[19]

Brain Ischemia

Brain ischemia is insufficient blood flow to the brain. Studies with ischaemic gerbils indicate that after a delay levels of quinolinic acid significantly increase which correlates with increased neuronal damage.[17]

Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)

Studies have found that there is a correlation between levels of quinolinic acid in CSF and HIV associated neurocognitive disorder (HAND) severity. About 20% of HIV patients suffer from this disorder. Concentrations of quinolinic acid in the CSF are associated to different stages of HAND. For example, raised levels of quinolinic acid after infection are correlated to perceptual-motor slowing in patients. Then, in later stages of HIV, increased concentrations of quinolinic acid in the of HAND patients CSF correlates with HIV encephalitis and cerebral atrophy.[20]

Quinolinic acid has also been found in HAND patients’ brains. In fact, the amount of quinolinic acid found in the brain of HAND patients can be up to 300 times greater than that found in the CSF.[21] Neurons exposed to quinolinic acid for long periods of time can develop cytoskeletal abnormalities, vacuolization, and cell death. HAND patients’ brains contain many of these defects. Furthermore, studies in rats have demonstrated that quinolinic acid can lead to neuronal death in brains structures that are affected by HAND, including the striatum, hippocampus, the substantia nigra, and non-limbic cortex.[20]

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.[21]

Huntington’s Disease

Researchers utilize quinolinic acid in order to study Huntington’s disease in many model organisms. Because injection of quinolinic acid into the striatum of rodents induces electrophysiological, neuropathological, and behavioral changes similar to those found in Huntington’s disease, this is the most common method researchers use to produce a Huntington’s disease phenotype.[17] Neurological changes produced by quinolinic acid injections include altered levels of glutamate, GABA, and other amino acids. Lesions in the pallidum can suppress effects of quinolinic acid in monkeys injected with quinolinic acid into their striatum. In humans, such lesions can also diminish some of the effects of Huntington’s disease and Parkinson’s disease.[21]

Parkinson's Disease

Studies show that quinolinic acid is involved in the degeneration of the dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease patients. Substantia nigra degeneration is one of the key characteristics of Parkinson's disease. Microglia associated with dopaminergic cells in the SN produce quinolinic acid at this location when scientists induce Parkinson's disease symptoms in macaques. quinolinic acid levels are too high at these sites to be controlled by KYNA, causing neurotoxicity to occur. [18]

Other

Quinolinic acid levels are increased in the brains of children infected with a range of bacterial infections of the central nervous system (CNS), of poliovirus patients, and of Lyme disease with CNS involvement patients. 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. Lastly, it has been found that people suffering from malaria and patients with olivopontocerebellar atrophy have raised quinolinic acid metabolism.[21]

Treatment Focus

Reduction of the excitotoxic effects of quinolinic acid is the subject of on-going research. NMDAr antagonists have been shown to provide protection to motor neurons from excitotoxicity resulting from quinolinic acid production.[13] Kyurenic acid (KYA), another product of the Kyurenine pathway in which quinolinic acid is also produced, provides the ability to block receptors for glutamate.[22] Kyurenic acid in this way acts as a neuroprotectant, by reducing the dangerous overactivation of the NMDAr. Manipulation of the KP away from quinolinic acid and towards kyurenic acid is therefore a major therapeutic focus. Nicotinylalanine has been shown to be an inhibitor of kynurenine hydroxylase which results in a decreased production of quinolinic acid, thus favoring kyurenic acid production.[22] This change in balance has the potential to reduce hyperexcitability, and thus excitotoxic damage produced from elevated levels of quinolinic acid.[22] Therapeutic efforts are also focusing on antioxidants which have shown to provide protection against the pro-oxidant properties of quinolinic acid.[13]


References

  1. ^ EP 0159769, Toomey Jr., Joseph E., "Electrochemical oxidation of pyridine bases", assigned to Reilly Industries, Inc. 
  2. ^ US Patent 4420616, Ikegami, Seishi & Hatano, Yoshihiro, "Oxidative process for the preparation of copper quinolinate", assigned to Yamamoto Kagaku Gosei KK 
  3. ^ Misztal M, Frankiewicz T, Parsons CG, Danysz W (1996). "Learning deficits induced by chronic intraventricular infusion of quinolinic acid--protection by MK-801 and memantine". Eur. J. Pharmacol. 296 (1): 1–8. doi:10.1016/0014-2999(95)00682-6. PMID 8720470. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Guillemin, G.; Smith, Danielle G.; Smythe, George A.; Armati, Patricia J.; Brew, George J. (2003). "Expression of the kynurenine pathway enzymes in human microglia and macrophages". Adv Exp Med Biol. Advances in Experimental Medicine and Biology. 527: 105–12. doi:10.1007/978-1-4615-0135-0_12. ISBN 978-0-306-47755-3. PMID 15206722.
  5. ^ Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F (2000). "Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages". J. Leukoc. Biol. 68 (2): 260–6. PMID 10947071. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Braidy N, Grant R, Adams S, Guillemin GJ (2010). "Neuroprotective effects of naturally occurring polyphenols on quinolinic acid-induced excitotoxicity in human neurons". FEBS J. 277 (2): 368–82. doi:10.1111/j.1742-4658.2009.07487.x. PMID 20015232. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Kalonia H, Kumar P, Kumar A, Nehru B (2010). "Protective effect of rofecoxib and nimesulide against intra-striatal quinolinic acid-induced behavioral, oxidative stress and mitochondrial dysfunctions in rats". Neurotoxicology. 31 (2): 195–203. doi:10.1016/j.neuro.2009.12.008. PMID 20043943. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Müller N (2010). "COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence". Curr Opin Investig Drugs. 11 (1): 31–42. PMID 20047157. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Guillemin, Gilles J (2012). "Quinolinic acid: neurotoxicity". FEBS Journal. 279 (8): 1355. doi:10.1111/j.1742-4658.2012.08493.x. PMID 22251552. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Skraup, Zd. H. (1881). "Synthetische Versuche in der Chinolinreihe". Monatshefte fü Chemie. 2: 139. doi:10.1007/BF01516502.
  11. ^ WO 2010011134, H. bruno, "Ozonolysis of Aromatics and/or Olefins" 
  12. ^ Marshall Kulka (1946). "Electrolytic Oxidation of Quinoline and 3-Picoline". J. Am. Chem. Soc. 68 (12): 2472. doi:10.1021/ja01216a008. PMID 20282382.
  13. ^ a b c d e f g h i j k l m n Guillemin, Giles (2012). "Quinolinic acid, the inescapable neurotoxin". FEBS Journal. 279 (8): 1356–1365. doi:10.1111/j.1742-4658.2012.08485.x. PMID 22248144. Retrieved 4 November 2012. {{cite journal}}: Unknown parameter |month= ignored (help)
  14. ^ a b c d Schwarcz, Robert (2012). "Kynurenines in the mammalian brain: when physiology meets pathology". Nature Reviews Neuroscience. 13 (7): 465–477. doi:10.1038/nrn3257. PMID 22678511. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  15. ^ Combes, Valery (2012). "The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes". Trends in Parasitology. 28 (8): 311–319. doi:10.1016/j.pt.2012.05.008. PMID 22727810. Retrieved 5 November 2012. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  16. ^ a b Pérez-De La Cruz, V. (2012). "Quinolinic acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms". International Journal of Tryptophan Research (5): 1–8. doi:10.4137/IJTR.S8158. Retrieved 4 November 2012. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ a b c d Myint, Aye M. (2012). "Kynurenines: from the perspective of major psychiatric disorders". FEBS Journal. 279 (8): 1375–1385. doi:10.1111/j.1742-4658.2012.08551.x. PMID 22404766. Retrieved 5 November 2012. {{cite journal}}: Unknown parameter |month= ignored (help)
  18. ^ a b Tan, Lin (15). "The kynurenine pathway in neurodegenerative diseases: Mechanistic and therapeutic considerations". Journal of the Neurological Sciences. 323 (1–2): 1–8. doi:10.1016/j.jns.2012.08.005. PMID 22939820. Retrieved 5 November 2012. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  19. ^ Severino, Patricia Cardoso (10). "Cell signaling in NMDA preconditioning and neuroprotection in convulsions induced by quinolinic acid". Life Sciences. 89 (15–16): 570–576. doi:10.1016/j.lfs.2011.05.014. PMID 21683718. Retrieved 5 November 2012. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  20. ^ a b Kandanearatchi, Apsara (2012). "The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders". FEBS Journal. 279 (8): 1366–1374. doi:10.1111/j.1742-4658.2012.08500.x. PMID 22260426. Retrieved 5 November 2012. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  21. ^ a b c d Stone, Trevor W. (2001). "Endogenous neurotoxins from tryptophan". Toxicon. 39 (1): 61–73. doi:10.1016/S0041-0101(00)00156-2. PMID 10936623. Retrieved 5 November 2012. {{cite journal}}: Unknown parameter |month= ignored (help)
  22. ^ a b c Kalonia, H. (2011). "Licofelone attenuates quinolinic acid induced huntington like symptoms: Possible behavioral, biochemical and cellular alterations". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 35 (35(2)): 607–615. doi:10.1016/j.pnpbp.2011.01.003. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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