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

M. P. Heyes, Kuniaki Saito, J. S. Crowley, L. E. Davis, M. A. Demitrack, M. Der, L. A. Dilling, J. Elia, M. J.P. Kruesi, A. Lackner, S. A. Larsen, K. Lee, H. L. Leonard, S. P. Markey, A. Martin, S. Milstein, M. M. Mouradian, M. R. Pranzatelli, B. J. Quearry, A. SalazarM. Smith, S. E. Strauss, T. Sunderland, S. W. Swedo, W. W. Tourtellotte

Research output: Contribution to journalArticle

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Abstract

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 lgG 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.

Original languageEnglish
Pages (from-to)1249-1273
Number of pages25
JournalBrain
Volume115
Issue number5
DOIs
Publication statusPublished - 01-10-1992
Externally publishedYes

Fingerprint

Quinolinic Acid
Kynurenine
Kynurenic Acid
Cerebrospinal Fluid
N-Methyl-D-Aspartate Receptors
Tryptophan
Indoleamine-Pyrrole 2,3,-Dioxygenase
Huntington Disease
Alzheimer Disease
Myoclonic Epilepsy
Neopterin
Excitatory Amino Acids
Parasitic Diseases
Mycoses
Brain
Macaca
Virus Diseases
N-Methylaspartate
Retroviridae
Blood-Brain Barrier

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Heyes, M. P., Saito, K., Crowley, J. S., Davis, L. E., Demitrack, M. A., Der, M., ... Tourtellotte, W. W. (1992). Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain, 115(5), 1249-1273. https://doi.org/10.1093/brain/115.5.1249
Heyes, M. P. ; Saito, Kuniaki ; Crowley, J. S. ; Davis, L. E. ; Demitrack, M. A. ; Der, M. ; Dilling, L. A. ; Elia, J. ; Kruesi, M. J.P. ; Lackner, A. ; Larsen, S. A. ; Lee, K. ; Leonard, H. L. ; Markey, S. P. ; Martin, A. ; Milstein, S. ; Mouradian, M. M. ; Pranzatelli, M. R. ; Quearry, B. J. ; Salazar, A. ; Smith, M. ; Strauss, S. E. ; Sunderland, T. ; Swedo, S. W. ; Tourtellotte, W. W. / Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. In: Brain. 1992 ; Vol. 115, No. 5. pp. 1249-1273.
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abstract = "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 lgG 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.",
author = "Heyes, {M. P.} and Kuniaki Saito and Crowley, {J. S.} and Davis, {L. E.} and Demitrack, {M. A.} and M. Der and Dilling, {L. A.} and J. Elia and Kruesi, {M. J.P.} and A. Lackner and Larsen, {S. A.} and K. Lee and Leonard, {H. L.} and Markey, {S. P.} and A. Martin and S. Milstein and Mouradian, {M. M.} and Pranzatelli, {M. R.} and Quearry, {B. J.} and A. Salazar and M. Smith and Strauss, {S. E.} and T. Sunderland and Swedo, {S. W.} and Tourtellotte, {W. W.}",
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Heyes, MP, Saito, K, Crowley, JS, Davis, LE, Demitrack, MA, Der, M, Dilling, LA, Elia, J, Kruesi, MJP, Lackner, A, Larsen, SA, Lee, K, Leonard, HL, Markey, SP, Martin, A, Milstein, S, Mouradian, MM, Pranzatelli, MR, Quearry, BJ, Salazar, A, Smith, M, Strauss, SE, Sunderland, T, Swedo, SW & Tourtellotte, WW 1992, 'Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease', Brain, vol. 115, no. 5, pp. 1249-1273. https://doi.org/10.1093/brain/115.5.1249

Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. / Heyes, M. P.; Saito, Kuniaki; Crowley, J. S.; Davis, L. E.; Demitrack, M. A.; Der, M.; Dilling, L. A.; Elia, J.; Kruesi, M. J.P.; Lackner, A.; Larsen, S. A.; Lee, K.; Leonard, H. L.; Markey, S. P.; Martin, A.; Milstein, S.; Mouradian, M. M.; Pranzatelli, M. R.; Quearry, B. J.; Salazar, A.; Smith, M.; Strauss, S. E.; Sunderland, T.; Swedo, S. W.; Tourtellotte, W. W.

In: Brain, Vol. 115, No. 5, 01.10.1992, p. 1249-1273.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease

AU - Heyes, M. P.

AU - Saito, Kuniaki

AU - Crowley, J. S.

AU - Davis, L. E.

AU - Demitrack, M. A.

AU - Der, M.

AU - Dilling, L. A.

AU - Elia, J.

AU - Kruesi, M. J.P.

AU - Lackner, A.

AU - Larsen, S. A.

AU - Lee, K.

AU - Leonard, H. L.

AU - Markey, S. P.

AU - Martin, A.

AU - Milstein, S.

AU - Mouradian, M. M.

AU - Pranzatelli, M. R.

AU - Quearry, B. J.

AU - Salazar, A.

AU - Smith, M.

AU - Strauss, S. E.

AU - Sunderland, T.

AU - Swedo, S. W.

AU - Tourtellotte, W. W.

PY - 1992/10/1

Y1 - 1992/10/1

N2 - 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 lgG 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.

AB - 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 lgG 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.

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