The kynurenine pathway is the predominant route of L-tryptophan metabolism in most tissues. Two a... more The kynurenine pathway is the predominant route of L-tryptophan metabolism in most tissues. Two aspects of L-tryptophan catabolism through this pathway are of particular interest. Firstly, the initial enzyme of the kynurenine pathway in extrahepatic tissues, indoleamine-2,3-dioxygenase (IDO), is induced by interferon-y and other immune stimuli (Saito et al., 1991,1992; Takikawa et al., 1986). Such induction is observed in patients with cancer, infectious disease and following therapeutic interferon administration, and has been implicated in the anti-proliferative and anti-microbial effects of interferon-y (Yasui et al., 1986; Taylor et al., 1991). Secondly, the neuroactive nature of certain metabolites, including quinolinic acid (QUIN), an excitotoxic agonist of N-methyl-D-aspartate receptors, and kynurenic acid (KYNA) an antagonist of excitatory amino acid receptors, has implicated their involvement in a broad spectrum of neurodegenerative disease (Heyes et al., 1992,1993). In a previous study, accumulation of QUIN in gerbil brain was observed 4 and 7 days following transient cerebral ischemia (Saito et al., see Figure 1). Such increases have been demonstrated to be secondary to increases of IDO and other kynurenine pathway enzymes in infiltrated
Journal of Cerebral Blood Flow and Metabolism, Jun 1, 1998
We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist ... more We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32°C) or normothermia (3rC) treatments for 24 hours. Oth erwise, patients received standard neurointensive care. Quino linie acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinie acid concentrations with age, gender, GCS, time after injury,
: Quinolinic acid is an excitatory, neurotoxic tryptophan metabolite proposed to play a role in t... more : Quinolinic acid is an excitatory, neurotoxic tryptophan metabolite proposed to play a role in the pathogenesis of hepatic encephalopathy. This involvement was investigated in rat and rabbit models of fulminant hepatic failure at different stages of hepatic encephalopathy. Although plasma and brain tryptophan levels were significantly increased in all stages of hepatic encephalopathy, quinolinic acid levels increased three‐ to sevenfold only in the plasma, CSF, and brain regions of animals in stage IV hepatic encephalopathy. Plasma‐CSF and plasma‐brain quinolinic acid levels in rats and rabbits with fulminant hepatic failure were strongly correlated, with CSF and brain concentrations ∼10% those of plasma levels. Moreover, there was no significant regional difference in brain quinolinic acid concentrations in either model. Extrahepatic indoleamine‐2,3‐dioxygenase activity was not altered in rats in stage IV hepatic encephalopathy, but hepatic l‐tryptophan‐2,3‐dioxygenase activity was increased. These results suggest that quinolinic acid synthesized in the liver enters the plasma and then accumulates in the CNS after crossing a permeabilized blood‐brain barrier in the end stages of liver failure. Furthermore, the observation of low brain concentrations of quinolinic acid only in stage IV encephalopathy suggests that the contribution of quinolinic acid to the pathogenesis of hepatic encephalopathy in these animal models is minor.
To assess the potential therapeutic effects of zidovudine, rhesus macaques were inoculated with s... more To assess the potential therapeutic effects of zidovudine, rhesus macaques were inoculated with simian immunodeficiency virus (SIV) strain SMM/B670 at birth and infused either continuously or intermittently with zidovudine for 6-7 months. Zidovudine did not prevent infection but did significantly increase survival time, which was associated with lower serum p26 viral core antigen levels, a lower virus burden in the cerebrospinal fluid (CSF), and lower CSF quinolinic acid levels than in untreated monkeys. Two of 5 infected, untreated monkeys developed motor impairment within 6 months following infection, whereas motor impairments did not occur in infected, zidovudine-treated monkeys until after the drug was discontinued. Zidovudine treatment was well tolerated by rhesus infants with minimal, transient side effects. These results demonstrate that zidovudine treatment significantly decreases virus load within the central nervous system (CNS) and delays the onset of CNS dysfunction and immune disease in rhesus monkeys perinatally infected with SIV.
Activation of the immune system which occurs in inflammatory diseases leads to parallel increases... more Activation of the immune system which occurs in inflammatory diseases leads to parallel increases in pterin synthesis and increased production of neuroactive L-tryptophan metabolites. Several model systems were studied to determine whether pterins, which are cofactors for hydroxylation reactions, could be required in the oxidative kynurenine pathway of L-tryptophan degradation. Treatment of mice with interferon-y increased Ltryptophan metabolism without any corresponding change in tissue biopterin concentrations. Cytokine-treated human fibroblasts, macrophages and glioblastoma cells all showed increases in kynurenine production, which were completely independent of
Apolipoproteins in cerebrospinal fluid (CSF) might have important functional roles in the pathoph... more Apolipoproteins in cerebrospinal fluid (CSF) might have important functional roles in the pathophysiology of brain and lipid metabolism in the vascular component. The present study examined apolipoprotein A-I (apo-A-I) and apolipoprotein E (apo-E) levels in CSF and serum from poliovirus-infected macaques. Poliovirus-infected macaques developed motor deficits and were classified into three groups : (1) muscle weakness in one or both legs ; (2) partial paralysis in one or both legs ; (3) complete paralysis in one or both legs. No motor deficits were evident in the control or sham-treated macaques. Apo-A-I concentrations in CSF were markedly elevated in poliovirus-infected macaques with weakness, partial or complete paralysis, in comparison with either control or sham-treated animals, and were proportional to the severity of motor impairment. Apo-E concentrations in CSF
Many of the characteristics neuroanatomical and neurochemical features of Huntington&#39;s di... more Many of the characteristics neuroanatomical and neurochemical features of Huntington&#39;s disease (HD) are produced in experimental animals by an intrastriatal injection of the endogenous N-methyl-D-aspartate receptor agonist quinolinic acid (QUIN). Conceivably, a chronic over-production of QUIN in brain could be involved in the pathogenesis of HD. To investigate this hypothesis, concentrations of QUIN were measured both in cerebrospinal fluid (CSF) and postmortem tissue from patients with HD and neurologically normal age-matched controls. CSF QUIN concentrations were slightly lower in patients with HD, however the changes were not significant. Mean concentrations of QUIN tended to be lower in HD putamen, dentate nucleus and several cortical regions, although significant reductions were found only in Brodmann areas 17, 20 and 28. The mechanisms responsible for these small reductions in brain QUIN concentrations remain to be determined. These results do not support the hypothesis that a chronic increase of QUIN production is responsible for neurodengeneration in HD.
The source of the neurotoxin quinolinic acid (QUIN) in brain and systemic tissues under normal an... more The source of the neurotoxin quinolinic acid (QUIN) in brain and systemic tissues under normal and pathologic circumstances reflects either de novo synthesis from L-tryptophan and other precursors, or entry of QUIN itself from the blood. To quantify the relative contributions of blood-versus tissue-derived QUIN, [13c71 QUIN was infused subcutaneously via osmotic pumps (0.55~.tl/h,30 mM) in gerbils, and the fraction of QUIN in tissue (Ti; measured in tissue homogenates) derived from blood (BI; measured in serum) was calculated by the formula ([13C 7]QUINT/QUINT)/([ 13C 7]QUINB/ QUINBI). In controls, blood QUIN contributed 38-49% of QUIN in brain, 70% in CSF, between 40 and 70% in kidney, heart, and skeletal muscle, but <5% in spleen, lung, liver, and intestine. Systemic endotoxin (450 fig/kg) increased blood, brain, CSF, and systemic tissue QUIN levels. Notably, the relative proportion of QUIN derived from blood in brain, spleen, lung, and intestine was unchanged by endotoxin, but increased in kidney, heart, and skeletal muscle. In contrast, cerebral ischemic injury (10 mm of bilateral carotid artery occlusion) increased regional brain QUIN concentrations at 4 days post ischemia, with a proportional increase in the amount of QUIN derived from de novo synthesis by brain tissue. In the blood and systemic tissues of postischemic gerbils, there were no changes in systemic tissue or blood QUIN levels, or changes in the relative proportions of blood-versus systemic tissue-derived QUIN. These results establish that the brain normally synthesizes QUIN, that the blood is a significant source of QUIN in controls and during acute systemic immune activation, and that the rate of QUIN formation by brain tissue increases in conditions of brain and systemic immune activation.
Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to... more Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P ؍ 0.037) and neopterin (P ؍ 0.003) were decreased, and biopterin (P ؍ 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated compared with controls (P < 0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid.
Journal of Neurosurgical Anesthesiology, Oct 1, 1997
We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist ... more We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] &amp;amp;amp;amp;lt; 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32 degrees C) or normothermia (37 degrees C) treatments for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5- to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid (P &amp;amp;amp;amp;lt; 0.00001), and quinolinic acid was higher in patients who died than in survivors (P = 0.003). Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage.
The pathogenic mechanisms resulting in the serious syndrome associated with acute and chronic liv... more The pathogenic mechanisms resulting in the serious syndrome associated with acute and chronic liver diseases, better kown as hepatic encephalopathy (HE), are still unknown. The syndrome is most often referred to as a neuropsychiatric disease of multifactorial origin (Conn and Lieberthal, 1979). Many different hypotheses have been suggested for the patogenesis of HE. No single such hypothesis has so far been proven to be valid. Among these hypotheses are increased brain levels of the compound quinolinic acid (QUIN; pyridine-2,3-dicarboxylic acid) one that suggests this potential neurotoxin to contribute to the development of HE (Moroni et al., 1986a,b)
Advances in Experimental Medicine and Biology, 1991
Profound insulin-induced hypoglycemia is associated with neurodegenera-tion which resembles lesio... more Profound insulin-induced hypoglycemia is associated with neurodegenera-tion which resembles lesions produced by administration of exogenous excito-toxins (Auer, 1986). Neuronal lesions in hypoglycemia begin within minutes of the hypoglycemie insult and are attenuated by local application of N-methyl-D-aspartate (NMDA) receptor antagonists (Wieloch 1985; Simon et al., 1986).
Study design: Blinded, placebo-controlled, parallel treatment group studies of the effects of met... more Study design: Blinded, placebo-controlled, parallel treatment group studies of the effects of methylprednisolone (MP) or 4-chloro-3-hydroxyanthranilate (4-Cl-3-HAA) on behavioral outcome and quinolinic acid tissue levels from experimental thoracic spinal cord injury in adult guinea pigs. Objectives: To compare the effects of treatment with high-dose MP, a corticosteroid, and 4-Cl-3-HAA, a compound that inhibits synthesis of the neurotoxin quinolinic acid (QUIN) by activated macrophages. To explore the effect of different times of treatment using these two approaches to ameliorating secondary tissue damage.
Advances in Experimental Medicine and Biology, 1996
Quinolinic acid (QUIN), kynurenic acid (KYNA) and L-kynurenine (L-KYN) are neuroactive L-tryptoph... more Quinolinic acid (QUIN), kynurenic acid (KYNA) and L-kynurenine (L-KYN) are neuroactive L-tryptophan metabolites that are synthesized via the kynurenine pathway. These metabolites accumulate in CNS following immune stimulation (particularly those with inflammatory lesions and monocyte infiltration into the CNS) and are attributed to induction of indoleamine-2,3-dioxygenase (IDO) and other kynurenine pathway enzymes (Saito et al., 1993a; Heyes et al., 1992a; 1993).
Advances in Experimental Medicine and Biology, 1991
The utility of stable isotope-labeled tryptophan as a precursor for studying the disposition of q... more The utility of stable isotope-labeled tryptophan as a precursor for studying the disposition of quinolinic acid was investigated. TRP-D5 at doses of 50, 25 or 10 mg/kg was administered to rabbits. Blood and CSF samples were taken for up to 6 hours. There was no loss of deuterium from the tryptophan and the specifically tri-deuterated quinolinic acid measured in plasma and CSF. CSF levels of QUIN-D3 remained elevated 6 hours following TRP-D5 administration. Further studies of the CNS disposition of quinolinic acid and other metabolites of the kynurenine pathway employing stable isotope-labeled tryptophan as precursor at appropriate doses and with extended sampling are in progress.
Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of pat... more Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of patients with inflammatory neurologic disease and may be of neuropathologic significance. The production of quinolinic acid was postulated to reflect local induction of indoleamine 2,3-dioxygenase by cytokines in reactive cells and inflammatory cell infiltrates within the central nervous system. To test this hypothesis, macaques received an intraspinal injection of poliovirus as a model of localized inflammatory neurologic disease. Seventeen days later, spinal cord indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations in spinal cord and cerebrospinal fluid were both increased in proportion to the degree of inflammatory responses and neurologic damage in the spinal cord, as well as the severity of motor paralysis. The absolute concentrations of quinolinic acid achieved in spinal cord and cerebrospinal fluid exceeded levels reported to kill spinal cord neurons in vitro. Smaller increases in indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations also occurred in parietal cortex, a poliovirus target area. In frontal cortex, which is not a target for poliovirus, indoleamine 2,3-dioxygenase was not affected. A monoclonal antibody to human indoleamine 2,3-dioxygenase was used to visualize indoleamine 2,3-dioxygenase predominantly in grey matter of poliovirus-infected spinal cord, in conjunction with local inflammatory lesions. Macrophage/monocytes in vitro synthesized [t3C6jquinolinic acid from [13C6JL-tryptophan, particularly when stimulated by interferon-y. Spinal cord slices from poliovirusinoculated macaques in vitro also converted ['3C6]Ltryptophan to [1'CsJquinolinic acid. We conclude that local synthesis of quinolinic acid from L-tryptophan within the central nervous system follows the induction of indoleamine-2,3-dioxygenase, particularly within macrophage/microglia. In view of this link between immune stimulation and the synthesis of neurotoxic amounts of quinolinic acid, we propose that attenuation of local inflammation, strategies to reduce the synthesis of neuroactive kynurenine pathway metabolites, or drugs that interfere with the neurotoxicity of quinolinic acid offer new approaches to therapy in inflammatory neurologic disease.
Substantial increases in the concentrations of the excitotoxin and N-methyl-D-aspartate-receptor ... more Substantial increases in the concentrations of the excitotoxin and N-methyl-D-aspartate-receptor agonist quinolinic acid (QUIN) occur in human patients and non-human primates with inflammatory diseases. Such increases were postulated to be secondary to induction of indoleamine 2,3-dioxygenase in inflammatory cells, particularly macrophages, by interferon-gamma. To test this hypothesis, human peripheral-blood macrophages were incubated with L-[13C6]tryptophan in the absence or presence of interferon-gamma. [13C6]QUIN was quantified by gas chromatography and electron-capture negative-chemical-ionization mass spectrometry. [13C6]QUIN was detected in the incubation medium of both unstimulated and stimulated cultures. Exposure to interferon-gamma substantially increased the accumulation of [13C6]QUIN in a dose- and time-dependent manner. The QUIN concentrations achieved exceeded those reported in both cerebrospinal fluid and blood of patients and of non-human primates with inflammatory d...
The kynurenine pathway is the predominant route of L-tryptophan metabolism in most tissues. Two a... more The kynurenine pathway is the predominant route of L-tryptophan metabolism in most tissues. Two aspects of L-tryptophan catabolism through this pathway are of particular interest. Firstly, the initial enzyme of the kynurenine pathway in extrahepatic tissues, indoleamine-2,3-dioxygenase (IDO), is induced by interferon-y and other immune stimuli (Saito et al., 1991,1992; Takikawa et al., 1986). Such induction is observed in patients with cancer, infectious disease and following therapeutic interferon administration, and has been implicated in the anti-proliferative and anti-microbial effects of interferon-y (Yasui et al., 1986; Taylor et al., 1991). Secondly, the neuroactive nature of certain metabolites, including quinolinic acid (QUIN), an excitotoxic agonist of N-methyl-D-aspartate receptors, and kynurenic acid (KYNA) an antagonist of excitatory amino acid receptors, has implicated their involvement in a broad spectrum of neurodegenerative disease (Heyes et al., 1992,1993). In a previous study, accumulation of QUIN in gerbil brain was observed 4 and 7 days following transient cerebral ischemia (Saito et al., see Figure 1). Such increases have been demonstrated to be secondary to increases of IDO and other kynurenine pathway enzymes in infiltrated
Journal of Cerebral Blood Flow and Metabolism, Jun 1, 1998
We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist ... more We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32°C) or normothermia (3rC) treatments for 24 hours. Oth erwise, patients received standard neurointensive care. Quino linie acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinie acid concentrations with age, gender, GCS, time after injury,
: Quinolinic acid is an excitatory, neurotoxic tryptophan metabolite proposed to play a role in t... more : Quinolinic acid is an excitatory, neurotoxic tryptophan metabolite proposed to play a role in the pathogenesis of hepatic encephalopathy. This involvement was investigated in rat and rabbit models of fulminant hepatic failure at different stages of hepatic encephalopathy. Although plasma and brain tryptophan levels were significantly increased in all stages of hepatic encephalopathy, quinolinic acid levels increased three‐ to sevenfold only in the plasma, CSF, and brain regions of animals in stage IV hepatic encephalopathy. Plasma‐CSF and plasma‐brain quinolinic acid levels in rats and rabbits with fulminant hepatic failure were strongly correlated, with CSF and brain concentrations ∼10% those of plasma levels. Moreover, there was no significant regional difference in brain quinolinic acid concentrations in either model. Extrahepatic indoleamine‐2,3‐dioxygenase activity was not altered in rats in stage IV hepatic encephalopathy, but hepatic l‐tryptophan‐2,3‐dioxygenase activity was increased. These results suggest that quinolinic acid synthesized in the liver enters the plasma and then accumulates in the CNS after crossing a permeabilized blood‐brain barrier in the end stages of liver failure. Furthermore, the observation of low brain concentrations of quinolinic acid only in stage IV encephalopathy suggests that the contribution of quinolinic acid to the pathogenesis of hepatic encephalopathy in these animal models is minor.
To assess the potential therapeutic effects of zidovudine, rhesus macaques were inoculated with s... more To assess the potential therapeutic effects of zidovudine, rhesus macaques were inoculated with simian immunodeficiency virus (SIV) strain SMM/B670 at birth and infused either continuously or intermittently with zidovudine for 6-7 months. Zidovudine did not prevent infection but did significantly increase survival time, which was associated with lower serum p26 viral core antigen levels, a lower virus burden in the cerebrospinal fluid (CSF), and lower CSF quinolinic acid levels than in untreated monkeys. Two of 5 infected, untreated monkeys developed motor impairment within 6 months following infection, whereas motor impairments did not occur in infected, zidovudine-treated monkeys until after the drug was discontinued. Zidovudine treatment was well tolerated by rhesus infants with minimal, transient side effects. These results demonstrate that zidovudine treatment significantly decreases virus load within the central nervous system (CNS) and delays the onset of CNS dysfunction and immune disease in rhesus monkeys perinatally infected with SIV.
Activation of the immune system which occurs in inflammatory diseases leads to parallel increases... more Activation of the immune system which occurs in inflammatory diseases leads to parallel increases in pterin synthesis and increased production of neuroactive L-tryptophan metabolites. Several model systems were studied to determine whether pterins, which are cofactors for hydroxylation reactions, could be required in the oxidative kynurenine pathway of L-tryptophan degradation. Treatment of mice with interferon-y increased Ltryptophan metabolism without any corresponding change in tissue biopterin concentrations. Cytokine-treated human fibroblasts, macrophages and glioblastoma cells all showed increases in kynurenine production, which were completely independent of
Apolipoproteins in cerebrospinal fluid (CSF) might have important functional roles in the pathoph... more Apolipoproteins in cerebrospinal fluid (CSF) might have important functional roles in the pathophysiology of brain and lipid metabolism in the vascular component. The present study examined apolipoprotein A-I (apo-A-I) and apolipoprotein E (apo-E) levels in CSF and serum from poliovirus-infected macaques. Poliovirus-infected macaques developed motor deficits and were classified into three groups : (1) muscle weakness in one or both legs ; (2) partial paralysis in one or both legs ; (3) complete paralysis in one or both legs. No motor deficits were evident in the control or sham-treated macaques. Apo-A-I concentrations in CSF were markedly elevated in poliovirus-infected macaques with weakness, partial or complete paralysis, in comparison with either control or sham-treated animals, and were proportional to the severity of motor impairment. Apo-E concentrations in CSF
Many of the characteristics neuroanatomical and neurochemical features of Huntington&#39;s di... more Many of the characteristics neuroanatomical and neurochemical features of Huntington&#39;s disease (HD) are produced in experimental animals by an intrastriatal injection of the endogenous N-methyl-D-aspartate receptor agonist quinolinic acid (QUIN). Conceivably, a chronic over-production of QUIN in brain could be involved in the pathogenesis of HD. To investigate this hypothesis, concentrations of QUIN were measured both in cerebrospinal fluid (CSF) and postmortem tissue from patients with HD and neurologically normal age-matched controls. CSF QUIN concentrations were slightly lower in patients with HD, however the changes were not significant. Mean concentrations of QUIN tended to be lower in HD putamen, dentate nucleus and several cortical regions, although significant reductions were found only in Brodmann areas 17, 20 and 28. The mechanisms responsible for these small reductions in brain QUIN concentrations remain to be determined. These results do not support the hypothesis that a chronic increase of QUIN production is responsible for neurodengeneration in HD.
The source of the neurotoxin quinolinic acid (QUIN) in brain and systemic tissues under normal an... more The source of the neurotoxin quinolinic acid (QUIN) in brain and systemic tissues under normal and pathologic circumstances reflects either de novo synthesis from L-tryptophan and other precursors, or entry of QUIN itself from the blood. To quantify the relative contributions of blood-versus tissue-derived QUIN, [13c71 QUIN was infused subcutaneously via osmotic pumps (0.55~.tl/h,30 mM) in gerbils, and the fraction of QUIN in tissue (Ti; measured in tissue homogenates) derived from blood (BI; measured in serum) was calculated by the formula ([13C 7]QUINT/QUINT)/([ 13C 7]QUINB/ QUINBI). In controls, blood QUIN contributed 38-49% of QUIN in brain, 70% in CSF, between 40 and 70% in kidney, heart, and skeletal muscle, but <5% in spleen, lung, liver, and intestine. Systemic endotoxin (450 fig/kg) increased blood, brain, CSF, and systemic tissue QUIN levels. Notably, the relative proportion of QUIN derived from blood in brain, spleen, lung, and intestine was unchanged by endotoxin, but increased in kidney, heart, and skeletal muscle. In contrast, cerebral ischemic injury (10 mm of bilateral carotid artery occlusion) increased regional brain QUIN concentrations at 4 days post ischemia, with a proportional increase in the amount of QUIN derived from de novo synthesis by brain tissue. In the blood and systemic tissues of postischemic gerbils, there were no changes in systemic tissue or blood QUIN levels, or changes in the relative proportions of blood-versus systemic tissue-derived QUIN. These results establish that the brain normally synthesizes QUIN, that the blood is a significant source of QUIN in controls and during acute systemic immune activation, and that the rate of QUIN formation by brain tissue increases in conditions of brain and systemic immune activation.
Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to... more Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P ؍ 0.037) and neopterin (P ؍ 0.003) were decreased, and biopterin (P ؍ 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated compared with controls (P < 0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid.
Journal of Neurosurgical Anesthesiology, Oct 1, 1997
We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist ... more We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] &amp;amp;amp;amp;lt; 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32 degrees C) or normothermia (37 degrees C) treatments for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5- to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid (P &amp;amp;amp;amp;lt; 0.00001), and quinolinic acid was higher in patients who died than in survivors (P = 0.003). Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage.
The pathogenic mechanisms resulting in the serious syndrome associated with acute and chronic liv... more The pathogenic mechanisms resulting in the serious syndrome associated with acute and chronic liver diseases, better kown as hepatic encephalopathy (HE), are still unknown. The syndrome is most often referred to as a neuropsychiatric disease of multifactorial origin (Conn and Lieberthal, 1979). Many different hypotheses have been suggested for the patogenesis of HE. No single such hypothesis has so far been proven to be valid. Among these hypotheses are increased brain levels of the compound quinolinic acid (QUIN; pyridine-2,3-dicarboxylic acid) one that suggests this potential neurotoxin to contribute to the development of HE (Moroni et al., 1986a,b)
Advances in Experimental Medicine and Biology, 1991
Profound insulin-induced hypoglycemia is associated with neurodegenera-tion which resembles lesio... more Profound insulin-induced hypoglycemia is associated with neurodegenera-tion which resembles lesions produced by administration of exogenous excito-toxins (Auer, 1986). Neuronal lesions in hypoglycemia begin within minutes of the hypoglycemie insult and are attenuated by local application of N-methyl-D-aspartate (NMDA) receptor antagonists (Wieloch 1985; Simon et al., 1986).
Study design: Blinded, placebo-controlled, parallel treatment group studies of the effects of met... more Study design: Blinded, placebo-controlled, parallel treatment group studies of the effects of methylprednisolone (MP) or 4-chloro-3-hydroxyanthranilate (4-Cl-3-HAA) on behavioral outcome and quinolinic acid tissue levels from experimental thoracic spinal cord injury in adult guinea pigs. Objectives: To compare the effects of treatment with high-dose MP, a corticosteroid, and 4-Cl-3-HAA, a compound that inhibits synthesis of the neurotoxin quinolinic acid (QUIN) by activated macrophages. To explore the effect of different times of treatment using these two approaches to ameliorating secondary tissue damage.
Advances in Experimental Medicine and Biology, 1996
Quinolinic acid (QUIN), kynurenic acid (KYNA) and L-kynurenine (L-KYN) are neuroactive L-tryptoph... more Quinolinic acid (QUIN), kynurenic acid (KYNA) and L-kynurenine (L-KYN) are neuroactive L-tryptophan metabolites that are synthesized via the kynurenine pathway. These metabolites accumulate in CNS following immune stimulation (particularly those with inflammatory lesions and monocyte infiltration into the CNS) and are attributed to induction of indoleamine-2,3-dioxygenase (IDO) and other kynurenine pathway enzymes (Saito et al., 1993a; Heyes et al., 1992a; 1993).
Advances in Experimental Medicine and Biology, 1991
The utility of stable isotope-labeled tryptophan as a precursor for studying the disposition of q... more The utility of stable isotope-labeled tryptophan as a precursor for studying the disposition of quinolinic acid was investigated. TRP-D5 at doses of 50, 25 or 10 mg/kg was administered to rabbits. Blood and CSF samples were taken for up to 6 hours. There was no loss of deuterium from the tryptophan and the specifically tri-deuterated quinolinic acid measured in plasma and CSF. CSF levels of QUIN-D3 remained elevated 6 hours following TRP-D5 administration. Further studies of the CNS disposition of quinolinic acid and other metabolites of the kynurenine pathway employing stable isotope-labeled tryptophan as precursor at appropriate doses and with extended sampling are in progress.
Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of pat... more Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of patients with inflammatory neurologic disease and may be of neuropathologic significance. The production of quinolinic acid was postulated to reflect local induction of indoleamine 2,3-dioxygenase by cytokines in reactive cells and inflammatory cell infiltrates within the central nervous system. To test this hypothesis, macaques received an intraspinal injection of poliovirus as a model of localized inflammatory neurologic disease. Seventeen days later, spinal cord indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations in spinal cord and cerebrospinal fluid were both increased in proportion to the degree of inflammatory responses and neurologic damage in the spinal cord, as well as the severity of motor paralysis. The absolute concentrations of quinolinic acid achieved in spinal cord and cerebrospinal fluid exceeded levels reported to kill spinal cord neurons in vitro. Smaller increases in indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations also occurred in parietal cortex, a poliovirus target area. In frontal cortex, which is not a target for poliovirus, indoleamine 2,3-dioxygenase was not affected. A monoclonal antibody to human indoleamine 2,3-dioxygenase was used to visualize indoleamine 2,3-dioxygenase predominantly in grey matter of poliovirus-infected spinal cord, in conjunction with local inflammatory lesions. Macrophage/monocytes in vitro synthesized [t3C6jquinolinic acid from [13C6JL-tryptophan, particularly when stimulated by interferon-y. Spinal cord slices from poliovirusinoculated macaques in vitro also converted ['3C6]Ltryptophan to [1'CsJquinolinic acid. We conclude that local synthesis of quinolinic acid from L-tryptophan within the central nervous system follows the induction of indoleamine-2,3-dioxygenase, particularly within macrophage/microglia. In view of this link between immune stimulation and the synthesis of neurotoxic amounts of quinolinic acid, we propose that attenuation of local inflammation, strategies to reduce the synthesis of neuroactive kynurenine pathway metabolites, or drugs that interfere with the neurotoxicity of quinolinic acid offer new approaches to therapy in inflammatory neurologic disease.
Substantial increases in the concentrations of the excitotoxin and N-methyl-D-aspartate-receptor ... more Substantial increases in the concentrations of the excitotoxin and N-methyl-D-aspartate-receptor agonist quinolinic acid (QUIN) occur in human patients and non-human primates with inflammatory diseases. Such increases were postulated to be secondary to induction of indoleamine 2,3-dioxygenase in inflammatory cells, particularly macrophages, by interferon-gamma. To test this hypothesis, human peripheral-blood macrophages were incubated with L-[13C6]tryptophan in the absence or presence of interferon-gamma. [13C6]QUIN was quantified by gas chromatography and electron-capture negative-chemical-ionization mass spectrometry. [13C6]QUIN was detected in the incubation medium of both unstimulated and stimulated cultures. Exposure to interferon-gamma substantially increased the accumulation of [13C6]QUIN in a dose- and time-dependent manner. The QUIN concentrations achieved exceeded those reported in both cerebrospinal fluid and blood of patients and of non-human primates with inflammatory d...
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Papers by Melvyn Heyes