SOURCES OF NEUROTOXIN QUINOLINIC ACID

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We investigated the sources of quinolinic acid, a neurotoxic tryptophan - kynurenine pathway metabolite, in brain and blood of HIV-infected patients and retrovirus-infected macaques In brain, quinolinic acid concentrations in HIV-infected patients were elevated by >300-fold to concentrations that exceeded CSF by 8 9-fold There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma Because non-retrovirus induced encephalitis confounds the interpretation of human post mortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations, and determine the relationships of quinolinic acid to encephalitis and systemic responses The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses Specifically, local quinolinic acid levels and indoleamine-2,3-dioxygenase activity were increased in cerebral cortex, and were highest in macaques with cortical encephalitis Cerebral cortex kynurenine-3-hydroxylase and kynureninase activities were only increased slightly in macaques with local encephalitis, while 3-hydroxyanthranilate-3,4-dioxygenase activity was unaffected CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus-induced encephalitis In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis versus those without Specifically, increased plasma L-kynurenine and quinolinic acid accompanied increased activities of indoleamine-2,3-dioxygenase, kynurenine-3-hydroxylase, kynureninase and 3-hydroxyanthranilate-3,4-dioxygenase in lung, and increased urinary excretion of quinolinic acid Hepatic tryptophan-2,3-dioxygenase was unchanged Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almos t all quinolinic acid (>98 %) was synthesized locally within the brain These results demonstrate a role for induction of indoleamine-2,3-dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood Strategies to reduce QUIN production, targeted at intracerebral sites are potential approaches to therapy