Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delayed increases in the levels of an endogenous N-methyl-D-aspartate receptor agonist, quinolinic acid (QUIN), have been demonstrated following transient ischemia in the gerbil and were postulated to be secondary to induction of indoleamine-2,3-dioxygenase (IDO) and other enzymes of the L-tryptophan-kynurenine pathway. In the present study, proportional increases in IDO activity and QUIN concentrations were found 4 days after 10 min of cerebral ischemia, with both responses in hippocampus > striatum > cerebral cortex > thalamus. These increases paralleled the severity of local brain injury and inflammation. IDO activity and QUIN concentrations were unchanged in the cerebellum of postischemic gerbils, which is consistent with the preservation of blood flow and resultant absence of pathology in this region. Blood QUIN and L-kynurenine concentrations were not affected by ischemia. Brain tissue QUIN levels at 4 days postischemia exceeded blood concentrations, minimizing a role for breakdown of the blood-brain barrier. Marked increases in the activity of kynureninase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilate-3,4-dioxygenase were also detected in hippocampus but not in cerebellum on day 4 of recirculation. In vivo synthesis of [13C6]QUIN was demonstrated, using mass spectrometry, in hippocampus but not in cerebellum of 4-day postischemic animals 1 h after intracisternal administration of L-[13C6]tryptophan. However, accumulation of QUIN was demonstrated in both cerebellum and hippocampus of control gerbils following an intracisternal injection of 3-hydroxyanthranilic acid, which verifies the availability of precursor to both regions when administered intracisternally. Notably, although IDO activity and QUIN concentrations were unchanged in the cerebellum of ischemic gerbils, both IDO activity and QUIN content were increased in cerebellum to approximately the same degree as in hippocampus, striatum, cerebral cortex, and thalamus 24 h after immune stimulation by systemic pokeweed mitogen administration, demonstrating that the cerebellum can increase IDO activity and QUIN content in response to immune activation. No changes in kynurenic acid concentrations in either hippocampus, cerebellum, or cerebrospinal fluid were observed in the postischemic gerbils compared with controls, in accordance with the unaffected activity of kynurenine aminotransferase activity. Collectively, these results support roles for IDO, kynureninase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilate-3,4-dioxygenase in accelerating the conversion of L-tryptophan and other substrates to QUIN in damaged brain regions following transient cerebral ischemia. Immunocytochemical results demonstrated the presence of macrophage infiltrates in hippocampus and other brain regions that parallel the extent of these biochemical changes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of delayed increases in kynurenine pathway metabolism in damaged brain regions following transient cerebral ischemia. 841 38

NMDA receptors play a critical role in neurotransmission and are also involved in the occurrence of excitotoxic nerve cell death. Synthetic halogenated analogs of the endogenous broad spectrum excitatory amino acid receptor blocker kynurenic acid are among the most potent and selective antagonists of the glycine co-agonist site of the NMDA receptor complex. Pharmacological blockade of this site provides neuroprotection in animal models of cerebral ischemia, epilepsy and neurodegenerative disorders, and does not appear to be associated with some of the undesirable side effects linked to classic competitive and non-competitive NMDA receptor antagonists. Here we demonstrate the neuroprotective quantities of 7-chloro-kynurenic acid (7-Cl-KYNA), one of the most selective and well-studied glycine site antagonists, can be synthesized in the brain from its bioprecursor L-4-chlorokynurenine (4-Cl-KYN). Intracerebral infusion of 4-Cl-KYN dose-dependently reduced quinolinate neurotoxicity in the rat hippocampus after enzymatic conversion to 7-Cl-KYNA by kynurenine aminotransferase. In accordance with previous studies demonstrating that kynurenine aminotransferase is preferentially localized in astrocytes, both the enzymatic formation of 7-Cl-KYNA and the neuroprotective potency of 4-Cl-KYN were substantially reduced following an intrahippocampal injection of the gliotoxin fluorocitrate. In situ produced 7-Cl-KYNA offers a novel neuroprotective strategy for targeting the glycine/NMDA site while avoiding excessive receptor blockade and reducing the clinical risks associated with conventional NMDA receptor antagonism.
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PMID:Enzyme-catalyzed production of the neuroprotective NMDA receptor antagonist 7-chlorokynurenic acid in the rat brain in vivo. 903 Aug 92