Graduate Thesis Or Dissertation
 

Effects of quinolinate and nitro-, or thio- substituted analogs of quinolinate on glutamate receptor-mediated neurotoxicity in cerebellar granule cell cultures

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  • Quinolinate (QUIN) is an endogenous neurotoxic product of the kynurenine pathway of tryptophan metabolism. Quinolinate is a selective agonist of the NMDA family of glutamate receptors and, as such, may play a role in the pathology of a number of major central nervous system (CNS) disorders. These include both chronic neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases and the AIDS-dementia complex, as well as the acute and delayed neuropathology resulting from traumatic, hypoxic, ischemic or hypoglycemic CNS insults. The work described herein sought to 1.) Compare the neurotoxicity of quinolinate to that of glutamate and to 2.) Explore the structural requirements for quinolinate neurotoxicity by evaluating substituted analogs of quinolinate with a goal of possible discovery of compounds of potential therapeutic value against glutamate receptor-mediated neurotoxicity. Quinolinate has been reported to excite neurons of the CNS ubiquitously, but with variable potency across regions of the mammalian brain, although in a manner consistently sensitive to blockade by specific pharmacological antagonists of NMDA receptor activation. We have compared the neurotoxic effects of exposure to glutamate and quinolinate and the combined effects of glutamate and quinolinate exposure on primary cultures of rat cerebellar granule cells in vitro, by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH) from cerebellar granule neurons. We also examined the effects of the novel quinolinate analogs: 2-nitropyridine-3-carboxylic acid (2NPC), 3-nitropyridine-2-carboxylic acid (3NPC) and 2-thiopyridine-3-carboxylic acid (2TPC). The results indicate that for cerebellar granule cell cultures at day 13 in vitro (13 DIV) 1.) Glutamate induces significant neurotoxicity with an EC₅₀ for LDH release of 76.2 (95% C.I.: 46.8-124.2) μM but 2.) Quinolinate, at concentrations as high as 1 mM effects no measurable neurotoxicity. 3.) Quinolinate, however, potentiates the neurotoxicity of 400 μM glutamate in a dose-dependent manner with an EC₅₀ of 152.4 (95% C.I.: 57.6-403.1) μM, and at a dose of 1 mM enhances 400 μM glutamate toxicity 2.5 fold. 4.) Both the NMDA receptor-channel blocker, MK-801 and the strychnine-insensitive, glycine site antagonist 5,7-dichlorokynurenic acid (5,7-DCKA) are able to fully block the neurotoxicity of 400 μM glutamate + 1 mM quinolinate with IC₅₀ values of 6.7 (95% C.I.: 0.7-69.0) nM and 14.2 (95% C.I: 10.8-18.7) nM, respectively. 5.) Quinolinate surmounts protection against neurotoxicity afforded by 32 nM 5,7-DCKA in a dose-dependent manner and appears capable of completely reversing the protective effects of 5,7-DCKA when concentration was increased to 1 mM. These findings provide evidence that quinolinate potentiates glutamate-mediated neurotoxicity through NMDA receptor activation, and that this potentiation cannot be readily explained by simple additivity to the neurotoxicity induced by glutamate at the NMDA-receptor agonist site. Quinolinate potentiation of glutamate toxicity may involve the glycine site of NMDA receptor. Saturating concentrations of the quinolinate analogs 2NPC, 3NPC and 2TPC, however, provide partial protection against glutamate-mediated neurotoxicity.
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