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Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites
K Jhamandas1, R J Boegman, R J Beninger
1Department of Pharmacology and Toxicology, Queen's University Kingston, Ont., Canada.
Abstract:
Certain products of tryptophan metabolism interact with excitatory amino acid receptors to produce or protect against excitotoxicity. In this study, the action of several tryptophan metabolites, yielded by the kynurenine pathway, on cortical cholinergic toxicity was evaluated following focal injection into the rat nucleus basalis magnocellularis (nbM). Metabolites were injected singly or in combination with a fixed dose of quinolinic acid (QUIN). Cholinergic toxicity, or protection against it, was evaluated by measurements of choline acetyltransferase (ChAT) activity or potassium-evoked release of [3H]acetylcholine [( 3H]ACh) from slices of the frontoparietal cortex, from the injected and uninjected sides. Focal injections of QUIN and 3-hydroxyanthranilic, but not kynurenic, picolinic, quinaldic or anthranilic acid, produced a dose-related decrease in ChAT activity, with QUIN being more potent. Kynurenic, picolinic, quinaldic and anthranilic acid, co-injected into the nbM with QUIN (120 nmol), produced dose-related antagonism of the neurotoxicity associated with QUIN alone. Picolinic acid also prevented the reduction in cortical [3H]ACh release induced by injections of QUIN. Kynurenic and picolinic acid produced a complete blockade of QUIN's effect on cortical ChAT activity, while quinaldic and anthranilic acid produced a partial blockade. The order of effectiveness against QUIN was kynurenic greater than picolinic greater than quinalidic or anthranilic acid. Evaluation of thin sections following Cresyl violet staining indicated that injections of QUIN produced neuronal loss and glial proliferation, while co-injections of picolinic or quinaldic acid with QUIN protected neurons. These findings show that several tryptophan metabolites have the potential to either produce or antagonize cholinergic toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Certain tryptophan metabolites can cause or prevent brain cell damage. Researchers found that quinolinic acid is toxic, while kynurenic and picolinic acids protect against this neurotoxicity.
Area of Science:
- Neuroscience
- Biochemistry
Background:
- Tryptophan metabolites, particularly those from the kynurenine pathway, are known to interact with excitatory amino acid receptors.
- These interactions can lead to either excitotoxicity or neuroprotection, influencing neuronal function.
Purpose of the Study:
- To investigate the effects of specific tryptophan metabolites on cholinergic toxicity in the rat nucleus basalis magnocellularis (nbM).
- To determine if these metabolites could either induce or antagonize neurotoxicity, particularly in combination with quinolinic acid.
Main Methods:
- Focal injections of various tryptophan metabolites into the rat nbM, both alone and in combination with quinolinic acid (QUIN).
- Assessment of cholinergic toxicity by measuring choline acetyltransferase (ChAT) activity and [3H]acetylcholine release in cortical tissue.
- Histological evaluation of neuronal loss and glial proliferation following injections.
Main Results:
- Quinolinic acid and 3-hydroxyanthranilic acid induced dose-related decreases in ChAT activity, indicating neurotoxicity.
- Kynurenic acid, picolinic acid, quinaldic acid, and anthranilic acid demonstrated dose-dependent antagonism of QUIN-induced neurotoxicity.
- Kynurenic and picolinic acids provided complete blockade of QUIN's toxic effects, while quinaldic and anthranilic acids offered partial blockade.
Conclusions:
- Several tryptophan metabolites, derived from the kynurenine pathway, possess the capacity to induce or protect against cholinergic neurotoxicity.
- The findings highlight the complex role of tryptophan metabolism in neuronal health and disease, with potential therapeutic implications.