Excitotoxic neuronal injury in chronic homocysteine neurotoxicity studied in vitro: the role of NMDA and group I metabotropic glutamate receptors

Elevated homocysteine is a risk factor in cardiovascular diseases and neurodegeneration. Among the putative mechanisms of homocysteine-evoked neurotoxicity, disturbances in methylation processes and NMDA receptor-mediated excitotoxicity have been suggested. Our previous studies demonstrated that gro...

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Bibliographic Details
Published inActa neurobiologiae experimentalis Vol. 66; no. 4; pp. 301 - 309
Main Authors Zieminska, Elzbieta, Lazarewicz, Jerzy W
Format Journal Article
LanguageEnglish
Published Poland 01.01.2006
Subjects
Animals
Animals, Newborn
Cell Survival - drug effects
Cells, Cultured
Cerebellum - pathology
Dose-Response Relationship, Drug
Drug Interactions
Excitatory Amino Acid Antagonists - pharmacology
Homocystine - toxicity
Neurons - drug effects
Neurons - pathology
Neurotoxins - toxicity
Rats
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate - physiology
Time Factors
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Summary:Elevated homocysteine is a risk factor in cardiovascular diseases and neurodegeneration. Among the putative mechanisms of homocysteine-evoked neurotoxicity, disturbances in methylation processes and NMDA receptor-mediated excitotoxicity have been suggested. Our previous studies demonstrated that group I metabotropic glutamate receptors along with NMDA receptors participate in acute homocysteine-induced neuronal damage. In this study, using propidium iodide staining, we tested whether the same mechanism may mediate chronic homocysteine neurotoxicity. Our results confirmed that the application of D,L-homocysteine in micromolar concentrations for 3 days induces neurodegeneration in primary cultures of cerebellar granule neurons. Uncompetitive NMDA receptor antagonist MK-801, and mGlul or mGlu5 receptor antagonists (LY367385 and MPEP, respectively), given alone provided very limited neuroprotection. However, simultaneous application of the NMDA receptor antagonists MK-801, memantine or amantadine and MPEP almost completely prevented chronic homocysteine neurotoxicity. These findings suggest a novel therapeutic strategy to combat neurodegeneration induced by hyperhomocysteinemia comprising a combination of antagonists of group 1 metabotropic glutamate receptors and NMDA receptors.
ISSN:0065-1400
1689-0035
DOI:10.55782/ane-2006-1619