Understanding regulation of nerve cell death by mGluRs as a method for development of successful neuroprotective strategies.

A common cause of nerve cell death often leading to vascular dementia is ischemic stroke. Attempts to develop clinically effective stroke treatment and prevention strategies based on pharmacological manipulations of a single mechanism have not led to clinical success. Analysis of clinical neuroprotection trials suggests that combination treatments may be more effective. To identify optimal components for such treatment, N-methyl-d-aspartate receptor (NMDAR) activation-induced cell death in organotypic hippocampal preparations was studied as a model of neurodegeneration that occurs in association with stroke or vascular dementia. Pharmacological manipulation of metabotropic glutamate receptors mGluR1 and 5 resulted in significant reduction of nerve cell susceptibility to NMDA-induced injury, suggesting that these receptors may function as physiological regulators of neuronal vulnerability. cDNA microarray analysis of over 1000 brain-related genes performed after the neuroprotective activation of group I metabotropic glutamate receptors (mGluRs) revealed a complex pattern of activation and inactivation of seemingly unrelated genes responsible for regulation of neuronal excitability, inflammation, cell death pathways, cell adhesion and transcriptional activation. Combined pharmacological targeting of these processes may provide basis for clinical trials of effective neuroprotective compounds.