METABOTROPIC GLUTAMATE RECEPTORS PREVENT NITRIC OXIDE-INDUCED PROGRAMMED CELL-DEATH

Activation of metabotropic glutamate receptor (mGluR) subtypes can pre vent neuronal injury through the signal transduction pathways of nitri c oxide (NO), It is this link to NO free radical injury and subsequent DNA damage that is the most intriguing, We therefore examined whether neuronal protection through mGluR activation was dependent on the mol ecular mechanisms of programmed cell death (PCD), The NO generators so dium nitroprusside and 3-morpholino-sydnonimine were administered to i nduce NO toxicity in primary hippocampal neurons, PCD was documented b y hematoxylin and eosin nuclear staining, DNA gel electrophoresis, tra nsmission electron microscopy, and protein synthesis assays, Following NO exposure, PCD induction was rapid and robust in approximately 70% of the neuronal population, Activation of specific mGluR subtypes with 1S,3R-ACPD and L-AP4, agents that are neuroprotective against NO, sig nificantly limited the progression of PCD, In contrast, antagonism of mGluRs with L-AP3 did not prevent the development of PCD, Induction of new protein synthesis, a common requisite for PCD, was evident follow ing NO exposure, but did not appear to represent a principal pathway o f modulation by the mGluR agonists, Our studies suggest that mGluR mod ulation of NO-induced PCD represents a primary molecular pathway respo nsible for neuronal survival, Further elucidation of the molecular mGl uR signaling pathways may yield new insight into specific genetic regu latory mechanisms responsible for neuronal injury. (C) 1997 Wiley-Liss , Inc.