MODULATION OF INJURY BY METABOTROPIC GLUTAMATE RECEPTORS

Georgetown University, Washington DC

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Abstract

Release of glutamate and activation of ionotropic glutamate receptors have been strongly implicated in the pathobiology of post-traumatic CNS injury. The role of metabotropic glutamate receptors (mGluR) has been less well studied. Using both in vivo and in vitro trauma models, we have acquired strong preliminary evidence that activation of group I mGluR contributes to neuronal loss, whereas activation of group II or group III receptors is neuroprotective. We have also demonstrated that among group I mGlur, mGluR1 but not mGluR5 activation, exacerbates post- traumatic neuronal injury. Pilot studies suggest that some of the protective effects provided by group II agonists may involve attenuation of post-traumatic apoptosis. Elucidation of the mechanisms involved in these modulatory actions can provide a better understanding of glutamatergic processes involved in secondary neuronal injury, as well as to provide a potential bias for novel treatment strategies. The proposed studies are intended to extend our initial findings by addressing the following hypotheses: (1) activation of post-synaptic group I mGluR potentiates post-traumatic neuronal injury in part though phospholipase C (PLC) mediated changes of protein kinase C (PKC), with subsequent positive modulation of NMDA receptors via reduction of Mg++ blockade of its ion channel; (2) these group I mGlur effects largely reflect actions mediated by mGlur1 and also include modulation of PLA2 and/or reduce post-traumatic neuronal injury through inhibition of adenylate cyclase activity and glutamate release; (4) antagonism of mGluR1 or NMDA receptors, and stimulation of groups II or III mGluR provide additive degrees of neuroprotection, both in vitro and in vivo, with important potential therapeutic implications. The specific aims propose to address these hypothesis by: (1) evaluating potential mechanisms of group I mGluR mediated neurotoxicity including assessment of the relative contributions of modulation of NMDA receptors, PLA2 and adenylate cyclase, as well as elucidating the relative roles of mGluR1 and mGluR5 in this process; (2) examining the effects of group I receptors antagonists in vivo on neurologic and histologic outcome in a clinically relevant head injury model, and whether beneficial actions may involve modulations of NMDA receptor mediated neurotoxicity; (3) establishing that activation of group II and group III receptors provide endogenous neuroprotective activity and elucidating the mechanisms involved; (4) determining the extent of neuroprotection provided by group II and group III agonists in vivo, using neurologic and histologic assessment (neuronal cell counts and apoptosis); and (5) evaluating the degree to which modulation of specific pre-synaptic and post-synaptic glutamate receptors provide additive or synergistic neuroprotective actions.