Exacerbation of neuronal cell death by activation of group I metabotropic glutamate receptors: role of NMDA receptors and arachidonic acid release

Abstract

Both ionotropic and metabotropic glutamate receptors have been implicated in the pathogenesis of neuronal injury. Activation of group I metabotropic glutamate receptors (mGluR) exacerbates neuronal cell death, whereas inhibition is neuroprotective. However, the mechanisms involved remain unknown. Activation of group I mGluR modulates multiple signal transduction pathways including stimulation of phosphoinositide hydrolysis, potentiation of NMDA receptor activity, and release of arachidonic acid. Here we demonstrate that whereas activation of group I mGluR by (S)-3,5-dihydroxyphenylglycine (DHPG) potentiates NMDA-induced currents and intracellular calcium increases in rat cortical neuronal cultures, partial effects of group I mGluR activation or inhibition on neuronal injury induced by oxygen-glucose deprivation remain despite NMDA receptor blockade. DHPG stimulation also increases basal arachidonic acid release from rat neuronal-glial cultures and potentiates injury-induced arachidonic acid release in these cultures. Thus, activation of group I mGluR may exacerbate neuronal injury through multiple mechanisms, which include positive modulation of NMDA receptors and enhanced release of arachidonic acid.