NEUROPROTECTIVE EFFECTS OF GROUP-III MGLUR IN TRAUMATIC NEURONAL INJURY

We have used an in vitro trauma model to examine the effects of modula tion of group III metabotropic glutamate receptors (mGluR) on post-tra umatic neuronal cell death, Rat cortical neuronal/glial cultures were subjected to standardized mechanical injury using a punch that deliver s 28 parallel cuts to 96-well culture plates, resulting in approximate ly 50% neuronal cell loss in untreated cultures, RT-PCR demonstrated e xpression of mRNA for mGluR4, mGluR6, mGluR7, and mGluR8 in uninjured cultures as well as in adult rat brain, Treatment with the group III a gonists L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) or L-serine-O-ph osphate (L-SOP) resulted in dose-dependent neuroprotection, In contras t, treatment with the group III antagonists alpha-methyl-AP4 (MAP4) or (RS)-alpha-methylserine-O-phosphate (MSOP) caused dose-dependent exac erbation of injury, which was significantly attenuated by L-AP4 or L-S OP, The neuroprotective actions of L-AP4 or L-SOP were markedly reduce d by the cyclic AMP analog 8-CPT-cAMP (500 mu m), which by itself had no effects at this concentration, Moreover, treatment with L-AP4 or L- SOP reduced basal cyclic AMP levels, Treatment with the NMDA antagonis t MK 801 decreased post-traumatic cell death by 45% at optimal concent rations; combined treatment with MK 801 and group III agonists showed a significant enhancement of neuroprotection as compared to treatment with the NMDA antagonist alone, Our findings indicate a clear neuropro tective action for group III agonists in this model and suggest that g roup III mGluR are endogenously activated in response to trauma. The n europrotective effects of group III agonists appear to result in part from modulation of adenylyl cyclase activity and are additive to those of an NMDA receptor antagonist.