Selective blockade of the mGluR1 receptor reduces traumatic neuronal injury in vitro and improves outcome after brain trauma

The effects of selective blockade of group I metabotropic glutamate recepto r subtype 1 (mGluR1) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. The selective mG luR1 antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), 7-(hydroxy imino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), and (S)-()-alpha -amino-4-carboxy-2-methylbezeneacetic acid (LY367385) provided sign ificant neuroprotection in rat cortical neuronal cultures subjected to mech anical injury, in both pretreatment or posttreatment paradigms. Administrat ion of the antagonists also attenuated glutamate-induced neuronal cell deat h in the cultures. Coapplication of these antagonists with the N-methyl-D-a spartate (NMDA) receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10- imine (MK-801) had additive neuroprotective e ffects in glutamate injured cultures. Intracerebroventricular administratio n of AIDA to rats markedly improved recovery from motor dysfunction after l ateral fluid percussion induced traumatic brain injury (TBI), Treatment wit h mGluR1 antagonists also significantly reduced lesion volumes in rats afte r TBI, as evaluated by MRI. It appears that these compounds mediate their n europrotective effect through an mGluR1 antagonist action, as demonstrated by inhibition of agonist induced phosphoinositide hydrolysis in our in vitr o system. Moreover, AIDA, CPCCOEt, and LY367385, at concentrations shown to be neuroprotective, had no significant effects on the steady state NMDA ev oked whole cell current. Taken together, these data suggest that modulation of mGluR1 activity may have substantial therapeutic potential in brain inj ury. (C) 2001 Academic Press.