Neuroprotection by metabotropic glutamate receptor agonists: LY354740, LY379268 and LY389795

In rat cortical neuronal cultures, metabotropic glutamate (mGlu) receptor a gonists: LY354740 (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate); LY379 268 (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate, and LY389795 ( -)-2-thia-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylate, were neuroprotect ive against toxicity induced by N-methyl-D-aspartic acid (NMDA), kainic aci d and staurosporine as measured by release of lactate dehydrogenase (LDH) a ctivity into culture supernatants and DNA fragmentation by oligonucleosome formation. The potencies of the agonists were at least 100 times greater in reducing nucleosome formation than LDH release indicating a differential e ffect on neurons dying by apoptosis than by necrosis. In vivo studies showe d that LY354740 was able to mediate a partial protection against apoptosis in CA1 hippocampal cells under ischaemic conditions where substantial CA1 c ell loss occurred. The effects of the agonists in vitro were: (a) reversed by mGlu receptor antagonist LY341495, (b) enhanced by the presence of glial cells, (c) abrogated by RNA and protein synthesis inhibitors, and (d) unal tered by inhibition of endogenous adenosine activity. These results suggest that group II mGlu receptor agonists may represent a novel therapeutic str ategy for the treatment of neurodegenerative diseases. (C) 1999 Elsevier Sc ience B.V. All rights reserved.