Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist:Investigations into possible mechanism of action in vivo

The mechanisms underlying the neuroprotective effects of the group II metab otropic glutamate receptor (mGluR) agonist LY379268 were investigated in a gerbil model of global ischemia. LY379268 (10 mg/kg i.p.) 30 or 60 min afte r 5-min bilateral carotid artery occlusion (BCAO) attenuated the ischemia-i nduced hyperactivity and provided protection in the CA1 hippocampal cells. This neuroprotective effect was maintained (P <.001) when histological anal ysis was performed 14 and 28 days after BCAO. Furthermore, 24- or 48-h pret reatment with LY379268, 10 mg/kg i.p., before 5-min BCAO markedly reduced ( P <.001 and P <.05, respectively) the damage to CA1 hippocampal neurons. Th is result is consistent with the induction of neuroprotective factors or a very long brain half-life. To study the possible induction of neuroprotecti ve factors as contributing to this action of LY379268, brains were examined for expression of neurotrophic factors. Results indicated that LY379268 (1 6 mg/kg i.p.) failed to alter the expression of transforming growth factor- p, brain-derived neurotrophic factor, nerve growth factor, and basic fibrob last growth factor in the hippocampal regions of brains taken from gerbils sacrificed at 6, 24, 72, and 120 h postinjection. The new group II mGlu ant agonist, LY341495, administered 1 h before 5-min BCAO, attenuated the neuro protective effect of LY379268 administered 24 h before 5-min BCAO. Compleme ntary pharmacokinetic studies showed that a significant receptor-active con centration persisted in the brain 24 h after LY379268 10 mg/kg i.p. We conc lude that group II mGluR occupancy, rather than induction of neuroprotectiv e factors, explains the long-lasting neuroprotective effect of LY379268 in the gerbil model of global ischemia.