PT - JOURNAL ARTICLE AU - Ann Bond AU - Nicole M. Jones AU - Caroline A. Hicks AU - Gary M. Whiffin AU - Mark A. Ward AU - Michael F. O'Neill AU - Ann E. Kingston AU - James A. Monn AU - Paul L. Ornstein AU - Darryle D. Schoepp AU - David Lodge AU - Michael J. O'Neill TI - Neuroprotective Effects of LY379268, a Selective mGlu2/3 Receptor Agonist: Investigations into Possible Mechanism of Action In Vivo DP - 2000 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 800--809 VI - 294 IP - 3 4099 - http://jpet.aspetjournals.org/content/294/3/800.short 4100 - http://jpet.aspetjournals.org/content/294/3/800.full SO - J Pharmacol Exp Ther2000 Sep 01; 294 AB - The mechanisms underlying the neuroprotective effects of the group II metabotropic glutamate receptor (mGluR) agonist LY379268 were investigated in a gerbil model of global ischemia. LY379268 (10 mg/kg i.p.) 30 or 60 min after 5-min bilateral carotid artery occlusion (BCAO) attenuated the ischemia-induced hyperactivity and provided protection in the CA1 hippocampal cells. This neuroprotective effect was maintained (P < .001) when histological analysis was performed 14 and 28 days after BCAO. Furthermore, 24- or 48-h pretreatment with LY379268, 10 mg/kg i.p., before 5-min BCAO markedly reduced (P < .001 andP < .05, respectively) the damage to CA1 hippocampal neurons. This result is consistent with the induction of neuroprotective factors or a very long brain half-life. To study the possible induction of neuroprotective factors as contributing to this action of LY379268, brains were examined for expression of neurotrophic factors. Results indicated that LY379268 (10 mg/kg i.p.) failed to alter the expression of transforming growth factor-β, brain-derived neurotrophic factor, nerve growth factor, and basic fibroblast 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 antagonist, LY341495, administered 1 h before 5-min BCAO, attenuated the neuroprotective effect of LY379268 administered 24 h before 5-min BCAO. Complementary pharmacokinetic studies showed that a significant receptor-active concentration persisted in the brain 24 h after LY379268 10 mg/kg i.p. We conclude that group II mGluR occupancy, rather than induction of neuroprotective factors, explains the long-lasting neuroprotective effect of LY379268 in the gerbil model of global ischemia. The American Society for Pharmacology and Experimental Therapeutics