Protection of neonatal rat brain from hypoxic-ischemic injury by LY379268,a Group II metabotropic glutamate receptor agonist

NEUROPROTECTIVE effects of a Group II metabotropic glutamate receptor agoni st, LY379268, were examined in a neonatal rat model of hypoxia-ischemia (un ilateral common carotid artery ligation followed by hypoxic exposure for 1. 5 h in 7-day-old rat pups). LY379268 administered 5 min after hypoxic expos ure (2, 5, or 10 mg/kg, i.p.) significantly reduced brain injury as measure d by reductions in the ipsilateral brain weight and in CA1 hippocampal neur on density. The significant neuroprotective effects were also observed when this compound (5 mg/kg) was administered 30 min, but not 60 min, after hyp oxic exposure. The neonatal hypoxia-ischemia (HI) procedure significantly i ncreased caspase-3 activity and induced DNA fragmentation in the ipsilatera l cortex compared with that in the contralateral cortex 24 and 72 h after t he insult, respectively. LY379268 did not prevent this increase in caspase- 3 activity and DNA fragmentation in the ipsilateral cortex. These results s uggest that activation of Group II metabotropic glutamate receptors may pro vide neuroprotection against HI brain injury. However, blockade of caspase- 3 activation and the apoptotic pathway appears not to be involved in the ne uroprotective effects of LY379268 observed in the neonatal rat model of HI. (C) 1999 Lippincott Williams & Wilkins.