MECHANISMS OF 1S,3R-ACPD-INDUCED NEUROPROTECTION IN RAT HIPPOCAMPAL SLICES SUBJECTED TO OXYGEN AND GLUCOSE DEPRIVATION

The efficacy and mechanisms of 1-amino-cyclopentyl-1S,3R-dicarboxylate (1S,3R-ACPD)-induced neuroprotection were investigated in rat hippoca mpal slices subjected to 10 min of oxygen and glucose deprivation. Neu ronal viability was assessed by measuring both the amplitude of evoked population spike in the CA1 pyramidale and by imaging CA1 neurons usi ng a live/dead fluorescence assay with confocal microscopy. CA1 pyrami dal neurons in oxygen-glucose deprived slices remained viable for up t o 120 min following the insult but were dead by 240 min. Pretreatment with 1S,3R-ACPD significantly protected the oxygen-glucose deprived sl ices in a concentration-dependent fashion. Oxygen-glucose deprived sli ces pretreated for the same period with the protein kinase C (PKC) act ivator, phorbol 12-myristate 13-acetate (PMA; 1 mu M) were significant ly protected whereas oxygen-glucose deprived slices treated with the a denylyl cyclase activator, forskolfin (30 mu M) were not. Oxygen-gluco se deprivation induced a rapid and persistent decrease (similar to 50% ) in PKC activity and a >6 fold increase in cyclic adenosine monophosp hate (cAMP) levels in whole hippocampal slices. While 1S,3R-ACPD did n ot stimulate PKC activity and had no effect on basal cAMP in whole sli ces, it significantly enhanced the rate of return of cAMP to basal lev els following reperfusion. Consistent with this observation, the 1S,3R -ACPD-induced neuroprotection was inhibited by forskolin (30 mu M). Th ese results suggest that in vitro neuroprotection of CA1 neurons by 1S ,3R-ACPD involves metabotropic glutamate receptors negatively linked t o cAMP and possibly those which increase PKC activity. Copyright (C) 1 996 Elsevier Science Ltd.