MODULATION OF ISCHEMIC SIGNAL BY ANTAGONISTS OF N-METHYL-D-ASPARTATE,NITRIC-OXIDE SYNTHASE, AND PLATELET-ACTIVATING-FACTOR IN GERBIL HIPPOCAMPUS

Cerebral ischemia in the gerbil results in early hippocampal changes, which include transient activation and/or translocation of protein kin ase C (PKC), increased enzymatic activity of ornithine decarboxylase ( ODC), and elevated DNA binding ability of activator protein-1 (AP1). T he time-course of all three of these postischemic responses was found to be almost parallel, peaking at 3 hr after the ischemic insult. The effectiveness of known modulators of postischemic morphological outcom e (MK-801, L-NAME, and gingkolides BN 52020 and BN 52021) in counterac ting the induction of PKC, ODC, and AP1 formation was tested. These dr ugs were administrated as followed: MK-801 (a noncompetitive inhibitor of NMDA channel), 0.8 mg/kg i.p., 30 min before ischemia, and 5 min a fter the insult; L-NAME (competitive inhibitor of NO synthase), 10 mg/ kg i.p., 30 min before ischemia, and 5 mg/kg, 5 min after ischemia; BN 52020 and BN52021 (inhibitors of platelet-activating factor: PAF recep tors) were administered as a suspension in 5% ethanol in water by oral route, 10 mg/kg for 3 days before ischemia. Three of these drugs, MK- 801, L-NAME, and BN52021, significantly reduced ischemia-elevated acti vity of PKC and ODC, whereas AP1 formation was only partially attenuat ed. Our observations implicate the existence of different mechanism(s) for postischemic PKC and ODC activation, which in turn is engaged in AP1 induction. (C) 1995 Wiley-Liss, Inc.