Rapid preconditioning neuroprotection following anoxia in hippocampal slices: Role of the K-ATP(+) channel and protein kinase C

Sublethal cerebral anoxic/ischemic insults may "precondition"; and thereby protect brain from subsequent anoxic/ischemic insults. We tested two hypoth eses in hippocampal slices: ii) that short periods of anoxia, each followed by reoxygenation, precondition and thereby improve recovery of synaptic ac tivity following "lethal" anoxic insults; and (ii) that the ATP-sensitive p otassium channel [K-ATP(+)] or protein kinase C mediates anoxic preconditio ning neuroprotection in hippocampal slices. Hippocampal slices were subject ed to three short periods of anoxia, each separated by 10 min of reoxygenat ion. These anoxic insults were prolonged only until the onset of anoxic dep olarization. Thirty minutes following these insults, slices underwent a "te st" anoxic insult, which was characterized by an anoxic insult that lasted 1 min of anoxic depolarization. Recovery of evoked potential amplitudes was followed for 30 min of reoxygenation. The beneficial effects of preconditi oning was shown by the significant recovery of evoked potentials after "tes t" anoxic insults in preconditioned slices, when compared to controls that only underwent a "test" anoxic insult. In control slices, transient superfu sion with an ATP-sensitive potassium channel agonist (10 mu M pinacidil) 30 min prior to "test" anoxia markedly improved evoked potential recovery. Ad ministration of 5 mu M of the sulfonylurea tolbutamide, an ATP-sensitive po tassium channel antagonist during preconditioning insults, blocked the prot ection afforded by preconditioning. Transient superfusion of a protein kina se C activator (500 nM phorbol 12-myristate 13-acetate) did not improve evo ked potential recovery. Administration of 50 nM chelerythrine, a protein ki nase C inhibitor during preconditioning insults did not block the protectio n afforded by preconditioning. These data support the hypothesis that the ATP-sensitive potassium channel is involved in the neuroprotection afforded by anoxic preconditioning in hi ppocampal slices. However, protein kinase C activation does not appear to p lay a role in this neuroprotection. (C) 1998 IBRO. Published by Elsevier Sc ience Ltd.