INCREASED EXPRESSION OF CYCLIN G1 AND P21(WAF1 CIP1) IN NEURONS FOLLOWING TRANSIENT FOREBRAIN ISCHEMIA - COMPARISON WITH EARLY DNA-DAMAGE/

Oxidative stress affecting DIVA integrity may be an important mediator of cell death induced by cerebral ischemia followed by reperfusion, G enes involved in the DNA repair processes may play an important role i n cell viability. We studied the spatial expression of the DNA damage inducible gene p53 and its transcriptional targets p21(WAF1/CIP1), cyc lin G1, and Bar and compared their expression with markers of early DN A damage following 10 min of transient forebrain ischemia in rats. Cyc lin G1 and p21(WAF1/CIP1) mRNA levels increased significantly between 2.5 and 4-fold in neurons of the hippocampus, cortex, and striatum dur ing the first 24 hr after reperfusion and decreased at 48 hr of reperf usion, Significant increases in the protein levels of Cyclin G1 and p2 1(WAF1/CIP1) Were only seen in the striatum at 48 hr of reperfusion, T he mRNA levels of the p21 family members p27(KIP1) or p57(KIP2) demons trated no significant changes. p53, bax alpha, and bcl-xl mRNA levels increased in all areas of the hippocampus by 12 to 24 hr and decreased over the next 2 days of reperfusion, bax alpha. mRNA was specifically induced in neurons of the outer cortical layers at 12 and 24 hr after reperfusion, and protein levels increased in the striatum at 48 hr, N o changes in protein levels of p53, Bcl-xl, or Bcl-2 were detected in the cerebral cortex, hippocampus, or striatum at any time point follow ing reperfusion, Single-stranded DNA breaks detected with DNA polymera se I-mediated in situ nick translation partly overlapped with nuclear cyclin G1 protein in the striatum, cortex, and hippocampus at 24 hr, h owever at 48 hr cyclin G1 remained elevated only in neurons bordering areas exhibiting DNA damage, Nuclear p53 protein, p21 mRNA, and bax al pha mRNA were absent in cells stained with the in situ nick translatio n method but p21 mRNA and bax alpha. mRNA were increased in neurons ad jacent to those with detectable DNA nick ends at 24 and 48 hr followin g reperfusion, The enhanced expression of cyclin G1, p21(WAF1/CIP1), a nd bax alpha in neurons surviving transient forebrain ischemia mag ind icate their participation in an adaptive response to cerebral ischemia and reperfusion, J, Neurosci, Res, 53:279-296, 1998, (C) 1998 Wiley-L iss, Inc.