INDUCTION OF TOLERANCE TO ISCHEMIA - ALTERATIONS IN 2ND-MESSENGER SYSTEMS IN THE GERBIL HIPPOCAMPUS

Preconditioning the brain with sublethal ischemia protects against neuronal damage following subsequent ischemic insult. Using [H-3]inositol 1,4,5-triphosphate (IP3), [H-3]phorbol 12,13-dibutyrate (PDBu), [H-3]forskolin, [H-3]cyclic adenosine monophosphate (cAMP) and [H-3]rolipram, we performed quantitative autoradiography to determine postischemic alterations in second-messenger systems in the gerbil hippocampus following preconditioning the brain with sublethal ischemia. At 7 days of reperfusion, no alterations were observed in brains subjected to 2 min of forebrain ischemia which produced no neuronal damage. However, 3-min ischemia caused a 75% reduction in [H-3]IP3 binding (p < 0.01 vs. control) and 15-25% reductions in [H-3]forskolin (p < 0.01 vs. control), [H-3]cAMP (p < 0.05 vs. control), and [H-3]rolipram (p < 0.01 vs. control) binding in the CA1 subfield coincident with histopathological CA1 pyramidal cell destruction, but no significant alterations in [H-3]PDBu binding. Preconditioning the brain with 2 min of ischemia followed by 4 days of reperfusion prevented both histopathological cell death and the reductions in binding following subsequent 3 min of ischemia. Interestingly, [H-3]IP3 and [H-3]rolipram binding in CA1 showed a transient reduction, by 30% and 20% (both p < 0.01 vs. control), respectively, in the early reperfusion period. This downregulation of the IP3 system may play a role in the protection against cell death.