Brain ischemia/reperfusion-induced expression of DP5 and its interaction with Bcl-2, thus freeing Bax from Bcl-2/Bax dimmers are mediated by c-Jun N-terminal kinase (JNK) pathway.

Our previous studies and those of others have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. But the downstream mechanism that accounts for the proapoptotic actions of JNK during cerebral ischemia/reperfusion still remains to be investigated in detail. DP5, one of the mammalian BH3-only proteins, was cloned as a neuronal apoptosis-inducing gene. In this study, we examined the changes of protein level of DP5 and its interaction with Bcl-2 family members in a rat model of global ischemia and reperfusion by immunoprecipitation and immunoblotting; furthermore, we investigated the effect of activated JNK on DP5-signaling pathway. We show here that DP5 was induced and interacted with Bcl-2 but not Bax in hippocampal CA1 6 h to 3 days after ischemia, while the interaction of Bcl-2 with Bax decreased. Systemic administration of SP600125, a small molecule JNK-specific inhibitor, diminished the induction of DP5 and its interaction with Bcl-2 after 2 days of ischemia. At the same time, SP600125 increased the interaction of Bax with Bcl-2 after 2 days of reperfusion. Thus, these results indicate that brain ischemia/reperfusion-induced activation of DP5 signaling pathway is mediated by JNK in postischemic rat hippocampal CA1.