Figure 3.

Model of neuronal ischemic preconditioning. Based on our observations that preconditioning elicits caspase cleavage and ROS generation, which are required for expression of protection and that this protection requires new protein synthesis, we propose the following pathway mediates protection. We hypothesize that the initial energetic stress put on cells generates ROS and activation of mitochondrial K_ATP channels. These events likely contribute to limited cytochrome c redistribution and caspase 3 activation. Cleaved caspases are likely held in check by preexisting proteins such as HSC 70. When these proteins are depleted, this results in the activation of a positive feedback cycle leading to increased production of HSPs and other neuroprotective proteins. Signal transduction cascades such as protein kinases of the MAPK family and PKC family as well as others, are likely critical components of this protective pathway. The upregulation of HSP 70 is able to block normally lethal exposure to subsequent injuries. Many of the kinases, proteases, chaperones and transcription factors in this pathway could be exploited for development of neurotherapeutics to recapitulate endogenous neuroprotection.