Hippocampal region-specific endogenous neuroprotection as an approach in the search for new neuroprotective strategies in ischemic stroke. Fiction or fact?

Ischemic stroke is the leading cause of death and long-term disability worldwide, and, while considerable progress has been made in understanding its pathophysiology, the lack of effective treatments remains a major concern. In that context, receiving more and more consideration as a promising therapeutic method is the activation of natural adaptive mechanisms (endogenous neuroprotection) - an approach that seeks to enhance and/or stimulate the endogenous processes of plasticity and protection of the neuronal system that trigger the brain's intrinsic capacity for self-defence. Ischemic preconditioning is a classic example of endogenous neuroprotection, being the process by which one or more brief, non-damaging episodes of ischemia-reperfusion (I/R) induce tissue resistance to subsequent prolonged, damaging ischemia. Another less-known example is resistance to an I/R episode mounted by the hippocampal region consisting of CA2, CA3, CA4 and the dentate gyrus (here abbreviated to CA2-4, DG). This can be contrasted with the ischemia-vulnerable CA1 region. There is not yet a good understanding of these different sensitivities of the hippocampal regions, and hence of the endogenous neuroprotection characteristic of CA2-4, DG. However, this region is widely reported to have properties distinct from CA1, and capable of generating resistance to an I/R episode. These include activation of neurotrophic and neuroprotective factors, greater activation of anti-excitotoxic and anti-oxidant mechanisms, increased plasticity potential, a greater energy reserve and improved mitochondrial function. This review seeks to summarize properties of CA2-4, DG in the context of endogenous neuroprotection, and then to assess the potential utility of these properties to therapeutic approaches. In so doing, it appears to represent the first such addressing of the issue of ischemia resistance attributable to CA2-4, DG.