Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus

Preconditioning (PC) is a phenomenon in which a brief ischemic insult induces tolerance against a subsequent severe ischemic insult. Recent studies showed that cerebral ischemia in adult rat upregulates progenitor cell proliferation in the hippocampal dentate gyrus. We presently evaluated whether PC can also stimulate progenitor cell proliferation in rat brain. Middle cerebral artery was transiently occluded in spontaneously hypertensive rats for 10 min to induce PC and 1 h to induce focal ischemia. Progenitor cell proliferation (defined as BrdU+ cell number) significantly increased after focal ischemia (by 3.9-fold; p < 0.05) as well as PC (by 2.7-fold; p < 0.05) compared to sham. PC 3 days prior had neither an inhibitory nor an additive effect on focal ischemia-induced progenitor cell proliferation. In both ischemia and PC groups, ∼45% of the progenitor cells proliferated in week 1 survived to the end of week 3 and ∼21% of those matured into NeuN+ neurons. Furthermore, cerebral mRNA expression of the growth factors IGF1, FGF2, TGFβ1, EGF and PDGF-A was significantly elevated after PC. Thus, we show that the beneficial effects of PC extend beyond providing neuroprotection during the acute phase after ischemia. Induction of growth factor expression and neurogenesis by PC might be a positive adaptation for an efficient repair and plasticity in the event of an ischemic insult.