1. ¹Legacy Health Research, Portland, Oregon, USA
2. ²Fujieda Heisei Memorial Hospital, Shizuoka, Japan

Correspondence: Dr RP Simon, Dow Neurobiology Lab, Legacy Health Research, Portland, OR 97232, USA. E-mail: rsimon@downeurobiology.org

Received 31 October 2007; Revised 26 December 2007; Accepted 14 January 2008; Published online 5 March 2008.

Abstract

Permanent cerebral blood flow reduction results in brain injury (stroke), whereas transient ischemic stress results in preconditioning, which can ameliorate the extent of irreversible brain injury from subsequent ischemia—the phenomena of ischemic tolerance. Neurogenesis in the brain occurs after both ischemic injury and the brief ischemia resulting in preconditioning. As neurogenesis is regarded as having an intrinsic neuroprotective role in the brain, we investigated the possible role of these endogenous progenitor cells in the induction of ischemic tolerance. Methylazoxymethanol acetate (MAM) was injected in wild-type mice to attenuate precursor cell proliferation and ganciclovir was used to diminish newly generated cells in GFAP/HSV-TK mice. Both MAM and ganciclovir significantly attenuated ischemia-induced progenitor cell proliferation in the subventricular zone, dentate gyrus, penumbra, and corpus callosum as quantified by 5-bromo-2'-deoxyuridine- or Ki-67-positive cells. Attenuation of ischemia-induced progenitor cell proliferation in the brain blocked the induction of ischemic tolerance. Further the number of TUNEL (TdT-mediated dUTP nick end labeling)-positive cells was considerably increased in MAM-treated animals, whereas MAM did not cause cell death in sham-operated controls. The results of this study suggest a role for endogenous progenitors in the protective effect of ischemic tolerance.