Old age is associated with an enhanced susceptibility to
stroke and poor recovery from
brain injury, but the cellular mechanisms underlying such phenomena are not known. Using
BrdU-labeling, quantitative immunohistochemistry and 3D-reconstruction of confocal images in a rat model of mild
cerebral ischemia, we found that aged rats are highly susceptible to develop an early
infarct that is associated with premature cellular proliferation originating from the vascular tree. In aged rats we also found a rapid delimitation of the
infarct area by capillary-derived neuroepithelial cells and an early incorporation of these cells into the
glial scar. Since most proliferating cells at the
infarct site are microglia or
nestin-positive cells derived from the vascular wall, we conclude that the vasculature plays a hitherto unrecognized role as a source of proliferating neuroepithelial cells after
stroke. Age-associated alterations in the timing and origin of the cytogenic response to
cerebral ischemia may underlie the poor functional recovery from
stroke. Clarifying the molecular basis of these phenomena could yield novel approaches to enhancing neurorestoration in the elderly. Studies of
stroke in experimental animals have demonstrated the neuroprotective efficacy of a variety of interventions, but most of the strategies that have been clinically tested failed to show benefit in aged humans. One possible explanation for this discrepancy between laboratory and clinical investigations is the role that age plays in the recovery of the brain from insult. Although it is well known that aging is a risk factor for
stroke (Barnett HJ, 2002), the majority of experimental studies of
stroke have been performed on young animals, and therefore may not fully replicate the effects of
ischemia on neural tissue in aged subjects (Wang LC et al., 1995; Davies M et al., 1995; Sutherland GR et al., 1996; Popa-Wagner A et al., 1998, 1999a). Hence, the aged post-acute animal model is clinically most relevant to
stroke rehabilitation and cellular studies (Lindner MD et al., 2003; Brown AW et al., 2003;
Badan I et al., 2003).