Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

The relationship between stressful life events and the onset of disease is well documented. However, the role of psychological stress as a risk factor for life-threatening cerebrovascular insults such as stroke remains unspec ified, but could explain individual variation in stroke outcome. To discove r the mechanisms through which psychological stress may alter stroke outcom e, we modeled the effects of chronic social intimidation and stress on isch emia-induced bcl-2 expression and early neuronal cell loss resulting from c erebral artery occlusion in mice (C57BL/6). The bcl-2 protooncogene promote s cell survival and protects against apoptosis and cellular necrosis in num erous neurodegenerative disorders, including stroke. In our study, male mic e were chronically exposed to aggressive social stimuli before induction of a controlled, mild ischemic insult. Stressed mice expressed approximate to 70% less bcl-2 mRNA than unstressed mice after ischemia. In addition, soci al stress greatly exacerbated infarct in wild-type mice but not in transgen ic mice that constitutively express increased neuronal bcl-2. Despite simil ar postischemic concentrations of corticosterone, the major stress hormone in mice, high corticosterone concentrations were significantly correlated w ith larger infarcts in wild-type mice but not bcl-2 transgenic mice. Thus, enhanced bcl-2 expression offsets the potentially deleterious consequences of high postischemic plasma corticosterone concentrations. Taken together, these data demonstrate that stressful prestroke social milieu strongly comp romises an endogenous molecular mechanism of neuroprotection in injured bra in and offer a new behavioral target for stroke therapy.