Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

Abstract

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 unspecified, but could explain individual variation in stroke outcome. To discover the mechanisms through which psychological stress may alter stroke outcome, we modeled the effects of chronic social intimidation and stress on ischemiainduced bcl-2 expression and early neuronal cell loss resulting from cerebral artery occlusion in mice (C57BL͞6). The bcl-2 protooncogene promotes cell survival and protects against apoptosis and cellular necrosis in numerous neurodegenerative disorders, including stroke. In our study, male mice were chronically exposed to aggressive social stimuli before induction of a controlled, mild ischemic insult. Stressed mice expressed Ϸ70% less bcl-2 mRNA than unstressed mice after ischemia. In addition, social stress greatly exacerbated infarct in wild-type mice but not in transgenic mice that constitutively express increased neuronal bcl-2. Despite similar postischemic concentrations of corticosterone, the major stress hormone in mice, high corticosterone concentrations were significantly correlated with 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 compromises an endogenous molecular mechanism of neuroprotection in injured brain and offer a new behavioral target for stroke therapy.

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

“…Accumulating data suggest that not only is bcl-2 neuropotective, it also exerts neurotrophic effects and promotes neurite sprouting, neurite outgrowth, and axonal regeneration (Chen and Tonegawa 1998;Chen et al 1997;Chierzi et al 1999;Holm et al 2001;Oh et al 1996). Moreover, a recent study demonstrated that severe stress exacerbates stroke outcome by suppressing bcl-2 expression (DeVries et al 2001). In this study, the stressed mice expressed ϳ70% less bcl-2 mRNA than did unstressed mice after ischemia.…”

“…In view of the robust effects of bcl-2 on neurite sprouting, neurite outgrowth, and axonal regeneration (Chen and Tonegawa 1998;Chen et al 1997;Chierzi et al 1999;Holm et al 2001;Oh et al 1996), and protection against the deleterious CNS effects of severe stress (DeVries et al 2001), it is quite possible that bcl-2 enhancers will have utility in the treatment of depressive disorders. Indeed, it is quite possible that lithium's ability to robustly upregulate bcl-2 may play a role in its antidepressant potentiating effects.…”

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…Moreover, a recent study demonstrated that severe stress exacerbates stroke outcome by suppressing Bcl-2 expression. 159 In this study, the stressed mice expressed approximately 70% less Bcl-2 mRNA than unstressed mice after ischemia. Furthermore, stress greatly exacerbated infarct in control mice but not in transgenic mice that constitutively express increased neuronal Bcl-2.…”

Delayed recovery and exaggerated infarct size by post-lesion stress in a rat model of focal cerebral stroke

“…Stress can cause the release of glutamate contributing to excitotoxic processes (Madrigal et al, 2003), inducing hyperglycemia (Sapolsky, 1985;Payne et al, 2003) and inhibiting the expression of anti-apoptotic (DeVries et al, 2001) or neurotrophic factors (Adlard and Cotman, 2004). Thus, stress potentially enlarges lesion size or limits plasticity of intact tissue (Scheff et al, 1980;Magarinos and McEwen, 1995).…”

“…Stress can increase cognitive deficits along with infarct size after middle cerebral artery occlusion (MCAO) in mice (DeVries et al, 2001;Sugo et al, 2002). Moreover, chronic multiple stress after 2-vein occlusion increases cell death within the hippocampus of rats (Ritchie et al, 2004).…”