The role of tumor necrosis factor-alpha in stress-induced worsening of cerebral ischemia in rats

Whereas stress is known to be one of the risk factors of stroke, few experimental studies have examined the possible mechanisms by which stress may affect stroke outcome. Most of the knowledge on the effects of stress on cerebrovascular disease in humans is restricted to catecholamines and glucocorticoids effects on blood pressure and/or development of atherosclerosis. By using an experimental paradigm consisting of the exposure of Fischer rats to repeated immobilization sessions (1 h daily during seven consecutive days) prior to permanent middle cerebral artery occlusion (MCAO), we have found that stress worsens behavioral outcome and increases infarct size after MCAO. These changes occur concomitantly to an increase in inducible nitric oxide synthase (NOS) expression and to the accumulation of lipid peroxidation markers in brain tissue. The possible regulatory role of TNF alpha was studied by looking at the mechanisms of release of this cytokine as well as to the expression of its receptors (TNFR1 and 2). The results of the present study suggest an increase in TNF alpha expression and release after stress, as well as an increase in the expression of TNFR1. Pharmacological blockade of TNF alpha with anti-TNF alpha led to a decrease in the infarct size as well as in the oxidative/nitrosative biochemical parameters seen after ischemia. In summary, our results indicate that TNF alpha accounts, at least partly, for the worsening of MCAO consequences in brain of rats exposed to stress. Furthermore, the data presented here provide evidence that stress can increase brain ischemic damage and support a possible protective effect of treatment of stressful situations before and during the development of the brain ischemia. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.