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 (iNOS) expression and to the accumulation of lipid peroxidation markers in brain tissue. The possible regulatory role of TNFalpha 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 TNFalpha expression and release after stress, as well as an increase in the expression of TNFR1. Pharmacological blockade of TNFalpha with anti-TNFalpha 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 TNFalpha 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.
Caso
J R
JR
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Lizasoain
I
I
Lorenzo
P
P
Moro
M A
MA
Leza
J C
JC
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D013312:Stress, Physiological / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D003345:Corticosterone