The novel beta-blocker, carvedilol, provides neuroprotection in transient focal stroke

Increasing evidence supports a role for oxidative stress, proinflammatory c ytokines, and apoptosis in the pathophysiology of focal ischemic stroke. Pr evious studies have found that the multi-action drug, carvedilol, is a mixe d adrenergic antagonist, and that it behaves as an antioxidant and inhibits apoptosis. In the current study, the authors investigated whether carvedil ol provides protection in focal cerebral ischemia and whether this protecti on is associated with reduced apoptosis and the downregulation of the infla mmatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin- 1 beta (IL-1 beta) Male Sprague-Dawley rats were subjected to transient mid dle cerebral artery occlusion (MCAO) by an intraluminal filament technique. Carvedilol (1, 3, and 10 mg/kg) was injected daily subcutaneously 2 or 3 d ays before the induction of ischemia. Neurologic scores, infarct volumes, T UNEL staining, and mRNA levels of TNF-alpha and IL-1 beta were assessed at 24 hours reperfusion. The effect of carvedilol on microvascular cortical pe rfusion was studied with continuous laser-Doppler flowmetry. Twenty-four ho urs after MCAO. carvedilol at all three doses reduced infarct volumes by at least 40% and reduced neurologic deficits on average by 40% compared with vehicle-treated controls when given 2 or 4 days before the induction of isc hemia. This protection was not mediated by changes in temperature or blood flow. Treatment with all three dose regimens resulted in fewer TUNEL positi ve cells compared with controls. At 24 hours reperfusion, carvedilol decrea sed TNF-alpha and IL-1 beta expression by 40% to 50% in the ipsilateral isc hemic cortex compared with the contralateral controls. The results of the c urrent study indicate that carvedilol is neuroprotective in focal cerebral ischemia and may protect the ischemic brain by inhibiting apoptosis and att enuating the expression of TNF-alpha and IL-1 beta.