The novel beta-blocker, carvedilol, provides neuroprotection in transient focal stroke.
Increasing evidence supports a role for oxidative stress, proinflammatory cytokines, and apoptosis in the pathophysiology of focal ischemic stroke. Previous studies have found that the multi-action drug, carvedilol, is a mixed adrenergic antagonist, and that it behaves as an antioxidant and inhibits apoptosis. In the current study, the authors investigated whether carvedilol provides protection in focal cerebral ischemia and whether this protection is associated with reduced apoptosis and the downregulation of the inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin- 1beta (IL-1beta). Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) by an intraluminal filament technique. Carvedilol (1, 3, and 10 mg/kg) was injected daily subcutaneously 2 or 4 days before the induction of ischemia. Neurologic scores, infarct volumes, TUNEL staining, and mRNA levels of TNF-alpha and IL-1beta were assessed at 24 hours reperfusion. The effect of carvedilol on microvascular cortical perfusion was studied with continuous laser-Doppler flowmetry. Twenty-four hours 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 ischemia. This protection was not mediated by changes in temperature or blood flow. Treatment with all three dose regimens resulted in fewer TUNEL positive cells compared with controls. At 24 hours reperfusion, carvedilol decreased TNF-alpha and IL-1beta expression by 40% to 50% in the ipsilateral ischemic cortex compared with the contralateral controls. The results of the current study indicate that carvedilol is neuroprotective in focal cerebral ischemia and may protect the ischemic brain by inhibiting apoptosis and attenuating the expression of TNF-alpha and IL-1beta.
Savitz
S I
SI
Department of Neurology, Kennedy Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Erhardt
J A
JA
Anthony
J V
JV
Gupta
G
G
Li
X
X
Barone
F C
FC
Rosenbaum
D M
DM
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002540:Cerebral Cortex / Q000098:blood supply; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D007375:Interleukin-1 / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D009420:Nervous System / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D007375:Interleukin-1; D018696:Neuroprotective Agents; D011412:Propanolamines; D014409:Tumor Necrosis Factor-alpha; D000077261:Carvedilol