Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat.
Tumor necrosis factor-alpha (TNF-alpha) is acutely expressed following focal cerebral ischemia, but its pathophysiological role remains to be extensively characterized. In this study we determined the effect of inhibiting TNF-alpha on the microvascular perfusion impairment and ischemic injury induced by permanent middle cerebral artery occlusion (MCAO). TNF-alpha activity was inhibited with recombinant type I soluble TNF receptor (TNFbp; 1 mg/kg i.v., 0.5 h pre- or post-MCAO). TNFbp significantly attenuated the microvessel perfusion impairment observed in vehicle treated rats, particularly in perifocal/penumbral regions of cortex, and significantly reduced (by 34-38%) the total volume of ischemic injury. These results demonstrate that TNF-alpha contributes to focal ischemic injury and that inhibition of TNF-alpha can confer dramatic neuroprotection. The association of the neuroprotective effect of TNFbp with improved microvascular perfusion suggests that inflammatory and vascular responses to TNF-alpha contribute to its pathological action.
Dawson
D A
DA
Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Martin
D
D
Hallenbeck
J M
JM
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha