title: Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia.
abstract: Two contrasting roles, one beneficial and the injurious, have been proposed for tumor necrosis factor (TNF) in the pathogenesis of cerebral ischemia. Reported here are results obtained in a standard model of permanent focal cortical ischemia in rats, in which the volume of cerebral infarction is measured after permanent occlusion of the middle cerebral artery. Administration of neutralizing anti-rat TNF antibodies (P114) into the brain cortex significantly reduced ischemic brain damage (85% reduced infarct volume as compared with preimmune-treated controls). Similar results were achieved by systemic administration of CNI-1493, a recently described tetravalent guanylhydrazone compound, which effectively inhibited endogenous brain TNF synthesis and conferred significant protection against the development of cerebral infarction (80% reduced infarct volume as compared with vehicle controls treated 1 h postischemia with 10 mg/kg). P114 anti-TNF and CNI-1493 were each cerebroprotective when given within a clinically relevant time window for up to 2 h after the onset of ischemia. These findings establish an important, pathophysiological role of TNF in mediating the progression of ischemic brain damage, and suggest that inhibiting TNF with CNI-1493 may be beneficial in the future treatment of stroke.
authors.affiliation: Department of Surgery, North Shore University Hospital-New York University Medical School, Manhasset, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Meistrell
authors.forename: G I
authors.initials: GI
authors.lastname: Botchkina
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Di Santo
authors.forename: K M
authors.initials: KM
authors.lastname: Cockroft
authors.forename: O
authors.initials: O
authors.lastname: Bloom
authors.forename: J M
authors.initials: JM
authors.lastname: Vishnubhakat
authors.forename: P
authors.initials: P
authors.lastname: Ghezzi
authors.forename: K J
authors.initials: KJ
authors.lastname: Tracey
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D002545:Brain Ischemia / Q000209:etiology* / Q000503:physiopathology* / Q000517:prevention & control; D002540:Cerebral Cortex / Q000378:metabolism; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000633:toxicity*; D000813:Anilides; D006146:Guanidines
chemical_list: D000906:Antibodies; D006835:Hydrazones; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines