Antisense Oligodeoxynucleotide Inhibition of Tumor Necrosis Factor-α Expression Is Neuroprotective After Intracerebral Hemorrhage

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Abstract
Background and Purpose—Tumor necrosis factor-α (TNF-α) expression is increased in brain after cerebral ischemia, although little is known about its abundance and role in intracerebral hemorrhage (ICH). A TNF-α–specific antisense oligodeoxynucleotide (ORF4-PE) was used to study the extent to which TNF-α expression influenced neurobehavioral outcomes and brain damage in a collagenase-induced ICH model in rat. Methods—Male Sprague-Dawley rats were anesthetized, and ICH was induced by intrastriatal administration of heparin and collagenase. Immediately before or 3 hours after ICH induction, ORF4-PE was administered directly into the site of ICH. TNF-α mRNA and protein levels were measured by reverse transcriptase–polymerase chain reaction and immunoblot analyses. Cell death was measured by terminal deoxynucleotidyl transferase–mediated uridine 5′triphosphate-biotin nick end labeling (TUNEL). Neurobehavioral deficits were measured for 4 weeks after ICH. Results—ICH induction (n=6) elevated TNF-α mRNA and protein levels (PPPPPPConclusions—These results indicate a pathogenic role for TNF-α during ICH and demonstrate that reducing TNF-α expression using antisense oligodeoxynucleotides is neuroprotective.