Abstract P776: Post-Stroke Tenascin-C Induction Mediates the Ischemic Pathogenesis

Abstract

The mechanistic role of Tenascin-C (TNC) in the pathogenesis of acute ischemic stroke is not known despite its prognostic association with cerebrovascular diseases. We currently observed that transient middle cerebral artery occlusion (MCAO) upregulated cerebral TNC mRNA and protein expression between 3h and 24h reperfusion in adult mice of both sexes. We then evaluated the effect of TNC knockdown on ischemic outcome in adult mice of both sexes by treating with either TNC siRNA or control siRNA (intravenous) at 5 min of reperfusion following transient MCAO. TNC siRNA treatment significantly reduced the post-ischemic TNC protein induction tested at 72h reperfusion compared with the sex-matched control siRNA treated cohorts (n=6/group/sex). TNC siRNA cohorts showed significantly improved post-stroke motor function identified by beam walk test and rotarod test between days 1 and 14 of reperfusion compared with the sex-matched control siRNA cohorts (n=7/group/sex). TNC siRNA cohorts of both sexes also showed decreased post-ischemic BBB disruption (evaluated with T1-weighted MRI with gadobenate dimeglumine as contrast agent) and reduced infarction (assessed with T2-weighted MRI) at 3 days of reperfusion compared with the sex-matched control siRNA treated cohorts (n =4/group for BBB and n =12/group/sex for infarct). At day 21 of reperfusion, the survival rate was observed to be higher in the TNC siRNA treated mice compared with the control siRNA treated mice (n =7/group/sex). These studies thus show that induction of TNC during the acute period after stroke might be a mediator of ischemic brain damage and its knockdown is neuroprotective. Importantly this effect is independent of sex. The study was funded by the Department of Neurological Surgery, Univ. of Wisconsin-Madison.