Abstract WP127: TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice
Cerebral ischemia/reperfusion (I/R) induces in situ inflammatory responses which contribute to further brain injury. Toll-like receptors (TLRs) are a trans-membrane, pattern-recognition receptor family with important roles in the induction and regulation of immune/inflammatory responses. TLR4 is known to be involved in cerebral I/R injury and is considered a potential target for the treatment of ischemic stroke. This experiment evaluated the hypothesis that an exogenous TLR4 antagonist, TAK-242, protects brain from I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion (tMCAO). TAK-242 (3 mg/kg body weight) was intraperitoneally injected (i.p.) 1 hour after ischemia. Concentrations of TAK-242 in plasma and brain tissue were measured 3, 8, and 24 hrs after injection. Neurological scores were evaluated 24 hrs after cerebral I/R. Brain infarct areas were detected by TTC staining. Inflammatory cytokines were analyzed by antibody arrays 6 hrs after cerebral I/R. Group comparisons for infarct size were made with the t-test, and cytokine levels were analyzed by one-way ANOVA with post-hoc comparisons. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/ml 3 hrs after i.p, was maintained at 54.1 ng/ml 8 hrs after i.p., and decreased to 22.6 ng/ml 24 hrs after i.p. The concentration of TAK-242 in brain tissue increased to 26.1 ng/ml (ipsilateral) and 14.2 ng/ml (contralateral) 3 hrs after i.p, was maintained at 26.4 ng/ml (ipsilateral) and 15.1 ng/ml (contralateral) 8 hrs after i.p., and was still maintained at 25.0 ng.ml (ipsilateral) and 17.5 ng/ml (contralateral) 24 hrs after i.p. TAK-242 treatment significantly reduced brain infarct size (12.5%) compared to control mice (21.3%) (p<0.05). Cerebral I/R increased the levels of sTNF RI, sTNF RII, KC, GSCF, IL-6, MCP-1, MIP-1γ, and TIMP-1. TAK-242 treatment significantly reduced the levels of sTNF RII, MCP-1, MIP-1γ, and TIMP-1 (p<0.05). Our data demonstrate that TAK-242 can pass through the blood-brain barrier and that treatment with TAK-242 protects the brain from damage at the acute stage after cerebral I/R by mediating the expression of inflammatory cytokines.
- © 2012 by American Heart Association, Inc.