Excessive α-tocopherol exacerbates microglial activation and brain injury caused by acute ischemic stroke.

The vitamin E family includes both tocopherols and tocotrienols, where alpha-tocopherol (alpha TOC) is the most bioavailable form. Clinical trials testing the therapeutic efficacy of high-dose alpha TOC against stroke have largely failed or reported negative outcomes when a "more is better" approach to supplementation (>400 IU/d) was used. This work addresses mechanisms by which supraphysiologic alpha TOC may contribute to stroke-induced brain injury. Ischemic stroke injury and the neuroinflammatory response were studied in tocopherol transfer protein-deficient mice maintained on a diet containing alpha TOC vitamin E at the equivalent human dose of 1680 IU/d. Ischemic stroke-induced brain injury was exacerbated in the presence of supraphysiologic brain alpha TOC levels. At 48 h after stroke, S100B and RAGE expression was increased in stroke-affected cortex of mice with elevated brain alpha TOC levels. Such increases were concomitant with aggravated microglial activation and neuroinflammatory signaling. A poststroke increase in markers of oxidative injury and neurodegeneration in the presence of elevated brain alpha TOC establish that at supraphysiologic levels, alpha TOC potentiates neuroinflammatory responses to acute ischemic stroke. Exacerbation of microglial activation by excessive alpha TOC likely depends on its unique cell signaling regulatory properties independent of antioxidant function. Against the background of clinical failure for high-dose alpha TOC, outcomes of this work identify risk for exacerbating stroke-induced brain injury as a result of supplementing diet with excessive levels of alpha TOC.