title: Excessive α-tocopherol exacerbates microglial activation and brain injury caused by acute ischemic stroke.
abstract: The vitamin E family includes both tocopherols and tocotrienols, where α-tocopherol (αTOC) is the most bioavailable form. Clinical trials testing the therapeutic efficacy of high-dose αTOC 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 αTOC 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 αTOC vitamin E at the equivalent human dose of 1680 IU/d. Ischemic stroke-induced brain injury was exacerbated in the presence of supraphysiologic brain αTOC levels. At 48 h after stroke, S100B and RAGE expression was increased in stroke-affected cortex of mice with elevated brain αTOC 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 αTOC establish that at supraphysiologic levels, αTOC potentiates neuroinflammatory responses to acute ischemic stroke. Exacerbation of microglial activation by excessive αTOC likely depends on its unique cell signaling regulatory properties independent of antioxidant function. Against the background of clinical failure for high-dose αTOC, outcomes of this work identify risk for exacerbating stroke-induced brain injury as a result of supplementing diet with excessive levels of αTOC.
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Mallory
authors.initials: M
authors.lastname: Heigel
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Weist
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Surya
authors.initials: S
authors.lastname: Gnyawali
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Teplitsky
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA cameron.rink@osumc.edu.
authors.forename: Cameron
authors.initials: C
authors.lastname: Rink
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D001930:Brain Injuries / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007511:Ischemia / Q000150:complications* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020521:Stroke / Q000150:complications* / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D024502:alpha-Tocopherol / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D013481:Superoxides; D024502:alpha-Tocopherol
keywords: antioxidant; inflammation; microglia; vitamin