Therapeutic Effects of Pretreatment with Tocovid on Oxidative Stress in Postischemic Mice Brain

J Stroke Cerebrovasc Dis. 2018 Aug;27(8):2096-2105. doi: 10.1016/j.jstrokecerebrovasdis.2018.03.012. Epub 2018 May 21.

Abstract

Background: Dietary supplement is an attempt to reduce the risk of ischemic stroke in high-risk population. A new mixed vitamin E-Tocovid that mainly contains tocotrienols other than tocopherol, attenuated the progression of white matter lesions by oral in humans. However, the effect of Tocovid on ischemic stroke has not been examined. In the present study, we assessed the therapeutic effects of Tocovid pretreatment on transient middle cerebral artery occlusion (tMCAO) in mice.

Materials and methods: After pretreatment with Tocovid (200 mg/kg/d) or vehicle for 1 month, 60-minute tMCAO was performed, and these mice were examined at 1 day, 3 days, and 7 days after reperfusion. We histologically assessed the effects of Tocovid pretreatment on the expressive changes of oxidative stress markers, cleaved caspase-3, and LC3-II after tMCAO in mice.

Results: We observed that Tocovid pretreatment significantly improved the rotarod time, reduced infarct volume, decreased the number of 4-HNE, nitrotyrosine, and 8-OhdG positive cells, inhibited advanced glycation end products biomarkers RAGE, CMA, and CML expressions, and increased Nrf2 and MRP1 levels with GSSG/GSH ratio decrease. Furthermore, Tocovid pretreatment greatly decreased cleaved caspase-3 and LC3-II expressions after tMCAO.

Conclusions: The present study obviously demonstrated that Tocovid pretreatment showed neuroprotective effects against oxidative stress and at least in part by antiapoptotic/autophagic cell death in ischemic mice brain.

Keywords: Apoptosis; Tocovid; autophagic cell death; ischemic stroke; oxidative stress.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Glutathione / metabolism
  • Glycation End Products, Advanced / metabolism
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Male
  • Mice, Inbred ICR
  • Microtubule-Associated Proteins / metabolism
  • Multidrug Resistance-Associated Proteins / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Random Allocation
  • Rotarod Performance Test
  • Time Factors
  • Tocotrienols / pharmacology*

Substances

  • Antioxidants
  • Glycation End Products, Advanced
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Multidrug Resistance-Associated Proteins
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse
  • Tocotrienols
  • Tocovid
  • CASP3 protein, human
  • Caspase 3
  • Glutathione
  • multidrug resistance-associated protein 1