Inhibition of Peripheral TNF-α and Downregulation of Microglial Activation by Alpha-Lipoic Acid and Etanercept Protect Rat Brain Against Ischemic Stroke

Mol Neurobiol. 2016 Sep;53(7):4961-71. doi: 10.1007/s12035-015-9418-5. Epub 2015 Sep 15.

Abstract

Ischemic stroke, caused by obstruction of blood flow to the brain, would initiate microglia activation which contributes to neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation could be a therapeutic strategy for ischemic stroke. This study was aimed to elucidate the anti-inflammatory effects of alpha-lipoic acid and etanercept given either singly or in combination in rats subjected to middle cerebral artery occlusion. Both α-lipoic acid and etanercept markedly reduced cerebral infarct, blood-brain barrier disruption, and neurological motor deficits with the former drug being more effective with the dosage used. Furthermore, when used in combination, the reduction was more substantial. Remarkably, a greater diminution in the serum levels of tumor necrosis factor-alpha as well as the brain levels of microglial activation (e.g., microgliosis, amoeboid microglia, and microglial overexpression of tumor necrosis factor-α) was observed with the combined drug treatment as compared to the drugs given separately. We conclude that inhibition of peripheral tumor necrosis factor-alpha as well as downregulation of brain microglial activation by alpha-lipoic acid or etanercept protect rat brain against ischemic stroke. Moreover, when both drugs were used in combination, the stroke recovery was promoted more extensively.

Keywords: Activated microglia; Cerebral ischemia; Etanercept; Stroke recovery; α-Lipoic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / administration & dosage
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Brain Ischemia / prevention & control
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Drug Therapy, Combination
  • Etanercept / administration & dosage*
  • Male
  • Neuroprotective Agents / administration & dosage
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Stroke / metabolism*
  • Stroke / pathology
  • Stroke / prevention & control
  • Thioctic Acid / administration & dosage*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Antioxidants
  • Neuroprotective Agents
  • Tumor Necrosis Factor-alpha
  • Thioctic Acid
  • Etanercept