Co-administration of resveratrol and lipoic acid, or their synthetic combination, enhances neuroprotection in a rat model of ischemia/reperfusion

PLoS One. 2014 Jan 31;9(1):e87865. doi: 10.1371/journal.pone.0087865. eCollection 2014.

Abstract

The present study demonstrates the benefits of combinatorial antioxidant therapy in the treatment of ischemic stroke. Male Sprague-Dawley rats were anaesthetised and the middle cerebral artery (MCA) was occluded for 30 minutes followed by 5.5 hours of reperfusion. Pretreatment with resveratrol 30 minutes prior to MCA occlusion resulted in a significant, dose-dependent decrease in infarct volume (p<0.05) compared to vehicle-treated animals. Neuroprotection was also observed when resveratrol (2 × 10(-3) mg/kg; iv) was administered within 60 minutes following the return of blood flow (reperfusion). Pretreatment with non-neuroprotective doses of resveratrol (2 × 10(-6) mg/kg) and lipoic acid (LA; 0.005 mg/kg) in combination produced significant neuroprotection as well. This neuroprotection was also observed when resveratrol and LA were administered 15 minutes following the onset of MCA occlusion. Subsequently, we synthetically combined resveratrol and LA in both a 1 ∶ 3 (UPEI-200) and 1 ∶ 1 (UPEI-201) ratio, and screened these new chemical entities in both permanent and transient ischemia models. UPEI-200 was ineffective, while UPEI-201 demonstrated significant, dose-dependent neuroprotection. These results demonstrate that combining subthreshold doses of resveratrol and LA prior to ischemia-reperfusion can provide significant neuroprotection likely resulting from concurrent effects on multiple pathways. The additional protection observed in the novel compound UPEI 201 may present opportunities for addressing ischemia-induced damage in patients presenting with transient ischemic episodes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / physiopathology
  • Disease Models, Animal
  • Humans
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / physiopathology
  • Resveratrol
  • Stilbenes / pharmacology*
  • Stroke / drug therapy*
  • Stroke / physiopathology
  • Thioctic Acid / pharmacology*

Substances

  • Antioxidants
  • Stilbenes
  • Thioctic Acid
  • Resveratrol

Grants and funding

This work was supported by the Atlantic Canada Opportunities Agency Atlantic Innovation fund (AIF; file #1999294). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.