Co-administration of resveratrol and lipoic acid, or their synthetic combination, enhances neuroprotection in a rat model of ischemia/reperfusion.
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.
Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, P.E.I., Canada.
Monique C
MC
Saleh
Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, P.E.I., Canada.
Barry J
BJ
Connell
Carmel BioSciences Inc., Atlanta, Georgia, United States of America.
Desikan
D
Rajagopal
Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, P.E.I., Canada ; Carmel BioSciences Inc., Atlanta, Georgia, United States of America.
Bobby V
BV
Khan
Department of Chemistry, University of Prince Edward Island, Charlottetown, P.E.I., Canada.
Alaa S
AS
Abd-El-Aziz
Department of Chemistry, University of Prince Edward Island, Charlottetown, P.E.I., Canada.
Inan
I
Kucukkaya
Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, P.E.I., Canada.
Tarek M
TM
Saleh
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D013267:Stilbenes; D008063:Thioctic Acid; D000077185:Resveratrol