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.
Highlights
Despite ongoing advances in the arena of stroke research, the worldwide consequences of death and disability remain considerable and delivery of successful therapeutics continues to present a challenge
Treatment outcomes for ischemic events involves the reestablishment of blood flow to compromised tissue, with the reintroduction of oxygen transiently adding to the injury due to generation of inflammatory mediators and toxic levels of oxidative free radicals [2] culminating in lipid peroxidation, protein synthesis arrest, and cell death [3]
Resveratrol or vehicle was injected during MCAO or during the period of reperfusion (Figure 2)
Summary
Despite ongoing advances in the arena of stroke research, the worldwide consequences of death and disability remain considerable and delivery of successful therapeutics continues to present a challenge. The application of combinatorial drug therapy in treating stroke has become increasingly attractive in recent years. As researchers uncover the complexity of disease progression following stroke which includes both immediate as well as delayed neuronal effects at multiple levels [1], it has become evident that multi-targeted drug therapy may hold more promise in the treatment and/or prevention of stroke than conventional single class drug regimens. There is evidence that some drug combinations display pharmacological potentiation (ie synergism) which optimistically translates into lower doses, fewer adverse side effects and an extended treatment window. Successful treatment options are required to address several critical mediators of neuronal death simultaneously
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