Co-Administration of Resveratrol and Lipoic Acid, or Their Synthetic Combination, Enhances Neuroprotection in a Rat Model of Ischemia/Reperfusion

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.

The neuroprotective effects of resveratrol preconditioning in transient global cerebral ischemia-reperfusion in mice

“…Resveratrol also regulates the expression of various proteins associated with oxidative stress and energy metabolism in focal cerebral ischemia (25). Furthermore, resveratrol can enhance the neuroprotection when coadministrated with lipoic acid in cerebral ischemia (24). In the present study, we first established the model of BCCAO, and then we found that resveratrol pretreatment could protect the brain from ischemic injury, which is associated with its antiapoptotic effect.…”

Neuroprotective effect of safranal, an active ingredient of Crocus sativus , in a rat model of transient cerebral ischemia

“…Despite the ongoing advances in the field of stroke research, consequences of death and disability have remained considerable throughout the world and delivery of successful therapeutics is still a challenge [23,26]. Treatment outcomes for ischemic events involve the restoration of blood supply to an ischemic tissue.…”

UPEI-400, a Conjugate of Lipoic Acid and Scopoletin, Mediates Neuroprotection in a Rat Model of Ischemia/Reperfusion

“…We have previously published the detailed methodology for occlusion of the middle cerebral artery [12,13,32,33] in both permanent (pMCAO) and transient (tMCAO) models.…”

“…Thus, there has been a recent interest in the use of co-drugs as a therapeutic approach in various pathologies [9,10]. The development and administration of a co-drug, containing lipoic acid (LA) covalently linked to another compound, have been demonstrated to have a greater efficacy/potency compared to the administration of a mixture of the two drugs [11,12,13,14,15,16]. The antioxidant LA, is a known free radical scavenger [17,18], and many researchers have shown that in several different stroke models administration of lipoic acid on its own can be neuroprotective but only at relatively high doses [19,20,21,22,23,24].…”

“…Further, combining lipoic acid with other drugs has been shown to produce an additive or synergistic protective effect in several different animal models of pathology [25,26,27,28,29,30,31], when compared to the effect of either drug alone. Our laboratory has demonstrated that LA covalently bonded to various naturally occurring antioxidant compounds has provided superior neuroprotection following I/R injury compared to either drug alone or a mixture of 2 compounds administered simultaneously [11,12,13,14,32]. Based on the above observations demonstrating the beneficial effects of developing a co-drug, our laboratory has developed a new synthetic co-drug that is a covalent conjugate between LA and scopoletin, named UPEI-400.…”