Systemic administration of the dietary constituent resveratrol inhibits the nociceptive jaw-opening reflex in rats via the endogenous opioid system.

The aim of the present study was to investigate whether, under in vivo conditions, systemic administration of resveratrol could attenuate the rat nociceptive jaw-opening reflex (JOR) via the endogenous opioid system. The JOR evoked by electrical stimulation of the tongue was recorded as digastric muscle electromyograms (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG increased significantly in proportion to the intensity of electrical stimulation (from 1× to 5 × threshold for the JOR). dEMG amplitude in response to 3× threshold electrical stimulation of the tongue was dose-dependently inhibited by intravenous administration of resveratrol (0.5-2mg/kg). Maximum inhibition of dEMG amplitude was seen within approximately 10min. These inhibitory effects were reversible, with dEMG responses returning to control levels after approximately 20min. Pretreatment of rats with naloxone resulted in significant, dose-dependent attenuation of the inhibitory effects of resveratrol on dEMG amplitude compared with control. These findings suggest that resveratrol inhibits the nociceptive JOR via the endogenous opioid system. Further, the findings of the present study strongly support the idea that resveratrol, which is not known to have any toxic side effects, combined with an opioid could be a potential therapeutic agent for the prevention of acute trigeminal nociception.

Insulin and resveratrol act synergistically, preventing cardiac dysfunction in diabetes, but the advantage of resveratrol in diabetics with acute heart attack is antagonized by insulin.

Resveratrol (RSV), a natural phenolic compound, has been found to display cardiovascular protective and insulin-sensitizing properties. In this study, the effects of RSV and its combination with insulin on mortality, hemodynamics, insulin signaling, and nitrosative stress were compared in streptozotocin (STZ)-induced diabetic rats with or without acute myocardial ischemia/reperfusion (I/R) injury. Under normoxic conditions, cardiac systolic and diastolic functions and insulin-mediated Akt/GLUT4 (glucose transporter 4) activation were impaired in STZ-diabetic rats. The combination of RSV and insulin significantly prevented the above diabetes-associated abnormalities. Notwithstanding that, the diabetic state rendered the animals more susceptible to myocardial I/R injury, and the mortality rate and inducible nitric oxide synthase (iNOS)/nitrotyrosine protein expression and superoxide anion production were also further increased in I/R-injured diabetic hearts. In contrast, RSV treatment alone resulted in a lower mortality rate (from 62.5 to 18%) and better cardiac systolic function than its combination with insulin. RSV also inhibited iNOS/nitrotyrosine protein overexpression and superoxide anion overproduction in I/R-injured diabetic myocardium. Hyperglycemia, impairment of insulin signaling, overexpression of iNOS/nitrotyrosine, and superoxide anion overproduction were markedly rescued by the combination treatment, which did not show an improvement in mortality rate (30%) or cardiac performance over RSV treatment alone. These results indicate that insulin and RSV synergistically prevented cardiac dysfunction in diabetes and this may be in parallel with activation of the insulin-mediated Akt/GLUT4 signaling pathway. Although activation of the protective signal (Akt/GLUT4) and suppression of the adverse markers (iNOS, nitrotyrosine, and superoxide anion) were simultaneously observed in insulin and RSV combination treatment, insulin counteracted the advantage of RSV in diabetics with acute heart attack.

Tetrahydroxystilbene glucoside ameliorates diabetic nephropathy in rats: involvement of SIRT1 and TGF-ß1 pathway.

Oxidative stress caused by hyperglycaemia is believed to be a major molecular mechanism underlying diabetic nephropathy. 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside (TSG), an active component extract from Polygonum multiflorum Thunb, exhibits antioxidative and anti-inflammatory effects. Possible protective mechanisms of TSG on diabetic nephropathy were investigated in rats and cultured rat mesangial cells. Total cholesterol and triglyceride levels of diabetic rats were clearly increased and these increases were diminished by treatment with TSG. Treatment of diabetic rats with TSG also significantly reduced blood urea nitrogen, creatinine, 24 h urinary protein levels, and kidney weight/body weight. The activities of superoxide dismutase and glutathione peroxidase in renal homogenate were increased markedly, whereas malonaldehyde levels were decreased significantly in TSG-treated diabetic rats. TSG dramatically inhibited diabetes-induced overexpression of TGF-ß1 and COX-2, and restored the decrease of SIRT1 expression in diabetic rats. High glucose-induced overexpression of TGF-ß1 in cultured mesangial cells was significantly inhibited, whereas the decease of SIRT1 expression was restored by pretreatment of TSG. Nicotinamide, the inhibitor of SIRT1, partially relieved the inhibitory effect of TSG on TGF-ß1 expression under high glucose condition. These findings indicate that the protective mechanisms of TSG on diabetic nephropathy are involved in the alleviation of oxidative stress injury and overexpression of COX-2 and TGF-ß1, partially via activation of SIRT1.

Antinociceptive effect of trans-resveratrol in rats: Involvement of an opioidergic mechanism.

trans-Resveratrol, a polyphenolic compound with potent antioxidant activity has recently been shown to be effective against carrageenan-induced hyperalgesia. In the present study, the effect of graded doses of trans-resveratrol was studied using a hot plate analgesiometer in rats. trans-Resveratrol at graded doses of 5, 10, 20 and 40 mg/kg i.p. produced dose-dependent analgesia. Pretreatment (20 min) with naloxone (1 mg/kg i.p.) blocked the analgesic effect. When the submaximal dose of trans-resveratrol (5 mg/kg i.p.) was combined with a submaximal dose of morphine (2 mg/kg i.p.), a potentiation effect was observed. The effect of trans-resveratrol (20 mg/kg i.p.) was also studied on morphine tolerance. Rats were divided into different groups: Group 1: morphine (10 mg/kg i.p.); Group 2: trans-resveratrol (5 mg/kg i.p.) administered 10 min before morphine (2 mg/kg i.p.); Group 3: trans-resveratrol (20 mg/kg i.p.) per se. Vehicle treated groups were run parallel. The treatment continued for 7 days. The occurrence of tolerance was estimated by comparing the antinociceptive effect of morphine with trans-resveratrol on day 1 and day 8. Both morphine and trans-resveratrol produced tolerance. However, in the group that received the combination of submaximal doses of trans-resveratrol and morphine, there was insignificant tolerance. These findings suggest that trans-resveratrol analgesia is mediated via an opioidergic mechanism and produces tolerance to its analgesic effect similar to morphine.

External anions relieve DIDS inhibition of SO4 efflux from placental membrane vesicles.

Sulphate efflux from human placental microvillus membrane vesicles was inhibited by external DIDS (KI congruent to 10(-6) M). This inhibition was partially reversed on addition of the translocated substrates sulphate or selenate to the external medium: selenite which is not translocated does not protect against DIDS inhibition. These findings show that the mechanism responsible for sulphate efflux can be modified by substrate in the external medium.