Nobiletin improves propofol-induced neuroprotection via regulating Akt/mTOR and TLR 4/NF-κB signaling in ischemic brain injury in rats

Background: Stroke is regarded as one of the main health concerns globally, presenting with high mortality and morbidity rates. Cerebral ischemic damage and infarction are critically associated with stroke. Various mechanisms related to inflammation, oxidative stress and excitotoxicity are found to be involved in ischemic damage. Very short time period for treatment has necessitated in development of more effective neuroprotective agents. Study aimed in investigated the effects of nobiletin on experimentally induced ischemic brain injury and also to assess whether nobiletin potentiated the neuroprotective effects of propofol. Methods: Male Sprague-Dawley rats were subjected to ischemia/reperfusion (I/R) injury. Induction of cerebral infarction and I/R was done by middle cerebral artery occlusion (MCAO). Nobiletin (100 or 200 mg/kg b.wt.) was intragastrically administered to rats for 9 days before ischemia induction and on the day of induction nobiletin was administered an hour prior. Separate group of rats were postconditioned with propofol (50 mg/kg/h;i.v.) for 30 min following 24 h of reperfusion. Results: Propofol post-conditioning either with or without administration of nobiletin prior I/R injury attenuated pulmonary edema, neuronal apoptosis and reduced cerebral infarct volume. Overproduction of pro-inflammatory cytokines (TNF-alpha, IL-1 beta and IL-6) and nitric oxide following I/R were reduced. Propofol either alone or with prior nobiletin treatment had down-regulated TLR4 and TLR4-mediated NFkB signaling and caused activation of Akt/mTOR cascade. Conclusion: Propofol post-conditioning either with nobiletin prior I/R injury was found to be more effective than propofol alone, suggesting the positive effects of nobiletin on propofol-mediated anti-inflammatory and neuroprotective effects. (C) 2017 Elsevier Masson SAS. All rights reserved.