الفهرس 
Mechanistic Study of Paracetamol Role in Ameliorating Cerebral Ischemia Reperfusion Injury in Rats
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Abstract
Paracetamol (PAR) has been used to mitigate stroke-associated hyperthermia and its associated deleterious effects. Alongside, it is reported that PAR enhances cannabinoid receptor (CB1) activation through AM404 metabolite, the anandamide transporter blocker. However, to the best of our knowledge, the role of PAR/AM404/CB1 axis in stroke has not been studied yet.The present study aimed to decipher the neuroprotective effect of PAR in cerebral ischemia/reperfusion (IR) rat model and unmask its link with AM404/CB1/PI3K/Akt axis. Animals were allocated into 5 groups: (I) SO; (II) IR; (III) IR + PAR (100 mg/kg); (IV) IR + PAR (100 mg/kg) + 0.3 mg/kg URB597 (anandamide degrader inhibitor); and (V) IR + PAR (100 mg/kg) + 5 mg/kg AM4113 (CB1 receptor blocker). All drugs were administered intraperitoneally prior to the reperfusion period. PAR was able to alleviate the cognitive impairment as confirmed by Morris water maze test, histopathological examination of hippocampal specimens and immunohistochemical examination of glial fibrillary acidic protein (GFAP).PAR resulted in increased level of anandamide, expression of CB1 receptor and the survival proteins pS⁴⁷³-Akt, P (tyr202/thr204)-ERK1/2 and pS⁹-GSK3Ý.These findings were paralleled by the observable increase in the expression of hippocampal brain-derived neurotrophic factor and Ý-arrestin1 Abstract ii alongside a decrease in the level of glutamate. Moreover, PAR was able to restore oxidative stress as reflected by dampening lipid peroxide level, myeloperoxidase activity, NF-mB expression while increasing total antioxidant capacity and the levels of glutathione level, nitric oxide and nuclear factor erythroid 2-related factor 2 (Nrf2). Interestingly, all these effects were abolished by pre-administration of the CB-1 blocker, AM4113. Collectively, PAR showed a significant neuroprotective effect in cerebral ischemia/reperfusion model that could be mediated, at least in part, via activation of the endocannabinoid signaling pathway, anandamide/CB1/PI3K/Akt