Role of PI3K/Akt axis in mitigating hippocampal ischemia-reperfusion injury via CB1 receptor stimulation by paracetamol and FAAH inhibitor in rat

Acetaminophen or paracetamol (PAR), the recommended antipyretic in COVID-19 and clinically used to alleviate stroke-associated hyperthermia interestingly activates cannabinoid receptor (CB1) through its AM404 metabolite, however, to date, no study reports the in vivo activation of PAR/AM404/CB1 axis in stroke. The current study deciphers the neuroprotective effect off PAR in cerebral ischemia/reperfusion (IR) rat model and unmasks its link with AM404/CB1/PI3K/Akt axis.Animals were allocated into 5 groups: (I) sham-operated (SO), (II) IR, (III) IR + PAR (100 mg/kg), (IV) IR + PAR (100 mg/kg) + URB597; anandamide degradation inhibitor (0.3 mg/kg) and (V) IR + PAR (100 mg/kg) + AM4113; CB1 Blocker (5 mg/kg). All drugs were intraperitoneally administered at the inception of the reperfusion period.PAR administration alleviated the cognitive impairment in the Morris Water Maze as well as hippocampal histopathological and immunohistochemical examination of GFAP. The PAR signaling was associated with elevation of anandamide level, CB1 receptor expression and survival proteins as pS473-Akt. P(tyr202/thr204)-ERK1/2 and pS9-GSK3β. Simultaneously, PAR increased hippocampal BDNF and β-arrestin1 levels and decreased glutamate level. PAR restores the deranged redox milieu induced by IR Injury, by reducing lipid peroxides, myeloperoxidase activity and NF-κB and increasing NPSH, total antioxidant capacity, nitric oxide and Nrf2 levels. The pre-administration of AM4113 reversed PAR effects, while URB597 potentiated them.PAR poses a significant neuroprotective effect which may be mediated, at least in part, via activation of anandamide/CB1/PI3K/Akt pathway in the IR rat model.