Boswellic acid and apigenin alleviate methotrexate-provoked renal and hippocampal alterations in rats: Targeting autophagy, NOD-2/NF-κB/NLRP3, and connexin-43

The neuronal and renal deteriorations observed in patients exposed to methotrexate (MTX) therapy highlight the need for medical interventions to counteract these complications. Boswellic acid (BA) and apigenin (APG) are natural phytochemicals with prominent neuronal and renal protective impacts in various ailments. However, their impacts on MTX-provoked renal and hippocampal toxicity have not been reported. Thus, the present work is tailored to clarify the ability of BA and APG to counteract MTX-provoked hippocampal and renal toxicity. BA (250 mg/kg) or APG (20 mg/kg) were administered orally in rats once a day for 10 days, while MTX (20 mg/kg, i.p.) was administered once on the sixth day of the study. At the histopathological level, BA and APG attenuated MTX-provoked renal and hippocampal aberrations. They also inhibited astrocyte activation, as proven by the inhibition of glial fibrillary acidic protein (GFAP). These impacts were partially mediated via the activation of autophagy flux, as proven by the increased expression of beclin1, LC3-II, and the curbing of p62 protein, alongside the regulation of the p-AMPK/mTOR nexus. In addition, BA and APG displayed anti-inflammatory features as verified by the damping of NOD-2 and p-NF-κB p65 to reduce TNF-α, IL-6, and NLRP3/IL-1β cue. These promising effects were accompanied with a notable reduction in one of the gap junction proteins, connexin-43 (Conx-43). These positive impacts endorse BA and APG as adjuvant modulators to control MTX-driven hippocampal and nephrotoxicity.