Chrysophanol Attenuates Cognitive Impairment, Neuroinflammation, and Oxidative Stress by TLR4/ NFκB-Nrf2/HO-1 Signaling in Ethanol-Induced Neurodegeneration

Ethanol-induced neurodegeneration refers to the progressive loss of structure and function of neurons caused by chronic ethanol consumption. According to the World Health Organization (WHO), over 2.3 billion people globally consume alcohol. This contributes to a significant amount of alcohol-related brain damage. This study evaluated the effect of chrysophanol in ethanol-induced neurodegeneration. Mice were administered 10 mg/kg i.p. chrysophanol, 30 min after a 2 g/kg i.p. injection of ethanol, for 11 days. Y-maze, Morris water maze (MWM), and novel object recognition (NOR) test were carried out to analyze learning and memory impairment. Analysis of antioxidant levels, histopathological examinations, measurement of COX-2 & NLRP3 using ELISA, and gene expression analysis of TLR4, NFκB, IL-1β, TNF-α, Caspase-3, and Nrf-2, HO-1, and in hippocampus and cortex using RT-PCR, as well as DNA damage by comet assay, were carried out. Chrysophanol has shown a remarkable impact in reversing cognitive decline and spatial memory. It effectively boosted antioxidant levels such as GSH, GST, and CAT, while simultaneously reducing the levels of MDA and NO. The histopathological analysis also showed improvement in overall morphology and survival of neurons. Chrysophanol treatment effectively showed an increase in the expression of HO-1 and Nrf-2, with a decrease in TLR4, NFκB, IL-1β, TNF-α, and Caspase-3 expression confirmed through RT-PCR. Production of inflammatory cytokines and apoptotic gene expression was successfully reversed after chrysophanol treatment. COX-2 & NLRP3 levels decreased, and an improvement in DNA damage was observed after chrysophanol treatment. In conclusion, chrysophanol demonstrated remarkable neuroprotective activity against ethanol-induced neurodegeneration.