Effects of Dictyophora polysaccharide on cerebellar Purkinje cell degeneration in a chronic alcohol mouse model.

Abstract

Background: Recent research showed that the NLRP3 inflammasome was activated in the central nervous system of mice administered chronic ethanol (EtOH). Dictyophora polysaccharides (DIPs) are essential components of the valuable edible fungus Dictyophora, which has antioxidant properties that can delay the aging process of the body. This study aimed to investigate the roles of NLRP3 in chronic EtOH-induced cerebellar Purkinje cell (PC) degeneration and behavioral changes.

Methods: C57BL/6J normal and NLRP3 knockout mice were exposed to EtOH for 14 days. Dictyophora polysaccharide (DIP) and NLRP3 inhibitor were administered to the EtOH mice. The pathology and NLRP3-ASC-caspase-1 signaling pathway proteins were analyzed in EtOH mice cerebellar tissues and behavioral performance was assessed in the mice.

Results: In the EtOH mouse model, we observed increases in the NLRP3 inflammasome proteins, including NLRP3, ASC, caspase-1, mature IL-1β and pro IL-1β, loss of PCs, and motor coordination disorders. We found that DIPs could suppress the NLRP3-ASC-caspase-1 signaling pathway, and alleviate the motor deficits and cerebellar pathological changes in chronic EtOH mice. Next, we used MCC950, a NLRP3 inhibitor, and an NLRP3 knockout strategy to further verify the effects of NLRP3-ASC-caspase-1 signaling in chronic EtOH mice. MCC950 or NLRP3 knockout alleviated the EtOH-induced latency to decreases in fall time, increases in stride width and decreases in stride length. MCC950 or NLRP3 knockout also attenuated PC number loss and suppressed NLRP3 inflammation induced by EtOH. Taken together, pharmacologically or genetically inhibiting NLRP3 alleviated EtOH-induced cerebellar degeneration and behavioral deficits.

Conclusion: These findings indicated that DIPs might diminish EtOH-induced cerebellar degeneration and behavioral deficits through the NLRP3-ASC-caspase-1 signaling pathway, which provides a potential therapeutic target for the prevention and treatment of alcoholism and EtOH-induced cerebellar pathology.