Salidroside Derivative SHPL-49 Exerts Anti-Neuroinflammatory Effects by Modulating Excessive Autophagy in Microglia

The neuroinflammation triggered by cellular demise plays a pivotal role in ameliorating the injury associated with ischemic stroke, which represents a significant global burden of mortality and disability. The compound SHPL-49, a derivative of rhodioloside, was discovered by our research team and has previously demonstrated neuroprotective effects in rats with ischemic stroke. This study aimed to elucidate the underlying mechanisms of SHPL-49's protective effects. Preliminary investigations revealed that SHPL-49 effectively alleviates PMCAO-induced neuroinflammation. Further studies indicated that SHPL-49 downregulates the expression of the lysosomal protein LAMP-2 and reduces lysosomal activity, impeding the fusion of lysosomes and autophagosomes, thus inhibiting excessive autophagy and increasing the expression levels of the autophagy proteins LC3-II and P62. Furthermore, SHPL-49 effectively reverses the NF-κB nuclear translocation induced by the autophagy inducer rapamycin, significantly lowering the expression levels of the inflammatory factors IL-6, IL-1β, and iNOS. In a co-culture system of BV2 and PC12 cells, SHPL-49 enhanced PC12 cell viability by inhibiting excessive autophagy in BV2 cells and reducing the ratio of apoptotic proteins Bax and BCL-2. The overall findings suggest that SHPL-49 exerts its neuroprotective effects through the inhibition of excessive autophagy and the suppression of the NF-κB signaling pathway in microglia, thereby attenuating neuroinflammation.