右美托咪定通过调控MeCP2/NLGN1通路减轻脓毒症相关炎症与脑病

PURPOSE: Sepsis-associated encephalopathy (SAE) is a common and serious complication in septic patients that significantly reduces quality of life. Besides its sedative and analgesic effects, dexmedetomidine has been suggested to have potential neuroprotective benefits. This study aims to determine whether dexmedetomidine guards against cognitive dysfunction in a murine model of sepsis and to investigate the possible role of the MeCP2/NLGN1 signaling pathway in this neuroprotection.

METHODS: An animal model of SAE was established by cecal ligation and puncture (CLP). Sham-operated mice underwent the same surgical procedure but without ligation or puncture. Mice in the Dex-treated group received intraperitoneal administration of Dex (25µg/kg) once daily for three consecutive days, starting immediately after CLP. Selective knockdown of MeCP2 in the hippocampal CA1 region was achieved via adeno‑associated virus (AAV)‑mediated RNA interference. Between postoperative days 14 and 17, a series of behavioral tests-including the open field, novel object recognition, and Y-maze tests-were conducted to evaluate locomotor activity and cognitive function. Hippocampal expression of MeCP2 and NLGN1 proteins was analyzed by Western blot. Immunofluorescence staining was used to assess microglia activation and neuronal activity. Levels of inflammatory cytokines in the serum and hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). In addition, dendritic spine density and morphology were assessed using Golgi staining.

RESULTS: In mice subjected to CLP, cognitive deficits were associated with increased levels of inflammatory factors in both the serum and hippocampus, aberrant microglial activation, upregulation of MeCP2 protein, and downregulation of NLGN1. These alterations contributed to reduced neuronal activity and a decrease in dendritic spine density. Selective knockdown of MeCP2 in the hippocampal CA1 region reversed NLGN1 downregulation and ameliorated cognitive dysfunction, confirming the pathogenic role of the MeCP2/NLGN1 pathway in SAE‑associated cognitive impairment. Treatment with Dex attenuated the inflammatory response, normalized MeCP2/NLGN1 expression, and reversed the aforementioned pathological changes.

CONCLUSION: The neuroprotective effects of Dex, which include the attenuation of neuroinflammation and improvement of synaptic plasticity and cognitive function in SAE mice, are associated with the regulation of the hippocampal MeCP2/NLGN1 signaling pathway.