miR-365a-3p Alleviates Isoflurane-Induced Neuroinflammation and Cognitive Impairment by Targeting MyD88 to Inhibit NF-κB Signaling.

Isoflurane (ISO) exposure is associated with neuroinflammation and postoperative cognitive dysfunction (POCD) in aged populations, although the underlying mechanisms remain unclear. This study aimed to determine whether ISO-induced cognitive decline involves miR-365a-3p and its downstream signaling targets. Aged rats were exposed to ISO to establish a POCD model. Cognitive and motor functions were evaluated using Morris water maze tests and neurological scoring. The expression of miR-365a-3p, inflammatory factors, synaptic proteins, and apoptotic markers in the hippocampus was measured by qRT-PCR, ELISA, and Western blotting. In vitro, LPS-treated BV-2 microglia were co-cultured with differentiated SH-SY5Y neurons to assess neuronal apoptosis rate (by flow cytometry) and synaptic integrity. Dual-luciferase reporter assays verified the direct interaction between miR-365a-3p and MyD88. ISO exposure reduced hippocampal miR-365a-3p, resulting in memory/motor deficits, increased pro-inflammatory factors, microglial activation, synaptic protein loss, and neuronal apoptosis. Adding extra miR-365a-3p reversed these problems. LPS treatment reduced miR-365a-3p expression and enhanced pro-inflammatory cytokine production in BV-2 cells, which subsequently induced apoptosis in co-cultured neurons and impaired synaptic integrity. These conditions were reversed by miR-365a-3p overexpression. Mechanistically, miR-365a-3p directly targeted MyD88, inhibiting its expression and downstream NF-κB activation. MyD88 overexpression reversed protective effects of miR-365a-3p on inflammation and synaptic function. ISO causes POCD by reducing miR-365a-3p, which protects the brain by blocking MyD88/NF-κB. Boosting miR-365a-3p may represent a potential strategy to help prevent ISO-related brain harm in elderly patients, warranting further translational investigation.