Estrogen improves sevoflurane-induced cognitive dysfunction by regulating synaptic zinc homeostasis

Sevoflurane is known to induce cognitive dysfunction, but the underlying mechanisms remain unclear. Recent evidence suggests that disruptions in synaptic zinc homeostasis may contribute to neurotoxicity and cognitive impairment. This study investigates the role of synaptic zinc imbalance in sevoflurane-induced cognitive dysfunction and evaluates the neuroprotective effects of estrogen.

Aged female C57BL/6 mice were exposed to sevoflurane to induce neurotoxicity. Synaptic zinc levels, Tau phosphorylation, synaptic vesicle numbers, neuronal firing frequency, and neuronal damage were assessed. The effects of zinc chelation with CaEDTA and estrogen supplementation on these parameters, as well as cognitive performance in the Morris water maze and Y-maze tests, were evaluated.

Sevoflurane exposure disrupts synaptic zinc homeostasis by upregulating Znt3 expression, leading to increased Tau phosphorylation, reduced synaptic vesicle numbers, decreased neuronal firing frequency, elevated neuronal death, and cognitive impairment. Chelation of zinc with CaEDTA attenuated Tau phosphorylation and neuronal death, enhanced neuronal firing, and improved cognitive function. Estrogen supplementation alleviates synaptic zinc imbalance by downregulating Znt3 expression, thereby reducing Tau phosphorylation and neuronal loss, increasing synaptic vesicle density and neuronal firing frequency, and improving cognitive function.

This study reveals that sevoflurane-induced cognitive dysfunction is closely associated with synaptic zinc imbalance. Estrogen exerts its neuroprotective effects by restoring synaptic zinc homeostasis. These findings provide insights into the pathophysiological mechanisms underlying anesthesia-related cognitive impairment and highlight the therapeutic potential of estrogen in perioperative neuroprotection.