Fasudil Alleviates Postoperative Neurocognitive Disorders in Mice by Downregulating the Surface Expression of α5GABAAR in Hippocampus.

Abstract

Postoperative neurocognitive disorder (PND) refers to the cognitive impairment experienced by patients after surgery. As a target of sevoflurane, a kind of inhalation anesthetic, the balance of the GABAergic system can be disrupted during the perioperative period. In this study, we explored the promoting effect of abnormal elevation of the α5 subtype of γ-aminobutyric acid type A (GABAA) receptors caused by sevoflurane and surgical trauma on PND, as well as the therapeutic effect of fasudil on PND. Eight-week-old mice were pretreated with fasudil, and after 10 days, sevoflurane-induced femoral fracture surgery was performed to establish an animal model of PND. The Morris water maze and fear conditioning tests were used to evaluate PND induced by this model. Biochemical and electrophysiological analyses were conducted to assess the protective effect of fasudil on the GABAergic system. Following artificial fracture, the hippocampus-dependent memory was damaged in these mice. Fasudil pretreatment, however, ameliorated cognitive function impairment in mice induced by sevoflurane and surgery. Mechanistically, fasudil was found to restore the increased hippocampus expression and function of α5GABAARs in mice with PND. In addition, pretreatment with Fasudil inhibited the enhancement in the calcium ion concentration and phosphorylation of Camk2, as well as the activation of the Radixin pathway which led to increased phosphorylation of the ERM family in the hippocampal CA1 region of the PND model. Preadministration of fasudil improved postoperative cognitive function in PND mice by inhibiting the activation of Camk2 and Radixin pathways and finally downregulating the surface expression of α5GABAAR in hippocampus neurons.