Noncanonical sustained actions of propofol reverse surgery-induced microglial activation and cognitive impairment in...

Perioperative neurocognitive disorder is a major concern in aged individuals, and currently, treatment options are limited. Chronic intermittent propofol (CIP) has been shown to have neuroprotective effects in aged mice and in a mouse model of Alzheimer's disease. Here, we investigated whether CIP could reverse surgery-induced cognitive deficits and propose a mechanism of action. Male and female mice (21-24 months old) underwent exploratory laparotomy under isoflurane anesthesia. Animals were administered either CIP (75 mg/kg i.p.) or vehicle every fifth day throughout the experiment. Cognitive function was assessed using a battery of behavioral tests: the Y-maze test (spatial working memory), the novel object recognition test (recognition memory), the Morris water maze (spatial learning and memory), and trace and contextual fear conditioning (nondeclarative associative memory). Expression of α5-GABA_A receptors, markers of apoptosis, and a microglial activation marker were assessed in the hippocampus using western blotting. The amount of α5-GABA_A receptor subunits in cell-surface membranes was determined by biotinylation followed by western blotting. CIP induced a sustained redistribution of α5-GABA_A receptors to the cell-surface membranes. Laparotomy led to an increased expression of the microglial activation marker Iba-1 and of proapoptotic markers, and impaired cognitive functions. CIP prevented these molecular and cognitive changes. Perioperative CIP redistributes α5-GABA_A receptors to cell-surface membranes and thus prevents or reverses surgery-induced increases in markers of microglial activation, apoptosis, and cognitive dysfunction. Increasing the number or activity of α5-GABA_A receptors on cell-surface membranes may be an effective therapeutic strategy to reduce postoperative morbidity in elderly patients.