Chronic intermittent propofol attenuates surgery-induced neuroinflammation, apoptosis, and cognitive impairment in aged mice

Background: Postoperative neurocognitive disorder (poNCD), previously also referred to as postoperative cognitive dysfunction (POCD) following surgery and anesthesia, is a significant public health problem in patients over 60 years. Propofol is the most commonly used intravenous anesthetic, acting primarily via GABAA receptors. However, it has also been shown to have apparent neuroprotective effects in aged mice and mouse models of Alzheimer s disease. Therefore, we postulated that chronic intermittent propofol would attenuate the development of postoperative cognitive deficits in aged mice. Methods: Abdominal surgery was performed under isoflurane anesthesia in 21-24 months-old mice. Animals received either chronic intermittent propofol (CIP, 75 mg/kg i.p.) or vehicle (IntralipidR) every 5th day throughout the experiment, starting 17 days before surgery. The levels of alpha5 GABAA receptors on cell surface membranes, as well as behavioral or biochemical manifestations of poNCD were studied. Results: CIP led to a sustained redistribution of the GABAA receptor alpha5-subunit to the cell surface membranes. Laparotomy impaired learning and memory functions, as determined using a behavioral test battery that included Y maze alternation, novel object recognition, water maze learning and reversal learning, and cued and contextual fear conditioning, compared to no surgery controls. Strikingly, CIP strongly attenuated the surgery-induced memory impairment. Western blots on hippocampal tissues showed increased expression of the pro-apoptotic markers cleaved caspase-3, cleaved caspase-9, and Bax, indicating that abdominal surgery promoted apoptosis. Moreover, surgery increased expression of Iba-1, a marker of microglial activation. Chronic intermittent propofol prevented this proapoptotic and microglial activation. Conclusions: Our results suggest that propofol - via mechanisms not fully understood, potentially via the sustained increased availability of alpha5-GABAA receptors on cell surface membranes - improves cognitive function by attenuating surgery-induced neuroinflammation and caspase activation and/or independently of this by rebalancing neuronal inhibition in aged mice. These findings support a therapeutic potential of perioperative propofol or of other compounds leading to a sustained redistribution of alpha5-GABAA receptors to the cell surface membranes in the perioperative period for reducing the risk of surgery-induced cognitive decline in aged individuals. ### Competing Interest Statement The authors have declared no competing interest.