Poster Session 1 - B15
1Shahin Khodaei, 1Yu-Feng Xie, 1Dian-Shi Wang, 1,2,3Beverley Orser
1 Dept. of Physiology, University of Toronto; 2 Dept. of Anesthesia, University of Toronto; 3 Dept. of Anesthesia, Sunnybrook Hospital
Introduction: Cognitive impairments following anesthesia and surgery are common. These deficits, seen in 30% of patients at the time of hospital discharge and 10% at three months after surgery, are associated with adverse outcomes and increased healthcare costs (Anesthesiology, 2008). The etiology of these impairments is poorly understood and likely multifactorial. A growing body of preclinical evidence suggests both inflammation and anesthetic agents may be important contributors to the development of these cognitive deficits. In laboratory animals, inflammation prior to surgery worsened cognitive performance in the postoperative period (PLoS One, 2017). Also, treatment with anesthetic drugs, such as etomidate, induced cognitive deficits that persisted long after the drug had been eliminated (J Clin Invest, 2014). Interestingly, our lab has shown that dysregulation of alpha-5 subunit-containing gamma-aminobutyric acid type A (a5GABA-A) receptors underlies both inflammation- and anesthetic-induced cognitive deficits (Cell Rep, 2012; J Clin Invest, 2014). Given this common mechanism, we hypothesized that pre-existing inflammation exacerbates cognitive dysfunction following etomidate-induced anesthesia.
Methods: Experiments were approved by the local animal care committee. Adult male mice were injected with lipopolysaccharide (LPS; 1 mg/kg, i.p) or vehicle (saline, 0.9%) to induce inflammation. Twenty-four hours later, mice were treated with a single anesthetic dose of etomidate (20 mg/kg, i.p) or vehicle (propylene glycol, 35% v/v saline). The acute neurodepressive properties of etomidate were assessed by measuring the latency to loss of righting reflex (LORR) and the duration of LORR. On Day 1 after etomidate, memory was assessed with the novel object recognition (NOR) assay. On Days 2-4 after etomidate, problem solving was assessed using the puzzle box (PB) assay. Statistical analyses were conducted using GraphPad Prism 7.
Results: LPS slightly reduced the latency to LORR, and significantly increased the duration of LORR in etomidate-treated animals. Mice injected with etomidate and/or LPS showed memory impairments, as seen by reduced preference for the novel object in the NOR assay. Additionally, LPS-treated mice showed a decreased total interaction time with the objects. On Trials 1 and 8 of the PB assay, mice treated with LPS + etomidate showed impaired problem-solving, exhibited by greater latency to complete the task, whereas mice injected with etomidate or LPS alone showed no impairment.
Conclusion: Pre-existing inflammation markedly impairs cognitive ability after a single dose of etomidate. Ongoing studies will determine whether inhibitors of a5GABA-A receptors reverse the behavioural deficits.