Critical role of inflammatory cytokines in impairing biochemical processes for learning and memory after surgery in rats

Abstract

BackgroundPatients with postoperative cognitive dysfunction have poor outcomes. Neuroinflammation may be the underlying pathophysiology for this dysfunction. We determined whether proinflammatory cytokines affect the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors to the plasma membrane, a fundamental biochemical process for learning and memory.MethodsFour-month-old male Fischer 344 rats were subjected to right carotid exposure under isoflurane anesthesia. Some rats received intravenous lidocaine infusion during anesthesia. Rats were tested two weeks later by Barnes maze. The hippocampus was harvested six hours after the surgery for western blotting of interleukin (IL)-1β or IL-6. Hippocampal slices were prepared from control rats or rats subjected to surgery two weeks previously. They were incubated with tetraethylammonium, an agent that can induce long term potentiation, for determining the trafficking of GluR1, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit.ResultsSurgery or anesthesia increased the time to identify the target box during the Barnes maze test training sessions and one day after the training sessions. Surgery also prolonged the time to identify the target box eight days after the training sessions. Surgery increased IL-1β and IL-6 in the hippocampus. The tetraethylammonium–induced GluR1 phosphorylation and trafficking were abolished in the hippocampal slices of rats after surgery. These surgical effects were partly inhibited by lidocaine. The incubation of control hippocampal slices with IL-1β and IL-6 abolished tetraethylammonium–induced GluR1 trafficking and phosphorylation. Lidocaine minimally affected the effects of IL-1β on GluR1 trafficking.ConclusionsOur results suggest that surgery increases proinflammatory cytokines that then inhibit GluR1 trafficking, leading to learning and memory impairment.

The Choice of General Anesthetics May Not Affect Neuroinflammation and Impairment of Learning and Memory After Surgery in Elderly Rats

“…Anesthetic choice for surgery is easy to achieve if it is a modifiable factor for POCD. Many animal studies have found that exposure to volatile anesthetics including isoflurane for a long time can induce brain cell injury and cognitive impairment (Xie et al 2008;Fidalgo et al 2012;Tan et al 2014). They can also induce mild neuroinflammation ).…”

“…Based on those data, it was estimated by analysis of variance that each group needed 10 rats to detect a minimum difference in means of 30 % among the three groups with an expected standard deviation of residuals at 20 % and a desired power of 0.8 at an α level of 0.05. Based on the proinflammatory cytokine data published in our previous studies (Zhang et al 2014a, b;Tan et al 2014) and estmated by analysis of variance, 4 rats in each were needed to detect a minimum difference in means of 60 % among the three groups with an expected standard deviation of residuals at 20 % and a desired power of 0.8 at an α level of 0.05.…”

The Role of Inflammation in Postoperative Cognitive Dysfunction

“…Centrally released cytokines, including TNF-α, IL-1β, and IL-6, have also been implicated in processes of synaptic formation and scaling, long-term potentiation (LTP), and neurogenesis (61). Recent studies have highlighted some of the possible mechanisms whereby surgery and the ensuing inflammatory response contribute to cognitive decline, including changes in synaptic plasticity (62,63), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking (64), and N-methyl-D -aspartate receptor (NMDA) subtype 2B (NR2B) expression (65).…”

Neuroinflammation and Postoperative Cognitive Dysfunction: What Do We Know?

“…Accumulating evidences have demonstrated that neuroinflammation plays a substantial role in the pathogenesis of POCD (8)(9)(10)(11)(12)(13)(14)(15). Systemic pro-inflammatory cytokines in response to aseptic surgical trauma disrupt the blood-brain barrier integrity, facilitate the migration of macrophages into the brain parenchyma and induce subsequent neuroinflammation (16).…”

“…Animal studies have shown that the development of POCD is associated with significantly enhanced expression of pro-inflammatory cytokines, including TNF-α, IL-1, IL-6, and high-mobility group box 1 protein (HMGB1) (8)(9)(10)(11)(12)(13)(14)(15). Several lines of evidence have demonstrated that primed microglia are the main cellular source for this amplified neuroinflammatory response in the development of POCD (5, 21).…”