Selective Anesthesia-induced Neuroinflammation in Developing Mouse Brain and Cognitive Impairment

Abstract

Background Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. We therefore have established an animal model with multiple versus single exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different anesthesia in cognitive impairment. Methods Six day and 60 day-old mice were exposed to various anesthesia regimen. We then determined the effects of the anesthesia on learning and memory function, levels of pro-inflammatory cytokine interleukin-6 and tumor necrosis factor-α in brain tissues, and the amount of ionized calcium binding adaptor molecule 1 positive cells, the marker of microglia activation, in the hippocampus. Results Here we show that anesthesia with 3% sevoflurane two hours daily for three days induced cognitive impairment and neuroinflammation [e.g., increased interleukin-6 levels: 151% ± 2.3 (mean ± SD) versus 100% ± 9.0, P = 0.035, n = 6] in young, but not adult, mice. Anesthesia with 3% sevoflurane two hours daily for one day and 9% desflurane two hours daily for three days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and anti-inflammation treatment (ketorolac) ameliorated the sevoflurane anesthesia-induced cognitive impairment. Conclusions Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and the number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for the anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.

Early‐life single‐episode sevoflurane exposure impairs social behavior and cognition later in life

“…2011; Murphy and Baxter 2013; Shen et al. 2013a). A majority of the human studies were conducted with a retrospective population cohort approach, by gathering data from a specific subpopulation and identifying incidences of general anesthetic exposure before the ages of 3–6.…”

SAHA attenuates sevoflurane-induced learning and memory impairments in fetal mice

“…Previous studies have found that sevoflurane, the most commonly used anesthetic in children, can induce apoptosis, increases in β-amyloid levels, and neuroinflammation in the brains of fetal mice and caused learning and memory impairment 3 weeks later (Shen et al, 2013;Zhang et al, 2013a,b). Clinical studies have also found that children with multiple exposures to general anesthesia and surgery at an early age may develop learning disabilities (Sun, 2010;Flick et al, 2011).…”

“…The temperature of the anesthetizing chamber was controlled to maintain a rectal temperature of 37° ± 0.5°C in the mice. Previous studies (Shen et al, 2013;Zhang et al, 2013a,b) have shown that anesthesia with 3% sevoflurane for two hours did not significantly change the values of pH, partial pressure of oxygen, or partial pressure of carbon dioxide in anesthetized mice compared with the control group. Furthermore, compared with control mice, the anesthetized mice did not show significant changes in behavior after anesthesia (e.g., eating, drinking, general activity, and body weight).…”

“…In previous studies, sevoflurane has been shown to inhibit the proliferation of mouse neural progenitor cells, decrease the capacity of neural stem cells for self-renewal, and induce neuroinflammation in microglial cells (Nie et al, 2013;Ye et al, 2013;Zhang et al, 2013a,b). Moreover, in animal studies, multiple exposures to sevoflurane have induced neuroinflammation and inhibited neurogenesis in the brain tissue of 6-day-old fetal mice, and caused subsequent learning and memory impairments 3 weeks later (Lei et al, 2013;Shen et al, 2013). Therefore, the neurotoxicity of sevoflurane is drawing increasing attention in the context of children exposed to inhalational general anesthetics for surgery.…”

Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3β/CRMP-2 signaling pathways in the developing rat brain

“…Sevoflurane is an inhaled anesthetic commonly used in the clinic, particularly in pediatric medicine, due to its minimal airway reactivity and low blood/gas partition coefficient (5). Previous studies have indicated that sevoflurane causes biochemical changes, including apoptosis, amyloid-β accumulation and neuroinflammation in the hippocampus or cortex, and induces hippocampus-dependent and -independent cognitive dysfunction in developing mice (4,6,7). However, its underlying mechanisms of action remain unknown.…”