Atorvastatin Attenuates Isoflurane-Induced Activation of ROS-p38MAPK/ATF2 Pathway, Neuronal Degeneration, and Cognitive Impairment of the Aged Mice

Abstract

Isoflurane, a widely used volatile anesthetic, induces neuronal apoptosis and memory impairments in various animal models. However, the potential mechanisms and effective pharmacologic agents are still not fully understood. The p38MAPK/ATF-2 pathway has been proved to regulate neuronal cell survival and inflammation. Besides, atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts neuroprotective effects. Thus, this study aimed to explore the influence of atorvastatin on isoflurane-induced neurodegeneration and underlying mechanisms. Aged C57BL/6 mice (20 months old) were exposed to isoflurane (1.5%) anesthesia for 6 h. Atorvastatin (5, 10, or 20 mg/kg body weight) was administered to the mice for 7 days. Atorvastatin attenuated the isoflurane-induced generation of ROS and apoptosis. Western blotting revealed a decrease in cleaved caspase-9 and caspase-3 expression in line with ROS levels. Furthermore, atorvastatin ameliorated the isoflurane-induced activation of p38MAPK/ATF-2 signaling. In a cellular study, we proved that isoflurane could induce oxidative stress and inflammation by activating the p38MAPK/ATF-2 pathway in BV-2 microglia cells. In addition, SB203580, a selected p38MAPK inhibitor, inhibited the isoflurane-induced inflammation, oxidative stress, and apoptosis. The results implied that p38MAPK/ATF-2 was a potential target for the treatment of postoperative cognitive dysfunction.

Metformin alleviates prolonged isoflurane inhalation induced cognitive decline via reducing neuroinflammation in adult mice

“…The length of use in mice might not exactly mimic the time used in humans in consideration of their length of life respectively. In this study, 6 h of isoflurane exposure was used based on previous research in a cognitive impairment mouse model induced by lengthy isoflurane inhalation [7] , [50] , [51] . Our previous study also has proved that 6 h isoflurane exposure could induce a significant cognitive decline in adult mice [10] , [11] , [52] .…”

“…Our previous study also has proved that 6 h isoflurane exposure could induce a significant cognitive decline in adult mice [10] , [11] , [52] . In addition, different to 2 h isoflurane exposure which can’t elicit the activation of BV-2 cells or primary microglial cells [9] , 6 h isoflurane or sevoflurane treatment can directly increase the expression level and transcription activity of nuclear factor kappa-B as well as the production of pro-inflammatory cytokines in H4 human neuroglioma cells, mouse primary microglia, and BV2 cells [7] , [51] , [53] . All in all, prolonged sub-MAC isoflurane inhalation can induce remarkable neuroinflammation and cognitive decline by promoting microglia and astrocyte activation in adults and should be fully considered for the use of inhaled anesthetics in prolonged sedation.…”

“…The shortage is that we merely investigated the effects of prolonged sub-MAC isoflurane inhalation in healthy adult mice, but not seriously infected adults who required lengthy isoflurane sedation. However, in vitro studies had found that the exposure of primary microglia or BV2 cells to 0.4%-2% isoflurane for 6 h caused notable proinflammatory responses [7] , [51] , [53] . In addition, even 2 h isoflurane exposure can promote the release of proinflammatory cytokines in lipopolysaccharide-activated BV-2 cells or primary microglial cells [9] .…”

Maprotiline ameliorates isoflurane-induced microglial activation via regulating triggering receptor expressed in myeloid cells 2 (TREM2)

“…In a male newborn piglet, exposure to isoflurane results in the activation of microglia and causes significant alternations to the genes mediating memory formation and recall [ 21 ]. Isoflurane induces cognitive impairment of aged mice and induces inflammation and oxidative stress in BV2 cells through the ROS-p38MAPK/ATF2 pathway [ 22 ]. Isoflurane induces the increased protein levels of TNF-α, IL-1β, interferon (IFN)-γ, and microglia marker Iba-1 [ 23 ].…”

Protective effects of chlorogenic acid on isoflurane‐induced cognitive impairment of aged mice

“…After 1 week of adaptation, 80 mice were randomly divided into four groups: control group, isoflurane group (ISO), ISO + 30 mg/kg CGA group, and ISO + 60 mg/kg CGA (N = 20 in each group). Chlorogenic acid (Sigma‐Aldrich, purity 95%; St. Louis, MO, USA) was dissolved in sterile saline and administered orally by gavage once daily for 7 days, while the normal group was given sterile saline (Liu et al, 2021). On day 8, the mice were exposed to 1.5% ISO (Nanjing Jiancheng Bioengineering Institute), mixed with 100% O 2 for 4 h, and the mice in the control group received 100% O 2 of 1.5 L/min for 4 h in an identical chamber (X.‐m.…”