Melatonin and Rapamycin Attenuate Isoflurane-Induced Cognitive Impairment Through Inhibition of Neuroinflammation by Suppressing the mTOR Signaling in the Hippocampus of Aged Mice.

Hui Yuan,Bo Lu,Guorong Wu,Bo Meng,Xiaojie Zhai,Junping Chen

doi:10.3389/fnagi.2019.00314

Abstract

Melatonin exerts neuroprotective effects on isoflurane-induced cognitive impairment. However, the underlying mechanism has yet to be elucidated. The present study sought to determine if melatonin confers its beneficial effects by acting on mammalian target of rapamycin (mTOR) and attenuates the neuroinflammation in the hippocampus of aged mice. A total of 72 male C57BL/6 mice, 16-month-old, were randomly and equally divided into six groups: (1) the control group (CON); (2) the rapamycin group (RAP); (3) the melatonin group (MEL); (4) the isoflurane group (ISO); (5) the rapamycin + isoflurane group (RAP + ISO); and (6) the melatonin + isoflurane group (MEL + ISO). RAP, RAP + ISO, MEL, MEL + ISO groups received 1 mg/kg/day mTOR inhibitor rapamycin solution or 10 mg/kg/day melatonin solution, respectively, intraperitoneally at 5:00 p.m. for 14 days consecutively. Mice in the CON and ISO groups were administered an equivalent volume of saline. Subsequently, ISO, RAP + ISO, and MEL + ISO groups were exposed to inhale 2% isoflurane for 4 h; the CON, RAP, and MEL mice received only the vehicle gas. Then, the memory function and spatial learning of the mice were examined via the Morris water maze (MWM) test. mTOR expression was detected via Western blot, whereas the concentration of inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and that of melatonin was quantified with enzyme-linked immunosorbent assay (ELISA). Melatonin and rapamycin significantly ameliorated the isoflurane-induced cognitive impairment and also led to a decrease in the melatonin levels as well as the expression levels of TNF-α, IL-1β, IL-6, and p-mTOR in the hippocampus. In conclusion, these results showed that melatonin and rapamycin attenuates mTOR expression while affecting the downstream proinflammatory cytokines. Thus, these molecular findings could be associated with an improved cognitive function in mice exposed to isoflurane.

Highlights

Perioperative neurocognitive disorders (PND) is defined as a cognitive impairment after surgery and anesthesia, especially in elderly patients (Evered et al, 2018)
The Morris water maze (MWM) test was employed to determine the effect of rapamycin and melatonin on isoflurane-induced deficits in memory and spatial learning activities
These investigations supported that 4-h exposure to 2% isoflurane induces cognitive dysfunction while decreasing the levels of melatonin in the hippocampus in aged mice. mammalian target of rapamycin (mTOR) inhibitor of rapamycin and exogenous melatonin exerted protective effects against cognitive dysfunction as well as against changes in mTOR and the expression profiles of inflammatory factors that are induced by isoflurane

Summary

Introduction

Perioperative neurocognitive disorders (PND) is defined as a cognitive impairment after surgery and anesthesia, especially in elderly patients (Evered et al, 2018). Studies have shown that mTOR promotes learning and memory formation through synaptic enhancement that relies on protein synthesis (Hoeffer and Klann, 2010), and the dysregulation of mTOR has resulted in impaired learning, memory, and social behavior in mice (Banko et al, 2007; Ehninger et al, 2008). It has been found that upregulation of mTOR leads to accumulation of highly phosphorylated tau in AD (Li et al, 2005), and the mTOR inhibitor rapamycin enhances spatial learning and memory function (Halloran et al, 2012; Majumder et al, 2012). Recent studies have shown that the overexpression of mTOR in the hippocampus is associated with the development of PND in elderly mice (Zhang C. et al, 2016). It has been proposed that rapamycin and other mTOR inhibitors exhibit therapeutic effects against PND (Yang et al, 2013)

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Conclusion