The PI3K-AKT-mTOR pathway activates recovery from general anesthesia.

Yun-Hui Zhang,Jian-Nan Song,Jin-Song Cai,Jin-Gui Gao,Jin Zhang,Yang Zhou,Xue Xu

doi:10.18632/oncotarget.10172

Abstract

We investigated roles of PI3K-AKT-mTOR pathway in recovery from general anesthesia. Sprague-Dawley rats divided into five groups: saline+artificial cerebrospinal fluid (ACSF; Group A), ketamine+ACSF (Group B), ketamine+IGF-1 (Group C), ketamine+PI3K inhibitor (Group D), and PI3K/Akt agonists (Group E). Proportion of δ waves on ECoGs was recorded. Rats were tested for duration of loss of righting reflex (LORR), ataxic period and behavior in Morris water maze. mRNA and protein expression of members of PI3K-AKT-mTOR pathway were measured by RT-qPCR and Western blots. Histopathologic changes in hippocampal tissues observed by HE staining. We found that the proportion of δ waves decreased in Group C, while increased in Group D compared with Group B; the durations of LORR and ataxic period were shorter in Group C, but longer in Group D. In Morris water maze, escape latency (EL) and duration and frequency of staying on platform was shorter in Group C and longer in Group D than in Group B. Group A exhibited low expression of proteins in PI3K-AKT-mTOR pathway, while p-AKT, p-mTOR and p-P70S6K expression increased in cerebral cortex, brain stem, and thalamus in Group C. By contrast, expression of those proteins was lower in Group D than Group B. Those proteins expressions were higher in Group E than in Group A. HE staining showed that anesthesia may induce cell apoptosis in rat hippocampal CA1 areas, and PI3K/Akt agonists could inhibit apoptosis. Our results suggest that activation of PI3K-AKT-mTOR pathway may promote recovery from general anesthesia and enhance spatial learning and memory.

Highlights

In this day and age, patients are able to undergo complicated surgical procedures under novel anesthetic techniques, but new drugs may still improve the safety of these procedures [1]
We found that the proportion of δ waves in ECoG in anaesthetized rats treated with PI3K/Akt agonist was decreased, while the proportion of δ waves in ECoG in anaesthetized rats treated with PI3K/Akt antagonists was increased
In the Morris water maze, the escape latency (EL), as well as the duration and frequency of stay in anaesthetized rats treated with PI3K/Akt agonists were shortened, while those same measures in rats treated with PI3K/Akt antagonists were prolonged

Summary

INTRODUCTION

In this day and age, patients are able to undergo complicated surgical procedures under novel anesthetic techniques, but new drugs may still improve the safety of these procedures [1]. The complications of anesthesia may prolong the length of stay and increase the cost of hospitalization, diminish the quality of the patient’s life, or even, increase patient morbidity or mortality [8, 9] In this regard, how best to promote patient’s recovery from general anesthesia is a crucial research question for medicine and neuroscience. The phosphatidylinositol-3 kinase/AKT/ mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway is crucial to various aspects of cellular maintenance, in both physiological and pathological conditions [10]. It is important for regulating the cell www.impactjournals.com/oncotarget. In order to understand the central action of the PI3K-AKT-mTOR pathway on the recovery from general anesthesia, we established an anesthetized rat model and investigated mRNA and protein expression of PI3K-AKT-mTOR pathway proteins in brain tissues

RESULTS

DISCUSSION

MATERIALS AND METHODS

Statistical methods