GluN2A/ERK/CREB Signaling Pathway Involved in Electroacupuncture Regulating Hypothalamic-Pituitary-Adrenal Axis Hyperactivity.

Yu Wang,Jing Zhu,Minda Ju,Zhanzhuang Tian,Jing Han,Mizhen Zhang,Yueshan Du

doi:10.3389/fnins.2021.703044

Abstract

The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis caused by stress will inevitably disrupt the homeostasis of the neuroendocrine system and damage physiological functions. It has been demonstrated that electroacupuncture (EA) can modulate HPA axis hyperactivity during the perioperative period. As the initiating factor of the HPA axis, hypothalamic corticotrophin-releasing hormone (CRH) is the critical molecule affected by EA. However, the mechanism by which EA reduces CRH synthesis and secretion remains unclear. Activated N-methyl-D-aspartate receptor (NMDAR) has been linked to over-secretion of hypothalamic CRH induced by stress. To determine whether NMDAR is involved in EA regulating the over-expression of CRH, a surgical model of partial hepatectomy (HT) was established in our experiment. The effect of EA on hypothalamic NMDAR expression in HT mice was examined. Then, we investigated whether the extracellular regulated protein kinases (ERK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling pathway mediated by NMDAR was involved in EA regulating HPA axis hyperactivity. It was found that surgery enhanced the expression of hypothalamic CRH and caused HPA axis hyperactivity. Intriguingly, EA effectively suppressed the expression of CRH and decreased the activation of GluN2A (NMDAR subunit), ERK, and CREB in HT mice. GluN2A, ERK, and CREB antagonists had similar effects on normalizing the expression of CRH and HPA axis function compared with EA. Our findings suggested that surgery enhanced the activation of the hypothalamic GluN2A/ERK/CREB signaling pathway, thus promoting the synthesis and secretion of CRH. EA suppressed the phosphorylation of GluN2A, ERK, and CREB in mice that had undergone surgery, indicating that the GluN2A/ERK/CREB signaling pathway was involved in EA alleviating HPA axis hyperactivity.

Highlights

The hypothalamic-pituitary-adrenal (HPA) axis is defined as an indispensable neuroendocrine axis that involves stress and immunity response (Herman et al, 2016; Tapp et al, 2019)
These results indicated that traumainduced HPA axis hyperactivity was relieved by EA, which means EA had a prominent therapeutic effect on regulating HPA axis dysfunction
Our results demonstrated that surgery caused activation of the hypothalamic GluN2A, ERK, and CREB, but EA could significantly ameliorate the activation of the GluN2A/ERK/CREB signaling pathway, and thereby suppress the expression of corticotropin-releasing hormone (CRH) and the hyperactivity of the HPA axis

Summary

Introduction

The hypothalamic-pituitary-adrenal (HPA) axis is defined as an indispensable neuroendocrine axis that involves stress and immunity response (Herman et al, 2016; Tapp et al, 2019). Exposure to anesthesia, trauma, and pain during surgical operation will inevitably cause HPA axis hyperactivity (El-Sibai et al, 2017; Khawandanah et al, 2019), which is characterized by the excessive release of hypothalamic corticotropin-releasing hormone (CRH), peripheral adrenocorticotropic hormone (ACTH), and corticosterone (CORT) (Wu et al, 2020). Previous reports indicated that NMDAR is involved in various stress responses and plays a vital role in coordinating HPA axis activity (Collison et al, 2018; Lin et al, 2019). The NMDAR/ERK/CREB signaling pathway may be a potential therapeutic target for CRH over-expression and HPA axis hyperactivity during the perioperative period

Methods

Results

Conclusion