Electroacupuncture Improves Cerebral Ischemic Injury by Enhancing the EPO-JAK2-STAT5 Pathway in Rats

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Electroacupuncture Improves Cerebral Ischemic Injury by Enhancing the EPO-JAK2-STAT5 Pathway in Rats

Authors Liu F, Lu Z, Li Z, Wang S, Zhuang L, Hong M, Huang K

Received 16 April 2021

Accepted for publication 24 June 2021

Published 30 July 2021 Volume 2021:17 Pages 2489—2498

DOI https://doi.org/10.2147/NDT.S316136

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Yuping Ning

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Fang Liu,^1,2 Zhen Lu,¹ Ziyu Li,¹ Shichao Wang,³ Lixing Zhuang,⁴ Min Hong,² Kangbai Huang<sup>1

1</sup>Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; ²Department of Chinese Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; ³Department of Cardiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; ⁴Department of Acupuncture, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China

Correspondence: Kangbai Huang
Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, No.12 Jichang Road, Baiyun District, Guangzhou, 510405, People’s Republic of China
Tel +86020-36585261
Email 56988403@qq.com
Shichao Wang
Department of Cardiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16 Jichang Road, Baiyun District, Guangzhou, 510405, People’s republic of China
Tel +86020-36591357
Email 401210188@qq.com

Objective: Clinically, electroacupuncture (EA) improves cerebral ischemic injury, but its mechanism remains unknown. The aim of this study was to confirm the protective effects of EA on focal cerebral ischemia (FCI)-induced injury and the possible mechanism.
Methods: Sprague-Dawley (SD) rats served as the FCI model and were divided into the sham, model, EA, AG490 and EA+AG490 groups. Rats in the EA and EA+AG490 groups were acupunctured at the Baihui (GV20) and Dazhui (GV14) acupoints, and those in the AG490 and EA+AG490 groups were administered an intracerebroventricular injection of AG490 (a Janus-tyrosine kinase-2 (JAK-2) phosphorylation inhibitor). Neurological deficits and morphological changes in the ischemic cortex were observed through neurological deficit scoring and HE staining, respectively, and neuronal apoptosis was examined using the TUNEL assay. Transmission electron microscopy was used to observe neuronal ultrastructure, and HIF-1α, erythropoietin (EPO), phosphorylated (p)-JAK2, p-STAT5, HSP70, Bax and Bcl-2 expression was measured by RT-PCR and immunohistochemistry.
Results: FCI model rats showed obvious neurological deficits and neuronal apoptosis compared with sham rats. EA alleviated FCI-induced neurological deficits, improved neuronal ultrastructure, reduced neuronal apoptosis, and induced HIF-1α, EPO, p-JAK2, p-STAT5, HSP70 and Bcl-2 expression in a time-dependent manner. In contrast, AG490 treatment impaired the effects of EA on neurological deficits, neuronal apoptosis and HIF-1α, EPO, p-JAK2, p-STAT5, HSP70, Bax and Bcl-2 expression.
Conclusion: EA at GV20 and GV14 could improve neurological deficits and reduce neuronal apoptosis, thereby improving FCI-induced injury, which may be related to enhancing the EPO-JAK2-STAT5 pathway.

Keywords: electroacupuncture, focal cerebral ischemia, apoptosis, EPO-JAK2-STAT5 pathway, AG490

Introduction

Ischemic stroke is a major disabling disease and the third leading cause of death in North America, Europe, and Asia.¹ In patients who have an ischemic stroke, there is a substantial rate of recurrence.² The middle cerebral artery (MCA) is the artery that is most often occluded, which leads to a sharply demarcated infarct and to scattered neuronal injury in the adjacent cortical tissue.³ Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited.⁴ Only intravenous tissue plasminogen activator (rt-PA) and endovascular thrombectomy for large-vessel occlusion are currently used to treat ischemic stroke, but the therapeutic window is only 3 h.^5,6 To address the current shortage of therapeutic approaches for treating stroke, it is critical to identify new potential therapeutic methods. Clinically, acupuncture is increasingly widely used in the treatment of ischemic stroke in Asia,^7,8 but the therapeutic mechanisms are still not clearly understood.

Recently, studies showed that erythropoietin (EPO) and its receptor (EPOR) play critical roles in neuronal survival, and their expression level markedly change after ischemic injury.⁹ Several studies have reported that EPO promotes neuronal survival and reduces neurological dysfunction in rodent models of stroke.^10,11 Under ischemic conditions, high levels of HIF-1α regulate the transcription of EPO, which induces several pathways associated with neuroprotection.⁹ The binding of EPO and EPOR can induce the autophosphorylation of EPOR-associated Janus-tyrosine kinase-2 (JAK-2), and JAK-2 activation leads to the phosphorylation of several downstream signaling pathways, including the transcription factor signal transducers and activators of transcription 5 (STAT5), Ras-mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K).¹² The JAK2-STAT pathway is one of the important pathways that regulates cellular development and survival.¹³ Han et al reported that acupuncture preconditioning enhanced the expression of EPO in neurons, glia and vascular endothelial cells in the ischemic peripheral zone, and EPO was involved in acupuncture preconditioning-induced neuroprotection following focal cerebral ischemia (FCI).¹⁴ Xu et al reported that EA stimulation at Baihui (GV20) and Zusanli (ST36) exerted neuroprotective effects possibly by regulating the EPO-mediated JAK2/STAT3 pathway and downstream apoptotic pathways in a cerebral ischemia rat model.¹⁵

In our previous study, we found that EA at GV20 and Dazhui (GV14) promoted neuronal repair in the cerebral cortex by reducing the expression of phosphorylated JAK2 and STAT3.¹⁶ However, the therapeutic mechanism of EA at GV20 and GV14 is not well understood. Are there other mechanisms associated with effect of EA at GV20 and GV14 on neuronal repair? In this study, an FCI model was established by middle cerebral artery occlusion (MCAO) via the heat-coagulation method, and EA was performed at GV20 and GV14 to reveal the other neural mechanisms associated with the therapeutic effects of EA on cerebral ischemia.

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