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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Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System

We need this. What is your doctor doing to accomplish this in your recovery? ANYTHING AT ALL? 

Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System

Xueting Luo³

,

Marcio Ribeiro

,

Eric R. Bray

,

Do-Hun Lee

,

Benjamin J. Yungher

,

Saloni T. Mehta

,

Kinjal A. Thakor

,

Francisca Diaz

,

Jae K. Lee

,

Carlos T. Moraes

,

John L. Bixby

,

Vance P. Lemmon

,

Kevin K. Park

³Present address: Department of Ophthalmology, Shanghai First People’s Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Fundus Disease, 100 Hai Ning Road, Shanghai 200080, China

Publication stage: In Press Corrected Proof

Open Access

DOI: http://dx.doi.org/10.1016/j.celrep.2016.03.029

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Highlights

• •STAT3 shifts to distinct cellular regions in CNS neurons upon cytokine stimulation
• •STAT3′s transcriptional activity and mitochondrial localization co-induce regeneration
• •MEK enhances STAT3 functions and localization and potentiates axon regeneration
• •Modulation of STAT3, MEK, and PTEN promotes extensive axon growth and sprouting

Summary

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor central to axon regrowth with an enigmatic ability to act in different subcellular regions independently of its transcriptional roles. However, its roles in mature CNS neurons remain unclear. Here, we show that along with nuclear translocation, STAT3 translocates to mitochondria in mature CNS neurons upon cytokine stimulation. Loss- and gain-of-function studies using knockout mice and viral expression of various STAT3 mutants demonstrate that STAT3′s transcriptional function is indispensable for CNS axon regrowth, whereas mitochondrial STAT3 enhances bioenergetics and further potentiates regrowth. STAT3′s localization, functions, and growth-promoting effects are regulated by mitogen-activated protein kinase kinase (MEK), an effect further enhanced by Pten deletion, leading to extensive axon regrowth in the mouse optic pathway and spinal cord. These results highlight CNS neuronal dependence on STAT3 transcriptional activity, with mitochondrial STAT3 providing ancillary roles, and illustrate a critical contribution for MEK in enhancing diverse STAT3 functions and axon regrowth.

STAT-dependent upregulation of 12/15-lipoxygenase contributes to neuronal injury after stroke

Whom in the world is going to follow through with more research on this to see if we can stop some of the neuronal death post stroke? Because we have NO fucking leaders or strategy in stroke this promising research will never get followed up. You're screwed, your children are screwed, your grandchildren are screwed, all for a lack of leadership in stroke. 

STAT-dependent upregulation of 12/15-lipoxygenase contributes to neuronal injury after stroke

Joo Eun Jung¹, Hulya Karatas^1,5, Yu Liu¹, Ayfer Yalcin^2,3, Joan Montaner⁴, Eng H Lo¹ and Klaus van Leyen¹

1. ¹Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
2. ²Department of Biochemistry, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey
3. ³Biruni University, Faculty of Pharmacy, Istanbul, Turkey
4. ⁴Laboratorio de Investigación Neurovascular Hospital Vall d'Hebron, Barcelona, Spain

Correspondence: Dr K van Leyen, Neuroprotection Research Laboratory, Massachusetts General Hospital, 149 13th Street, Room 2401, Charlestown, Massachusetts 02129, USA. E-mail: klaus_vanleyen@hms.harvard.edu

⁵Current Address: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara 06100, Turkey.

Received 10 December 2014; Revised 12 June 2015; Accepted 15 June 2015
Advance online publication 15 July 2015

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Abstract

Oxidative stress is a major brain injury mechanism after ischemic stroke. 12/15-lipoxygenase (12/15-LOX) is a key mediator of oxidative stress, contributing to neuronal cell death and vascular leakage. Nonetheless, the mechanism leading to its upregulation is currently unknown. We show here that Signal Transducers and Activators of Transcription (STATs), specifically STAT6 and possibly STAT1, increase transcription of 12/15-LOX in neuronal cells. Both p-STAT6 and -1 bound to specific STAT binding sites in the mouse 12/15-LOX promoter. Small interfering RNA (siRNA) knockdown showed STAT6 to be the dominant regulator, reducing 12/15-LOX promoter activation and cell death in oxidatively stressed HT22 cells. STAT6 siRNA efficiently prevented the increase of 12/15-LOX in murine primary neurons, both after induction of oxidative stress and after oxygen-glucose deprivation. Early activation of STAT6 and STAT1 in mice was consistent with a role in regulating 12/15-LOX in focal ischemia. Brains of human stroke patients showed increased p-STAT6 and p-STAT1 in the peri-infarct region, along with 12/15-LOX and markers of apoptosis. These results link STAT6 and STAT1 to the 12/15-LOX damage pathway and suggest disregulation of STAT-dependent transcription as injury mechanism in stroke. Selectively targeting STATs may thus be a novel therapeutic approach to reducing brain injury after a stroke.

IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity

This seems to be good but WHO is going to follow up with translational research that creates dosages/application methods and timeframes for survivors? 

IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity

Leticia Pereira^1,2, Miriam Font-Nieves^1,2, Chris Van den Haute^3,4, Veerle Baekelandt³, Anna M. Planas^1,2 and Esther Pozas^1,2*

• ¹Unit of Brain Ischemia, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
• ²Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
• ³Laboratory for Neurobiology and Gene Therapy, Faculty of Medicine, KU Leuven, Leuven, Belgium
• ⁴Leuven Viral Vector Core, KU Leuven, Leuven, Belgium

The adult subventricular zone (SVZ) contains Nestin+ progenitors that differentiate mainly into neuroblasts. Our previous data showed that interleukin-10 (IL-10) regulates SVZ adult neurogenesis by up-regulating the expression of pro-neural genes and modulating cell cycle exit. Here we addressed the specific mechanism through which IL-10 carries out its signaling on SVZ progenitors. We found that, in vitro and in vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3. The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels. Silencing STAT3 expression by lentiviral vectors also impaired neurogenesis by blocking the effects of IL-10. Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis.

Introduction

Postnatal neurogenesis takes place in restricted regions or niches in the adult brain. The SVZ lining the LVs is one of the main neurogenenic niches in the adult brain. The niche is composed by supporting cells, the vasculature and three progenitor cell types: slow-cycling glial-like NSCs or type B cells (GFAP+); TACs or type C cells (Ki67+, and Mash1+), and the more differentiated neuroblasts (type A cells; PSA-NCAM+; DCX+; TUBB3+) that migrate over long distances through the RMS to reach the olfactory bulb, where they finally become mainly GABAergic interneurons (Lois and Alvarez-Buylla, 1994; Doetsch and Alvarez-Buylla, 1996; Doetsch et al., 1997; Merkle et al., 2004; Ihrie et al., 2011). Nestin labels type B and C cells and a sub-population of immature committed neuroblasts (Doetsch et al., 1997; Perez-Asensio et al., 2013). The SVZ niche is unique in spatial localization and molecular characteristics. The relationships between the different cell types, the cerebrospinal fluid (CSF), and the vasculature modulate the molecular signals that regulate self-renewal, proliferation, the identity of VZ-SVZ-derived progeny, the integration of some intrinsic mechanisms (Guillemot, 2007; Lim et al., 2009; Ihrie et al., 2011).

Interleukin-10 (IL-10) is a general anti-inflammatory molecule that contributes to maintaining the pro- and anti-inflammatory balance in the body (Pestka et al., 2004; Saraiva and O’Garra, 2010; Ouyang et al., 2011). Recently, we demonstrated a new physiological role of this cytokine as a relevant factor that regulates postnatal neurogenesis. We deciphered how IL-10 targets the population of Nestin+ progenitors located in the dorsal SVZ, where it regulates the expression of undifferentiated neural progenitor markers, cell cycle activity, and the production of new neuroblasts (Perez-Asensio et al., 2013).

Here we aimed to identify the specific intracellular mechanism through which IL-10 acts specifically on adult Nestin+ progenitors. Our results show that IL-10 regulates the activation of ERK and STAT3 in Nestin+ progenitors and that this activity is required for IL-10 to exert its actions on neural progenitors.

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