Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway

Author:

Ksendzovsky Alexander123,Bachani Muznabanu4,Altshuler Marcelle2,Walbridge Stuart2,Mortazavi Armin2,Moyer Mitchell1,Chen Chixiang1ORCID,Fayed Islam2ORCID,Steiner Joseph3,Edwards Nancy2,Inati Sara K5,Jahanipour Jahandar6ORCID,Maric Dragan6,Heiss John D2,Kapur Jaideep78,Zaghloul Kareem A2ORCID

Affiliation:

1. Department of Neurosurgery, School of Medicine, University of Maryland , Baltimore, MD 21201 , USA

2. Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda, MD 20892 , USA

3. Department of Neurological Surgery, University of Virginia Health System, University of Virginia , Charlottesville, VA 22903 , USA

4. Drug Development Unit, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda, MD 20892 , USA

5. Office of the Clinical Director, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda, MD 20892 , USA

6. Flow and Cytometry Core, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda MD, 20892 , USA

7. Department of Neurology, University of Virginia Health System, University of Virginia , Charlottesville, VA 22903 , USA

8. Neuroscience Department, University of Virginia Health System, University of Virginia , Charlottesville, VA 22903 , USA

Abstract

Abstract Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A. In this study, we examine elevations in the lactate dehydrogenase A protein as a long-term cellular adaptation to elevated metabolic demand from chronic neuronal activation. We investigate this cellular adaptation in human tissue samples and explore the mechanisms of lactate dehydrogenase A upregulation using cultured neurones treated with low Mg2+, a manipulation that leads to NMDA-mediated neuronal activation. We demonstrate that human epileptic tissue preferentially upregulates neuronal lactate dehydrogenase A, and that in neuronal cultures chronic and repeated elevations in neural activity lead to upregulation of neuronal lactate dehydrogenase A. Similar to states of hypoxia, this metabolic change occurs through the AMP-activated protein kinase/hypoxia-inducible factor-1α pathway. Our data therefore reveal a novel long-term bioenergetic adaptation that occurs in chronically activated neurones and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy.

Funder

National Institute for Neurological Disorders and Stroke

Publisher

Oxford University Press (OUP)

Subject

Neurology,Cellular and Molecular Neuroscience,Biological Psychiatry,Psychiatry and Mental health

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3