AMPK: Potential Therapeutic Target for Ischemic Stroke

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Abstract

5'-AMP-activated protein kinase (AMPK), a member of the serine/threonine (Ser/Thr) kinase group, is universally distributed in various cells and organs. It is a significant endogenous defensive molecule that responds to harmful stimuli, such as cerebral ischemia, cerebral hemorrhage, and, neurodegenerative diseases (NDD). Cerebral ischemia, which results from insufficient blood flow or the blockage of blood vessels, is a major cause of ischemic stroke. Ischemic stroke has received increased attention due to its '3H' effects, namely high mortality, high morbidity, and high disability. Numerous studies have revealed that activation of AMPK plays a protective role in the brain, whereas its action in ischemic stroke remains elusive and poorly understood. Based on existing evidence, we introduce the basic structure, upstream regulators, and biological roles of AMPK. Second, we analyze the relationship between AMPK and the neurovascular unit (NVU). Third, the actions of AMPK in different phases of ischemia and current therapeutic methods are discussed. Finally, we evaluate existing controversy and provide a detailed analysis, followed by ethical issues, potential directions, and further prospects of AMPK. The information complied here may aid in clinical and basic research of AMPK, which may be a potent drug candidate for ischemic stroke treatment in the future.

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Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner.

Adem Kalender, Anand Selvaraj, So Young Kim … (2010)

Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.

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Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke.

Xiao-Yi Xiong, Liang-Liang Liu, Qing-Wu Yang (2016)

Microglia/macrophages are the major immune cells involved in the defence against brain damage. Their morphology and functional changes are correlated with the release of danger signals induced by stroke. These cells are normally responsible for clearing away dead neural cells and restoring neuronal functions. However, when excessively activated by the damage-associated molecular patterns following stroke, they can produce a large number of proinflammatory cytokines that can disrupt neural cells and the blood-brain barrier and influence neurogenesis. These effects indicate the important roles of microglia/macrophages in the pathophysiological processes of stroke. However, the modifiable and adaptable nature of microglia/macrophages may also be beneficial for brain repair and not just result in damage. These distinct roles may be attributed to the different microglia/macrophage phenotypes because the M1 population is mainly destructive, while the M2 population is neuroprotective. Additionally, different gene expression signature changes in microglia/macrophages have been found in diverse inflammatory milieus. These biofunctional features enable dual roles for microglia/macrophages in brain damage and repair. Currently, it is thought that the proper inflammatory milieu may provide a suitable microenvironment for neurogenesis; however, detailed mechanisms underlying the inflammatory responses that initiate or inhibit neurogenesis remain unknown. This review summarizes recent progress concerning the mechanisms involved in brain damage, repair and regeneration related to microglia/macrophage activation and phenotype transition after stroke. We also argue that future translational studies should be targeting multiple key regulating molecules to improve brain repair, which should be accompanied by the concept of a "therapeutic time window" for sequential therapies.

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Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease.

Tianfang Jiang, Qian Sun, Shengdi Chen (2016)

Oxidative stress reflects an imbalance between the overproduction and incorporation of free radicals and the dynamic ability of a biosystem to detoxify reactive intermediates. Free radicals produced by oxidative stress are one of the common features in several experimental models of diseases. Free radicals affect both the structure and function of neural cells, and contribute to a wide range of neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Although the precise mechanisms that result in the degeneration of neurons and the relevant pathological changes remain unclear, the crucial role of oxidative stress in the pathogenesis of neurodegenerative diseases is associated with several proteins (such as α-synuclein, DJ-1, Amyloid β and tau protein) and some signaling pathways (such as extracellular regulated protein kinases, phosphoinositide 3-kinase/Protein Kinase B pathway and extracellular signal-regulated kinases 1/2) that are tightly associated with the neural damage. In this review, we present evidence, gathered over the last decade, concerning a variety of pathogenic proteins, their important signaling pathways and pathogenic mechanisms associated with oxidative stress in Parkinson's disease and Alzheimer's disease. Proper control and regulation of these proteins' functions and the related signaling pathways may be a promising therapeutic approach to the patients. We also emphasizes antioxidative options, including some new neuroprotective agents that eliminate excess reactive oxygen species efficiently and have a certain therapeutic effect; however, controversy surrounds some of them in terms of the dose and length of therapy. These agents require further investigation by clinical application in patients suffering Parkinson's disease and Alzheimer's disease.

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Author and article information

Journal

Journal ID (nlm-ta): Theranostics

Journal ID (iso-abbrev): Theranostics

Journal ID (publisher-id): thno

Title: Theranostics

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1838-7640

Publication date Collection: 2018

Publication date (Electronic): 10 August 2018

Volume: 8

Issue: 16

Pages: 4535-4551

Affiliations

[1 ]Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China

[2 ]Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China

[3 ]Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China

[4 ]Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China

[5 ]Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA

Author notes

✉ Corresponding authors: Yang Yang MD., PhD. and Chunhu Gu MD., PhD., Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China. Telephone: +86 13379217366; Email address: yang200214yy@ 123456163.com (Yang Yang) and chunhuguxijing@ 123456126.com (Chunhu Gu)

*These authors contributed equally to this work.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: thnov08p4535

DOI: 10.7150/thno.25674

PMC ID: 6134933

PubMed ID: 30214637

SO-VID: 8dd39941-f544-475d-a396-640c256b98dd

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This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

AMPK: Potential Therapeutic Target for Ischemic Stroke

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cGMP: Generators, Effectors and Therapeutic Implications Conference

Most cited references 132

Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner.

Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke.

Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease.

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