Nuclear Factor of Activated T Cells 5 Deficiency Increases the Severity of Neuronal Cell Death in Ischemic Injury

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Abstract

Nuclear factor of activated T cells 5 (NFAT5) has been implicated in regulating several genes that are thought to be neuroprotective in ischemic injury. Because of the embryonic lethality of NFAT5 knockout (NFAT5–/–) mice, the heterozygous (NFAT5+/–) mice were used to study the in vivo role of NFAT5 in hypoxia/ischemia (H/I) condition. The NFAT5+/– mice exhibited more severe neurological deficits, larger infarct area and edema formation associated with increased aquaporin 4 expressions in the brain. Under in vitro H/I condition, increased apoptotic cell death was found in NFAT5–/– neurons. Moreover, SMIT, a downstream to NFAT5, was upregulated in NFAT5+/+ neurons, while the SMIT level could not be upregulated in NFAT5–/– neurons under H/I condition. The elevation of reactive oxygen species generation in NFAT5–/– neurons under H/I condition further confirmed that NFAT5–/– neurons were more susceptible to oxidative stress. The present study demonstrated that activation of NFAT5 and its downstream SMIT induction is important in protecting neurons from ischemia-induced oxidative stress.

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Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.

G. T. Manley, M Fujimura, T. Ma … (2000)

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.

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Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase.

Z Huang, P L Huang, N Panahian … (1994)

The proposal that nitric oxide (NO) or its reactant products mediate toxicity in brain remains controversial in part because of the use of nonselective agents that block NO formation in neuronal, glial, and vascular compartments. In mutant mice deficient in neuronal NO synthase (NOS) activity, infarct volumes decreased significantly 24 and 72 hours after middle cerebral artery occlusion, and the neurological deficits were less than those in normal mice. This result could not be accounted for by differences in blood flow or vascular anatomy. However, infarct size in the mutant became larger after endothelial NOS inhibition by nitro-L-arginine administration. Hence, neuronal NO production appears to exacerbate acute ischemic injury, whereas vascular NO protects after middle cerebral artery occlusion. The data emphasize the importance of developing selective inhibitors of the neuronal isoform.

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Contribution of polyol pathway to diabetes-induced oxidative stress.

Eric Ho, Bevan K S Chung, Phillip K N Lam … (2003)

Diabetes causes increased oxidative stress, which is thought to play an important role in the pathogenesis of various diabetic complications. However, the source of the hyperglycemia-induced oxidative stress is not clear. It was found that the polyol pathway is the major contributor to oxidative stress in the lenses and nerves of diabetic mice. The first enzyme in the pathway, aldose reductase (AR), reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SDH). Transgenic mice that overexpress AR specifically in their lenses showed a significant increase in oxidative stress when they became hyperglycemic, as indicated by a decrease in GSH and an increase in malondialdehyde in their lenses. Introducing an SDH-deficient mutation into these transgenic mice significantly normalized the GSH and malondialdehyde levels. These results indicate that both enzymes of the polyol pathway contributed to hyperglycemia-induced oxidative stress in the lens. In the wild-type mice, diabetes caused a significant decrease in GSH in their sciatic nerves, indicative of oxidative stress. In the AR null mutant mice, diabetes did not lead to any decrease in the nerve GSH level. These results indicate that similar to the situation in the lens, AR is also the major contributor to hyperglycemia-induced oxidative stress in the nerve. Although increased flux of glucose through the polyol pathway leads to diabetic lesions in both the lenses and nerve, the mechanisms may be different. AR-induced osmotic stress seems to be the cause of diabetic cataract, whereas AR-induced oxidative stress is probably the cause of neuronal dysfunction.

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Author and article information

Journal

Journal ID (publisher-id): NSG

Journal ID (nlm-ta): Neurosignals

Journal ID (doi): 10.1159/issn.1424-862X

Title: Neurosignals

Publisher: S. Karger AG

ISSN (Print): 1424-862X

ISSN (Electronic): 1424-8638

Publication date Subscription-year: 2012

Publication date (Print): November 2012

Publication date (Electronic): 18 January 2012

Volume: 20

Issue: 4

Pages: 237-251

Affiliations

^aDepartment of Anatomy, Li Ka Shing Faculty of Medicine, ^bResearch Center of Heart, Brain, Hormone and Healthy Aging, and ^cDepartment of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, SAR, China; ^dDivision of Science and Technology, United International College, Zhuhai, China

Author notes

*Prof. S.K. Chung, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, SAR (China), Tel. +852 2819 9172, E-Mail skchung@hkucc.hku.hk

Article

Publisher ID: 331899 Other ID: Neurosignals 2012;20:237–251

DOI: 10.1159/000331899

PubMed ID: 23172129

SO-VID: 1d60b2eb-ef3d-411d-b10f-86ef4285cee5

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 29 April 2011

Date accepted : 11 August 2011

Page count

Figures: 6, Tables: 1, Pages: 15

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Karger: Neurology and Neuroscience

Most cited references 46

Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.

Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase.

Contribution of polyol pathway to diabetes-induced oxidative stress.

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