Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury

The transient receptor potential melastatin 4 (TRPM4) channel has been suggested to play a key role in the treatment of ischemic stroke. However, in vivo evaluation of TRPM4 channel, in particular by direct channel suppression, is lacking. In this study, we used multimodal imaging to assess edema fo...

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Main Authors: Chen, Bo, Ng, Gandi, Gao, Yahui, Low, See Wee, Sandanaraj, Edwin, Ramasamy, Boominathan, Sekar, Sakthivel, Bhakoo, Kishore, Soong, Tuck Wah, Nilius, Bernd, Tang, Carol, Robins, Edward G., Goggi, Julian, Liao, Ping
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2019
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Online Access:https://hdl.handle.net/10356/106391
http://hdl.handle.net/10220/49616
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1063912023-02-28T17:07:21Z Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury Chen, Bo Ng, Gandi Gao, Yahui Low, See Wee Sandanaraj, Edwin Ramasamy, Boominathan Sekar, Sakthivel Bhakoo, Kishore Soong, Tuck Wah Nilius, Bernd Tang, Carol Robins, Edward G. Goggi, Julian Liao, Ping School of Biological Sciences Stroke Science::Biological sciences Reperfusion The transient receptor potential melastatin 4 (TRPM4) channel has been suggested to play a key role in the treatment of ischemic stroke. However, in vivo evaluation of TRPM4 channel, in particular by direct channel suppression, is lacking. In this study, we used multimodal imaging to assess edema formation and quantify the amount of metabolically functional brain salvaged after a rat model of stroke reperfusion. TRPM4 upregulation in endothelium emerges as early as 2 h post-stroke induction. Expression of TRPM4 channel was suppressed directly in vivo by treatment with siRNA; scrambled siRNA was used as a control. T2-weighted MRI suggests that TRPM4 inhibition successfully reduces edema by 30% and concomitantly salvages functionally active brain, measured by 18F-FDG-PET. These in vivo imaging results correlate well with post-mortem 2,3,5-triphenyltetrazolium chloride (TTC) staining which exhibits a 34.9% reduction in infarct volume after siRNA treatment. Furthermore, in a permanent stroke model, large areas of brain tissue displayed both edema and significant reductions in metabolic activity which was not shown in transient models with or without TRPM4 inhibition, indicating that tissue salvaged by TRPM4 inhibition during stroke reperfusion may survive. Evans Blue extravasation and hemoglobin quantification in the ipsilateral hemisphere were greatly reduced, suggesting that TRPM4 inhibition can improve BBB integrity after ischemic stroke reperfusion. Our results support the use of TRPM4 blocker for early stroke reperfusion. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version 2019-08-14T01:53:19Z 2019-12-06T22:10:33Z 2019-08-14T01:53:19Z 2019-12-06T22:10:33Z 2018 Journal Article Chen, B., Ng, G., Gao, Y., Low, S. W., Sandanaraj, E., Ramasamy, B., . . . Liao, P. (2019). Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury. Translational Stroke Research, 10(1), 91-103. doi:10.1007/s12975-018-0621-3 1868-4483 https://hdl.handle.net/10356/106391 http://hdl.handle.net/10220/49616 10.1007/s12975-018-0621-3 en Translational Stroke Research © 2018 The Author(s). Published by Springer US. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 13 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Stroke
Science::Biological sciences
Reperfusion
spellingShingle Stroke
Science::Biological sciences
Reperfusion
Chen, Bo
Ng, Gandi
Gao, Yahui
Low, See Wee
Sandanaraj, Edwin
Ramasamy, Boominathan
Sekar, Sakthivel
Bhakoo, Kishore
Soong, Tuck Wah
Nilius, Bernd
Tang, Carol
Robins, Edward G.
Goggi, Julian
Liao, Ping
Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury
description The transient receptor potential melastatin 4 (TRPM4) channel has been suggested to play a key role in the treatment of ischemic stroke. However, in vivo evaluation of TRPM4 channel, in particular by direct channel suppression, is lacking. In this study, we used multimodal imaging to assess edema formation and quantify the amount of metabolically functional brain salvaged after a rat model of stroke reperfusion. TRPM4 upregulation in endothelium emerges as early as 2 h post-stroke induction. Expression of TRPM4 channel was suppressed directly in vivo by treatment with siRNA; scrambled siRNA was used as a control. T2-weighted MRI suggests that TRPM4 inhibition successfully reduces edema by 30% and concomitantly salvages functionally active brain, measured by 18F-FDG-PET. These in vivo imaging results correlate well with post-mortem 2,3,5-triphenyltetrazolium chloride (TTC) staining which exhibits a 34.9% reduction in infarct volume after siRNA treatment. Furthermore, in a permanent stroke model, large areas of brain tissue displayed both edema and significant reductions in metabolic activity which was not shown in transient models with or without TRPM4 inhibition, indicating that tissue salvaged by TRPM4 inhibition during stroke reperfusion may survive. Evans Blue extravasation and hemoglobin quantification in the ipsilateral hemisphere were greatly reduced, suggesting that TRPM4 inhibition can improve BBB integrity after ischemic stroke reperfusion. Our results support the use of TRPM4 blocker for early stroke reperfusion.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Chen, Bo
Ng, Gandi
Gao, Yahui
Low, See Wee
Sandanaraj, Edwin
Ramasamy, Boominathan
Sekar, Sakthivel
Bhakoo, Kishore
Soong, Tuck Wah
Nilius, Bernd
Tang, Carol
Robins, Edward G.
Goggi, Julian
Liao, Ping
format Article
author Chen, Bo
Ng, Gandi
Gao, Yahui
Low, See Wee
Sandanaraj, Edwin
Ramasamy, Boominathan
Sekar, Sakthivel
Bhakoo, Kishore
Soong, Tuck Wah
Nilius, Bernd
Tang, Carol
Robins, Edward G.
Goggi, Julian
Liao, Ping
author_sort Chen, Bo
title Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury
title_short Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury
title_full Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury
title_fullStr Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury
title_full_unstemmed Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury
title_sort non-invasive multimodality imaging directly shows trpm4 inhibition ameliorates stroke reperfusion injury
publishDate 2019
url https://hdl.handle.net/10356/106391
http://hdl.handle.net/10220/49616
_version_ 1759856645481955328