TY - JOUR
T1 - Reduced Post-ischemic Brain Injury in Transient Receptor Potential Vanilloid 4 Knockout Mice
AU - Tanaka, Koji
AU - Matsumoto, Shoji
AU - Yamada, Takeshi
AU - Yamasaki, Ryo
AU - Suzuki, Makoto
AU - Kido, Mizuho A.
AU - Kira, Jun Ichi
N1 - Funding Information:
This study was supported by a Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant number 16K10727) and a Grant-in-Aid for Research Activity Start-up (grant number 19K21303).
Funding Information:
We appreciate the technical assistance from The Research Support Center, Research Center for Human Disease Modeling, Kyushu University. We thank Mr. Ryo Ugawa, Laboratory for Technical Support, Medical Institute of Bioregulation, Kyushu University for electron microscopy. We also thank Alison Sherwin, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. Funding. This study was supported by a Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant number 16K10727) and a Grant-in-Aid for Research Activity Start-up (grant number 19K21303).
Publisher Copyright:
© Copyright © 2020 Tanaka, Matsumoto, Yamada, Yamasaki, Suzuki, Kido and Kira.
PY - 2020/5/12
Y1 - 2020/5/12
N2 - Background and Purpose: In the acute phase of ischemia-reperfusion, hypoperfusion associated with ischemia and reperfusion in microvascular regions and disruption of the blood–brain barrier (BBB) contribute to post-ischemic brain injury. We aimed to clarify whether brain injury following transient middle cerebral artery occlusion (tMCAO) is ameliorated in Transient receptor potential vanilloid 4 knockout (Trpv4–/–) mice. Methods: tMCAO was induced in wild-type (WT) and Trpv4–/– mice aged 8–10 weeks. Ischemia-induced lesion volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining at 24 h post-tMCAO. Tissue water content and Evans blue leakage in the ipsilateral hemisphere and a neurological score were evaluated at 48 h post-tMCAO. Transmission electron microscopy (TEM) was performed to assess the morphological changes in microvasculature in the ischemic lesions at 6 h post-tMCAO. Results: Compared with WT mice, Trpv4–/– mice showed reduced ischemia-induced lesion volume and reduced water content and Evans blue leakage in the ipsilateral hemisphere alongside milder neurological symptoms. The loss of zonula occludens-1 and occludin proteins in the ipsilateral hemisphere was attenuated in Trpv4–/– mice. TEM revealed that parenchymal microvessels in the ischemic lesion were compressed and narrowed by the swollen endfeet of astrocytes in WT mice, but these effects were markedly ameliorated in Trpv4–/– mice. Conclusion: The present results demonstrate that TRPV4 contributes to post-ischemic brain injury. The preserved microcirculation and BBB function shortly after reperfusion are the key neuroprotective roles of TRPV4 inhibition, which represents a promising target for the treatment of acute ischemic stroke.
AB - Background and Purpose: In the acute phase of ischemia-reperfusion, hypoperfusion associated with ischemia and reperfusion in microvascular regions and disruption of the blood–brain barrier (BBB) contribute to post-ischemic brain injury. We aimed to clarify whether brain injury following transient middle cerebral artery occlusion (tMCAO) is ameliorated in Transient receptor potential vanilloid 4 knockout (Trpv4–/–) mice. Methods: tMCAO was induced in wild-type (WT) and Trpv4–/– mice aged 8–10 weeks. Ischemia-induced lesion volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining at 24 h post-tMCAO. Tissue water content and Evans blue leakage in the ipsilateral hemisphere and a neurological score were evaluated at 48 h post-tMCAO. Transmission electron microscopy (TEM) was performed to assess the morphological changes in microvasculature in the ischemic lesions at 6 h post-tMCAO. Results: Compared with WT mice, Trpv4–/– mice showed reduced ischemia-induced lesion volume and reduced water content and Evans blue leakage in the ipsilateral hemisphere alongside milder neurological symptoms. The loss of zonula occludens-1 and occludin proteins in the ipsilateral hemisphere was attenuated in Trpv4–/– mice. TEM revealed that parenchymal microvessels in the ischemic lesion were compressed and narrowed by the swollen endfeet of astrocytes in WT mice, but these effects were markedly ameliorated in Trpv4–/– mice. Conclusion: The present results demonstrate that TRPV4 contributes to post-ischemic brain injury. The preserved microcirculation and BBB function shortly after reperfusion are the key neuroprotective roles of TRPV4 inhibition, which represents a promising target for the treatment of acute ischemic stroke.
UR - http://www.scopus.com/inward/record.url?scp=85085318504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085318504&partnerID=8YFLogxK
U2 - 10.3389/fnins.2020.00453
DO - 10.3389/fnins.2020.00453
M3 - Article
AN - SCOPUS:85085318504
VL - 14
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
SN - 1662-4548
M1 - 453
ER -