Format

Send to

Choose Destination
J Neurosci. 2018 Jun 20;38(25):5700-5709. doi: 10.1523/JNEUROSCI.2888-17.2018. Epub 2018 May 23.

Ischemic Brain Injury Leads to Brain Edema via Hyperthermia-Induced TRPV4 Activation.

Author information

1
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan.
2
Laboratory of Bioanalytical Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan.
3
JST, PRESTO, Saitama, 332-0012 Japan.
4
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, 371-8514 Japan, and.
5
Center for Information and Neural Networks, National Institute of Information and Communications Technology, Suita City, Osaka, 565-0871 Japan.
6
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan, rkoyama@mol.f.u-tokyo.ac.jp.

Abstract

Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain largely unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which male mouse brain slices were treated with oxygen-glucose deprivation (OGD) to mimic ischemia. We continuously measured the cross-sectional area of the brain slice for 150 min under macroscopic microscopy, finding that OGD induces swelling of brain slices. OGD-induced swelling was prevented by pharmacologically blocking or genetically knocking out the transient receptor potential vanilloid 4 (TRPV4), a member of the thermosensitive TRP channel family. Because TRPV4 is activated at around body temperature and its activation is enhanced by heating, we next elevated the temperature of the perfusate in the recording chamber, finding that hyperthermia induces swelling via TRPV4 activation. Furthermore, using the temperature-dependent fluorescence lifetime of a fluorescent-thermosensitive probe, we confirmed that OGD treatment increases the temperature of brain slices through the activation of glutamate receptors. Finally, we found that brain edema following traumatic brain injury was suppressed in TRPV4-deficient male mice in vivo Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia.SIGNIFICANCE STATEMENT Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which mouse brain slices were treated with oxygen-glucose deprivation. Using this system, we showed that the increase in brain temperature and the following activation of the thermosensitive cation channel TRPV4 (transient receptor potential vanilloid 4) are involved in the pathology of edema. Finally, we confirmed that TRPV4 is involved in brain edema in vivo using TRPV4-deficient mice, concluding that hyperthermia activates TRPV4 and induces brain edema after ischemia.

KEYWORDS:

TRPV4; brain edema; hyperthermia; ischemia

PMID:
29793978
DOI:
10.1523/JNEUROSCI.2888-17.2018
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center