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

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 model of ischemic stroke-ind...

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Bibliographic Details
Published in:The Journal of neuroscience 2018-06, Vol.38 (25), p.5700-5709
Main Authors: Hoshi, Yutaka, Okabe, Kohki, Shibasaki, Koji, Funatsu, Takashi, Matsuki, Norio, Ikegaya, Yuji, Koyama, Ryuta
Format: Article
Language:English
Subjects:
Activation
Animals
Body temperature
Brain
Brain Edema - etiology
Brain Edema - metabolism
Brain Ischemia - complications
Brain Ischemia - metabolism
Brain slice preparation
Deprivation
Edema
Fever
Fever - etiology
Fever - metabolism
Fluorescence
Glucose
Glutamic acid receptors
Head injuries
Hyperthermia
In vivo methods and tests
Ischemia
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy
Moisture content
Oxygen
Pharmacology
Receptors
Recording
Swelling
Temperature dependence
Temperature effects
Transient receptor potential proteins
Traumatic brain injury
TRPV Cation Channels - metabolism
Water content
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Summary: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 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 Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia. 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 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 using TRPV4-deficient mice, concluding that hyperthermia activates TRPV4 and induces brain edema after ischemia.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.2888-17.2018