Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan.
Laboratory of Bioanalytical Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan.
J Neurosci. 2018 Jun 20;38(25):5700-5709. doi: 10.1523/JNEUROSCI.2888-17.2018. Epub 2018 May 23.
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.
脑水肿的特征是净脑含水量增加，导致脑体积增加。尽管脑水肿与高死亡率相关，但水肿的细胞和分子过程在很大程度上仍不清楚。在这里，我们开发了一种缺血性中风诱导水肿的模型，其中雄性小鼠脑片用氧葡萄糖剥夺（OGD）处理以模拟缺血。我们在宏观显微镜下连续 150 分钟测量脑片的横截面积，发现 OGD 诱导脑片肿胀。用药理学方法阻断或基因敲除瞬时受体电位香草醛 4（TRPV4），一种热敏性 TRP 通道家族成员，可预防 OGD 诱导的肿胀。因为 TRPV4 在体温左右被激活，并且其激活通过加热增强，所以我们接下来升高记录室灌流液的温度，发现通过 TRPV4 激活导致发热诱导肿胀。此外，使用荧光热敏探针的温度依赖性荧光寿命，我们证实 OGD 处理通过谷氨酸受体的激活增加脑片的温度。最后，我们发现 TRPV4 缺陷型雄性小鼠创伤性脑损伤后的脑水肿受到抑制。因此，我们的研究提出了一种新的机制：发热通过激活 TRPV4 并在缺血后诱导脑水肿。
