Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
J Cereb Blood Flow Metab. 2020 May;40(5):1117-1131. doi: 10.1177/0271678X19859381. Epub 2019 Jun 26.
Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical , and mRNA expression peaking around 1, 2 and 4 h, respectively. and were only modestly elevated. A single CSD also increased , and , and revealed an ultra-early response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.
皮质扩散性抑制（CSD）会引起脑组织内促炎基因的表达。然而，先前评估 CSD 与炎症之间关系的研究使用了直接引发炎症的侵入性方法。为了消除损伤混杂因素，我们使用光遗传学在 Thy1-通道视紫红质-2 转基因小鼠的完整颅骨下非侵入性地诱导 CSD。我们通过颅骨变薄的微创 KCl 诱导 CSD 来验证我们的发现。在 1 小时内诱导 6 次 CSD 会显著增加皮质 和 基因的表达，分别在 1、2 和 4 小时达到峰值。 和 仅略有升高。单次 CSD 还会增加 和 ，并在 10 分钟内显示出超早期的 反应。在白细胞介素-1 受体-1 基因敲除小鼠中，该反应减弱，表明白细胞介素-1β 是上游介质，地塞米松可抑制该反应，但布洛芬不可抑制。CSD 不会改变全身炎症指数。总之，这是首次报道非侵入性诱导 CSD 后促炎基因的表达。总之，我们的数据为 CSD 诱导的神经炎症在偏头痛发病机制中的作用提供了新的见解，并对急性脑损伤中发生数天的多个 CSD 的炎症过程具有重要意义。
