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Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex.


ABSTRACT: 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 interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β 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.

SUBMITTER: Takizawa T 

PROVIDER: S-EPMC7181092 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex.

Takizawa Tsubasa T   Qin Tao T   Lopes de Morais Andreia A   Sugimoto Kazutaka K   Chung Joon Yong JY   Morsett Liza L   Mulder Inge I   Fischer Paul P   Suzuki Tomoaki T   Anzabi Maryam M   Böhm Maximilian M   Qu Wen-Sheng WS   Yanagisawa Takeshi T   Hickman Suzanne S   Khoury Joseph El JE   Whalen Michael J MJ   Harriott Andrea M AM   Chung David Y DY   Ayata Cenk C  

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20190626 5


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 induce  ...[more]

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