Gastrodin Regulates the Notch Signaling Pathway and Sirt3 in Activated Microglia in Cerebral Hypoxic-Ischemia Neonatal R

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ORIGINAL PAPER

Gastrodin Regulates the Notch Signaling Pathway and Sirt3 in Activated Microglia in Cerebral Hypoxic‑Ischemia Neonatal Rats and in Activated BV‑2 Microglia Jing Guo1 · Xiao‑Li‑Na Zhang1,2 · Zhang‑Rui Bao1 · Xue‑Ke Yang1 · Ling‑Shuang Li1 · Yu Zi1 · Fan Li3 · Chun‑Yun Wu1 · Juan‑Juan Li1 · Yun Yuan1  Received: 6 August 2020 / Accepted: 16 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract In response to hypoxic-ischemic brain damage (HIBD), microglia activation and its mediated inflammation contribute to neuronal damage. Inhibition of over-activated microglia is deemed to be a potential therapeutic strategy. Our previous studies showed that gastrodin efficiently depressed the neuroinflammation mediated by activated microglia in HIBD neonatal rats. The underlying mechanisms through which gastrodin acts on activated microglia have not been fully elucidated. This study is designed to determine whether gastrodin would regulate the Notch signaling pathway and Sirtuin3 (Sirt3), which are implicated in regulating microglia activation. The present results showed that gastrodin markedly suppressed the expression of members of Notch signaling pathway (Notch-1, NICD, RBP-JK and Hes-1) in activated microglia both in vivo and in vitro. Conversely, Sirt3 expression was enhanced. In BV-2 microglia treated with a γ-secretase inhibitor of Notch pathway- DAPT, the expression of RBP-JK, Hes-1, and NICD was suppressed in activated microglia. Treatment with DAPT and gastrodin further decreased NICD and Hes-1 expression. Sirt3 expression was also decreased after DAPT treatment. However, Sirt3 expression in activated BV-2 microglia given a combined DAPT and gastrodin treatment was not further increased. In addition, combination of DAPT and Gastrodin cumulatively decreased tumor necrosis factor-α (TNF-α) expression. The results suggest that gastrodin regulates microglia activation via the Notch signaling pathway and Sirt3. More importantly, interference of the Notch signaling pathway inhibited Sirt3 expression, indicating that Sirt3 is a downstream gene of the Notch signaling pathway. It is suggested that Notch and Sirt3 synergistically regulate microglia activation such as in TNF-α production. Keywords  Activated microglia · Gastrodin · Notch signaling pathway · Sirtuin 3 · Hypoxic-ischemic brain damage Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s1201​7-020-08627​-x) contains supplementary material, which is available to authorized users.

Abbreviations AD Alzheimer’s disease AT1 Angiotensin II receptor 1

* Juan‑Juan Li [email protected]

Yu Zi [email protected]

* Yun Yuan [email protected]

Fan Li [email protected]

Jing Guo [email protected]

Chun‑Yun Wu [email protected]

Xiao‑Li‑Na Zhang [email protected]

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Zhang‑Rui Bao [email protected]

Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming 650500, China

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