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Gastrodin Attenuates Lipopolysaccharide-Induced Inflammatory Response and Migration via the Notch-1 Signaling Pathway in Activated Microglia

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Abstract

Microglia-mediated neuroinflammation is known to play a pivotal role in the pathogenesis of different neurological diseases. Gastrodin, a phenolic glucoside, has been reported to exert anti-inflammatory effects in activated microglia challenged with lipopolysaccharide (LPS); however, the underlying mechanism has remained obscure. The present study aimed to ascertain if Gastrodin would regulate the Notch signaling pathway involved in microglia activation. We show here that LPS increased the expression of various members of the Notch-1 pathway, including intracellular Notch receptor domain (NICD), recombining binding protein suppressor of hairless (RBP-Jκ) and transcription factor hairy and enhancer of split-1 (Hes-1) in microglia in postnatal rat brain and in BV-2 microglia. Remarkably, Gastrodin was found to markedly attenuate the expression of the above various biomarkers both in vivo and in vitro. Moreover, increased phosphorylation level of ERK, JNK and P38 induced by LPS was attenuated with pretreatment of Notch-1 signaling inhibitor, N-[N-(3,5-difluorophenacetyl)-1-alany1-Sphenyglycinet-butylester (DAPT) as well as Gastrodin. Gastrodin mimicked the effects of DAPT by inhibiting the LPS-induced expression of IL-1β, IL-6, IL-23, TNF-α and NO. Moreover, lentivirus transfection mediated NICD overexpression inhibited the anti-inflammatory effects of Gastrodin. Furthermore, the activation of Notch-1 signaling promoted microglia migration and Gastrodin could inhibit the migration of activated BV-2 microglia by regulating the Notch-1 signaling pathway. In light of the above, our results indicate that Notch-1 signaling pathway is involved in the anti-inflammatory effects of Gastrodin against LPS-induced microglia activation. These findings provide a new biological target of Gastrodin for the treatment of neuroinflammatory disorders.

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Data Availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

AD:

Alzheimer’s disease

ADAM:

A Disintegrin and Metalloproteinase

CNS:

Central nervous system

COX-2:

Cyclooxygenase-2

DAPT:

N-[N-(3,5-Difluorophenacetyl)-1-alany1-sphenygl-ycinet-butylester

DMEM:

Dulbecco’s Modified Eagle Medium

ECL:

Enhanced chemiluminescence

ELISA:

Enzyme-linked immunosorbent assay

ERK:

Extracellular signal-regulated kinases

FBS:

Fetal bovine serum

Hes-1:

Hairy and enhancer of split-1

IL-10:

Interleukin-10

IL-1β:

Interleukin-1β

IL-23:

Interleukin-23

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

JNK:

C-Jun N-terminal kinase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemotactic protein-1

NO:

Nitric oxide

PD:

Parkinson’s disease

PVDF membranes:

Polyvinylidene fluoride membranes

RBP-Jκ:

Recombining binding protein suppressor of hairless

ROS:

Reactive oxygen species

RT-PCR:

Real time polymerase chain reactions

TBS:

Tris-buffered saline

TNF-α:

Tumor necrosis factor-α

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Funding

This study was supported by the National Natural Sciences Foundation of China (Grants Nos. 81960251, 31760292, 81460210, 81360200), Department project of Science and Technology of Yunnan Province (Grants Nos. 2017FA035, 2019ZF011-2, 2018IA048, 2018FE001(-029), 202001AY070001-174) and the Department project of Education of Yunnan Province (Grants No. 2019J1214).

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Author notes

  1. Yue-yi Yao and Run Li have contributed equally to this work.

Authors and Affiliations

  1. Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Kunming, 650500, Yunnan, People’s Republic of China

    Yue-yi Yao, Yu Zhao, Jia-zhi Guo & Di Lu

  2. Department of Neurology, The First Affiliated Hospital, Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan, People’s Republic of China

    Run Li, Yan-ji Guo, Qing-long Ai & Lian-mei Zhong

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  1. Yue-yi Yao
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Y.Y., R.L., Y.Z. and J.G.; the first draft of the manuscript was written by Y.Y. and Y.G.; D.L. and L.Z. designed experiments and obtained science grant support. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lian-mei Zhong or Di Lu.

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All animal experiments were designed to minimize suffering and the number of animals used. All procedures were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications number 80-23). The project was approved by the Department of Science and Technology, Yunnan Province, China.

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Yao, Yy., Li, R., Guo, Yj. et al. Gastrodin Attenuates Lipopolysaccharide-Induced Inflammatory Response and Migration via the Notch-1 Signaling Pathway in Activated Microglia. Neuromol Med 24, 139–154 (2022). https://doi.org/10.1007/s12017-021-08671-1

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