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Gastrodin Regulates PI3K/AKT-Sirt3 Signaling Pathway and Proinflammatory Mediators in Activated Microglia

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Abstract

Activated microglia and their mediated inflammatory responses play an important role in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Therefore, regulating microglia activation is considered a potential therapeutic strategy. The neuroprotective effects of gastrodin were evaluated in HIBD model mice, and in oxygen glucose deprivation (OGD)-treated and lipopolysaccharide (LPS)activated BV-2 microglia cells. The potential molecular mechanism was investigated using western blotting, immunofluorescence labeling, quantitative realtime reverse transcriptase polymerase chain reaction, and flow cytometry. Herein, we found that PI3K/AKT signaling can regulate Sirt3 in activated microglia, but not reciprocally. And gastrodin exerts anti-inflammatory and antiapoptotic effects through the PI3K/AKT-Sirt3 signaling pathway. In addition, gastrodin could promote FOXO3a phosphorylation, and inhibit ROS production in LPSactivated BV-2 microglia. Moreover, the level P-FOXO3a decreased significantly in Sirt3-siRNA group. However, there was no significant change after gastrodin and siRNA combination treatment. Notably, gastrodin might also affect the production of ROS in activated microglia by regulating the level of P-FOXO3a via Sirt3. Together, this study highlighted the neuroprotective role of PI3K/AKT-Sirt3 axis in HIBD, and the anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects of gastrodin on HIBD.

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Data Availability

All data supporting this study are available from the corresponding author upon reasonable request.

Abbreviations

HIBD:

Hypoxic-ischemia brain damage

CNS:

Central nervous system

Sirt3:

Sirtuin3

LPS:

Lipopolysaccharide

OGD:

Oxygen-glucose deprivation

PI3Ks:

Phosphoinositol 3 kinases

AD:

Alzheimer’s disease

NAD:

Niacinamide adenine dinucleotide

IL-1β:

Interleukin-1β

TNF-α:

Tumor necrosis factor-α

iNOS:

Inducible nitric oxide synthase

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

BCA:

Bicinchoninic acid

ROS:

Reactive oxygen species

M1:

Pro-inflammatory

M2:

Anti-inflammatory

LY294002:

PI3K/AKT pathway inhibitor

FOXO3a:

Forkhead box O3

CD:

Cluster of differentiation

DAPI:

6-diamidino-2-phenylindole

IBA-1:

Ionized calcium-binding adaptor molecule

PBS:

Phosphate-buffered saline

PVDF:

Polyvinylidene fluoride

TTC:

2,3,5-Triphenyltetrazolium chloride staining

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Acknowledgements

The authors gratefully acknowledge the financial support: National Natural Science Foundation of China (No. 31960194, 31460274, J-J Li), Applied Basic Research Projects of Yunnan Province of China (No. 2019FE001 (-003), J-J Li), Scientific Research Fund Project of Education Department of Yunnan Province(No. K13219546, H-J Zuo) and Supported by the Special Fund of Clinical Research Center for Neurological Diseases of Yunnan Province(No. ZX2019030501, C Wan).

Funding

This project was supported by grants from National Natural Science Foundation of China (No. 31960194, 31460274, J-J Li), Applied Basic Research Projects of Yunnan Province of China (No. 2019FE001 (-003), J-J Li), Scientific Research Fund Project of Education Department of Yunnan Province(No. K13219546, H-J Zuo) and Supported by the Special Fund of Clinical Research Center for Neurological Diseases of Yunnan Province(No. ZX2019030501, C Wan).

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  1. Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, Yunnan, 650500, China

    Han-Jun Zuo, Peng-Xiang Wang, Xue-Qi Ren, Hao-Long Shi, Jin-Sha Shi, Tao Guo & Juan-Juan Li

  2. Department of Medical Imaging, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650031, China

    Cheng Wan

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Contributions

J-JL conceptualized and designed this study. J-JL supervised the whole project. H-JZ, P-XW, X-QR, H-LS, J-SS, TG and C-W carried out the experiments. H-JZ performed acquisition and analysis of data. H-JZ and J-JL prepared the manuscript. All authors read and approved the final manuscript.

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Correspondence to Juan-Juan Li.

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Supplementary Material 1: Fig. 1 The results of Nissl staining. (A-B) The results showed that the infarcted region was lighter in staining than the sham group at two time points 1d and 3d after HIBD. The number of degeneration neurons was significantly increased in the infarction and penumbral area, and the nucleus was denatured and deeply stained, and the disappearance of Nissl bodies and other intracellular components. However, the number of denatured necrotic neurons in the infarcted cerebral cortex or penumbral region decreased after gastrodin treatment, and was comparable to that of the sham mice. It suggests that gastrodin treatment can effectively reduce neuronal necrosis. Scale bar: 1000 μm(A1-A3, C1-C3) and 50 μm(B1-B3, D1-D3). Fig. 2 The results of Tunel staining. (A-B)The 1d and 3d after HIBD showed that, compared with Sham group, the number of Tunel positive cells was significantly increased in the cerebral cortex infarction and penumbral area of mice. However, the number of Tunel positive cells decreased obviously after gastrodin treatment. The green shows tunel positive cells of HIBD mice. DAPI (blue) shows the nucleus. Scale bar: 1000 μm(A1-A3, C1-C3) and 50 μm(B1-B3, D1-D3). Fig. 3 The cell viability assay of BV-2 microglia, and level of TNF-α by ELISA detdcted. (A) Incubation of BV-2 microglia with gastrodin (0–1 mg/mL) for 1 h did not result in significant cell death. (B) The result of ELISA showed the change in TNF-α level in BV-2 microglia was increased in the LPS group compared with the control group. and the levels in the gastrodin groups (0.17 mM, 0.34 mM) was significantly decreased when compared with the LPS group. *p < 0.05; **p < 0.01; ***p < 0.001. The values represent the mean ± SEM in triplicate.

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Zuo, HJ., Wang, PX., Ren, XQ. et al. Gastrodin Regulates PI3K/AKT-Sirt3 Signaling Pathway and Proinflammatory Mediators in Activated Microglia. Mol Neurobiol 61, 2728–2744 (2024). https://doi.org/10.1007/s12035-023-03743-8

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