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Salidroside Inhibits Reactive Astrogliosis and Glial Scar Formation in Late Cerebral Ischemia via the Akt/GSK-3β Pathway

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Abstract

Cerebral ischemia leads to reactive astrogliosis and glial scar formation. Glial scarring can impede functional restoration during the recovery phase of stroke. Salidroside has been shown to have neuroprotective effects after ischemic stroke, but its impact on long-term neurological recovery, especially whether it regulates reactive astrogliosis and glial scar formation, is unclear. In this study, male adult C57/BL6 mice were subjected to transient cerebral ischemia injury followed by intravenous salidroside treatment. Primary astrocytes were treated with lipopolysaccharide (LPS) or conditioned medium from cultured primary neurons subjected to oxygen-glucose deprivation (CM-OGD). Salidroside significantly improved long-term functional outcomes following ischemic stroke in the rotarod and corner tests. It also reduced brain glial scar volume and decreased expression of the glial scar marker, glial fibrillary acidic protein (GFAP) and inhibited astrocyte proliferation. In primary astrocyte cultures, salidroside protected astrocytes from CM-OGD injury-induced reactive astroglial proliferation, increasing the percentage of cells in G0/G1 phase and reducing the S populations. The inhibitory effect of salidroside on the cell cycle was related to downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4) mRNA expression and increased p27Kip1 mRNA expression. Similar results were found in the LPS-stimulated injury model in astroglial cultures. Western blot analysis demonstrated that salidroside attenuated the CM-OGD-induced upregulation of phosphorylated Akt and glycogen synthase kinase 3β (GSK-3β). Taken together, these results suggested that salidroside can inhibit reactive astrocyte proliferation, ameliorate glial scar formation and improve long-term recovery, probably through its effects on the Akt/GSK-3β pathway.

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Abbreviations

BrdU:

5-bromo-2′-deoxyuridine

CDK4:

Cyclin-dependent kinase 4

CM-OGD:

Conditioned medium suffering from oxygen-glucose deprivation

CNS:

Central nervous system

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

GFAP:

Glial fibrillary acidic protein

GSK-3β:

Glycogen synthase kinase 3β

LPS:

Lipopolysaccharide

MAP2:

Microtubule-associated protein 2

MCAO:

Middle cerebral artery occlusion

OGD:

Oxygen-glucose deprivation

PBS:

Phosphate buffered saline

SD:

Sprague-Dawley

tPA:

Tissue plasminogen activator.

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Acknowledgements

XL and CD designed the study. CD, SW, SZ, and XL performed the experiments. SW, SS, and WD analyzed the data. CD, SZ, PH, QC, TG, WC and WL arranged the Figs. CD and XL wrote the draft, SZ and SS revised the draft. All the authors approved the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (81871021, 81471209, 81641055) and the National Science and Technology Major Project (2017ZX09304018).

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Authors and Affiliations

  1. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China

    Chengya Dong, Shaohong Wen, Shunying Zhao, Wen Dong, Qingfang Chen, Ting Gong, Wentao Chen, Wenqian Liu & Xiangrong Liu

  2. Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100176, People’s Republic of China

    Si Sun & Shangfeng Zhao

  3. Department of Biomedicine, Beijing City University, Beijing, 100094, People’s Republic of China

    Pingxin Han & Ting Gong

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  1. Chengya Dong
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Dong, C., Wen, S., Zhao, S. et al. Salidroside Inhibits Reactive Astrogliosis and Glial Scar Formation in Late Cerebral Ischemia via the Akt/GSK-3β Pathway. Neurochem Res 46, 755–769 (2021). https://doi.org/10.1007/s11064-020-03207-8

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