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Gastrodin Inhibits Inflammasome Through the STAT3 Signal Pathways in TNA2 Astrocytes and Reactive Astrocytes in Experimentally Induced Cerebral Ischemia in Rats

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Abstract

This study was aimed to determine Gastrodin (GAS) and its underlying signaling pathway involved in suppression of inflammasome specifically in reactive astrocytes that are featured prominently in different neurological conditions or diseases including cerebral ischemia. For this purpose, TNA2 astrocytes in cultures were exposed to oxygen–glucose–deprivation (OGD) mimicking hypoxic cerebral ischemia. Separately, TNA2 cells were pretreated with GAS prior to OGD exposure. Additionally, Stattic, an inhibitor of STAT3 signaling pathway, was used to ascertain its involvement in regulating inflammasome in astrocytes exposed to OGD. In parallel to the above, adult rats subjected to middle cerebral artery occlusion (MCAO) with or without GAS pretreatment were sacrificed at different time points to determine the effects of GAS on astrocyte inflammasome. TNA2 astrocytes in different treatments as well as reactive astrocytes in MCAO were processed for immunofluorescence labeling and Western blot analysis for various protein markers. In the latter, protein expression levels of p-STAT3, NLRP3, and NLRC4 were markedly increased in TNA2 astrocytes exposed to OGD. Remarkably, the expression levels of these biomarkers were significantly suppressed by GAS. Of note, GAS especially at dose 20 μM inhibited NLRP3 and NLRC4 expression levels most substantially. Moreover, GAS inhibited the downstream proteins caspase-1 and IL-18. Concomitantly, GAS significantly suppressed the expression of STAT3 and NF-κB signaling pathway. It is noteworthy that Stattic at dose 100 μM inhibited STAT3 pathway and NF-κB activation in TNA2 astrocytes, an effect that was shared by GAS. In MCAO, GAS was found to effectively attenuate p-STAT3 immunofluorescence intensity in reactive astrocytes. Arising from the above, it is concluded that GAS is anti-inflammatory as it effectively suppresses inflammasome in OGD-stimulated astrocytes as well as in reactive astrocytes in MCAO via STAT3 and NF-κB signaling expression coupled with decreased expression of caspase-1 and IL-18.

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Abbreviations

GAS:

Gastrodin

OGD:

Oxygen glucose deprivation

MCAO:

Middle cerebral artery occlusion

STAT3:

Signal transducers and activators of transcription

NLRP3:

Nod-like receptor protein-3

NLRC4:

NLR Family CARD Domain Containing 4

NF-κB:

Nuclear factor κB

GFAP:

Glial fibrillary acidic protein

DMEM:

Dulbecco’s modified Eagle’s medium

TBS:

Tris-buffered saline

FBS:

Fetal bovine serum

PVDF:

Polyvinylidene fluoride

PBS:

Phosphate-buffered saline

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Funding

This research was supported by National Natural Science Foundation of China (Grant Nos. 31760292, 81460210, 81360200, and 81460350) and Yunnan Applied Basic Research Project (Grant Nos. 2017FA035, 2018FE001(-017), 2018FE001(-029) and 2013FB120).

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Correspondence to Lianmei Zhong or Di Lu.

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The authors declare that they have no conflict of interest.

Ethical Approval of Animal Studies

All animal procedures and studies were carried out in accordance with the guidelines as stipulated by the Opinions on Treating Experimental Animals of the Ministry of Science and Technology of China (2006).

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Sui, Y., Bian, L., Ai, Q. et al. Gastrodin Inhibits Inflammasome Through the STAT3 Signal Pathways in TNA2 Astrocytes and Reactive Astrocytes in Experimentally Induced Cerebral Ischemia in Rats. Neuromol Med 21, 275–286 (2019). https://doi.org/10.1007/s12017-019-08544-8

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  • DOI: https://doi.org/10.1007/s12017-019-08544-8

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