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Suberoylanilide Hydroxamic Acid Triggers Autophagy by Influencing the mTOR Pathway in the Spinal Dorsal Horn in a Rat Neuropathic Pain Model

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Abstract

Histone acetylation levels can be upregulated by treating cells with histone deacetylase inhibitors (HDACIs), which can induce autophagy. Autophagy flux in the spinal cord of rats following the left fifth lumber spinal nerve ligation (SNL) is involved in the progression of neuropathic pain. Suberoylanilide hydroxamic acid (SAHA), one of the HDACIs can interfere with the epigenetic process of histone acetylation, which has been shown to ease neuropathic pain. Recent research suggest that SAHA can stimulate autophagy via the mammalian target of rapamycin (mTOR) pathway in some types of cancer cells. However, little is known about the role of SAHA and autophagy in neuropathic pain after nerve injury. In the present study, we aim to investigate autophagy flux and the role of the mTOR pathway on spinal cells autophagy activation in neuropathic pain induced by SNL in rats that received SAHA treatment. Autophagy-related proteins and mTOR or its active form were assessed by using western blot, immunohistochemistry, double immunofluorescence staining and transmission electron microscopy (TEM). We found that SAHA decreased the paw mechanical withdrawal threshold (PMWT) of the lower compared with SNL. Autophagy flux was mainly disrupted in the astrocytes and neuronal cells of the spinal cord dorsal horn on postsurgical day 28 and was reversed by daily intrathecal injection of SAHA (n = 100 nmol/day or n = 200 nmol/day). SAHA also decreased mTOR and phosphorylated mTOR (p-mTOR) expression, especially p-mTOR expression in astrocytes and neuronal cells of the spinal dorsal horn. These results suggest that SAHA attenuates neuropathic pain and contributes to autophagy flux in astrocytes and neuronal cells of the spinal dorsal horn via the mTOR signaling pathway.

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Abbreviations

SAHA:

Suberoylanilide hydroxamic acid

mTOR:

Mammalian target of rapamycin

p-mTOR:

Phosphorylated mTOR

PMWT:

Paw mechanical withdrawal threshold

SNL:

Spinal nerve ligation

HDACI:

Histone deacetylation inhibitor

HDAC:

Histone deacetylase

LC3:

Microtubule associated protein light chain 3

CNS:

Central nervous system

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Acknowledgements

This work was supported by the National Nature Science Foundation of China (No. 81471858) and the Scientific Research Program of Hubei Health and Family Planning Committee (No. WJ2017M036).

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  1. Department of Anesthesiology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Rd, Wuhan, 430071, Hubei, China

    Xiang-Lan Feng, Hong-Bo Deng, Zheng-Gang Wang, Yun Wu, Jian-Juan Ke & Xiao-Bo Feng

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Feng, XL., Deng, HB., Wang, ZG. et al. Suberoylanilide Hydroxamic Acid Triggers Autophagy by Influencing the mTOR Pathway in the Spinal Dorsal Horn in a Rat Neuropathic Pain Model. Neurochem Res 44, 450–464 (2019). https://doi.org/10.1007/s11064-018-2698-1

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