Suppression of histone deacetylases by SAHA relieves bone cancer pain in rats via inhibiting activation of glial cells in spinal dorsal horn and dorsal root ganglia
| Autor: | Fa Ming Chen, Ze Xu Gu, Chen Zhang, Jian Ping Deng, Wei Wang, Yan Yan Wei, Kai Xiang Zhou, Chang Le Wu, Xiao Tao He, Wen Jun Zhao, Yu Lin Dong, Chao Zhu, Xiao Han, Xiao Fan Hu |
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| Rok vydání: | 2020 |
| Předmět: |
Spinal dorsal horn
Spinal Cord Dorsal Horn Immunology H&E stain Bone Neoplasms Pharmacology lcsh:RC346-429 Proinflammatory cytokine Rats Sprague-Dawley Pathogenesis Cellular and Molecular Neuroscience Neuroinflammation Downregulation and upregulation Western blot Ganglia Spinal Glial cells medicine Animals Bone cancer pain lcsh:Neurology. Diseases of the nervous system Analgesics Vorinostat medicine.diagnostic_test Chemistry Histone deacetylase 2 Research General Neuroscience HDACs Cancer Pain HDAC1 Rats Histone Deacetylase Inhibitors Neurology Female Neuroglia |
| Zdroj: | Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-20 (2020) Journal of Neuroinflammation |
| ISSN: | 1742-2094 |
| DOI: | 10.1186/s12974-020-01740-5 |
| Popis: | Background Robust activation of glial cells has been reported to occur particularly during the pathogenesis of bone cancer pain (BCP). Researchers from our group and others have shown that histone deacetylases (HDACs) play a significant role in modulating glia-mediated immune responses; however, it still remains unclear whether HDACs are involved in the activation of glial cells during the development of BCP. Methods BCP model was established by intra-tibia tumor cell inoculation (TCI). The expression levels and distribution sites of histone deacetylases (HDACs) in the spinal dorsal horn and dorsal root ganglia were evaluated by Western blot and immunofluorescent staining, respectively. Suberoylanilide hydroxamic acid (SAHA), a clinically used HDAC inhibitor, was then intraperitoneally and intrathecally injected to rescue the increased expression levels of HDAC1 and HDAC2. The analgesic effects of SAHA administration on BCP were then evaluated by measuring the paw withdrawal thresholds (PWTs). The effects of SAHA on activation of glial cells and expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in the spinal dorsal horn and dorsal root ganglia of TCI rats were further evaluated by immunofluorescent staining and Western blot analysis. Subsequently, the effects of SAHA administration on tumor growth and cancer cell-induced bone destruction were analyzed by hematoxylin and eosin (HE) staining and micro-CT scanning. Results TCI caused rapid and long-lasting increased expression of HDAC1/HDAC2 in glial cells of the spinal dorsal horn and dorsal root ganglia. Inhibiting HDACs by SAHA not only reversed TCI-induced upregulation of HDACs but also inhibited the activation of glial cells in the spinal dorsal horn and dorsal root ganglia, and relieved TCI-induced mechanical allodynia. Further, we found that SAHA administration could not prevent cancer infiltration or bone destruction in the tibia, which indicated that the analgesic effects of SAHA were not due to its anti-tumor effects. Moreover, we found that SAHA administration could inhibit GSK3β activity in the spinal dorsal horn and dorsal root ganglia, which might contributed to the relief of BCP. Conclusion Our findings suggest that HDAC1 and HDAC2 are involved in the glia-mediated neuroinflammation in the spinal dorsal horn and dorsal root ganglia underlying the pathogenesis of BCP, which indicated that inhibiting HDACs by SAHA might be a potential strategy for pain relief of BCP. |
| Databáze: | OpenAIRE |
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