Department of Orthopaedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University.
Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, the First Affiliated Hospital, Jinan University.
Biol Pharm Bull. 2024;47(10):1734-1745. doi: 10.1248/bpb.b23-00603.
Spinal cord injury (SCI), a public health problem caused by mechanical injury, leads to secondary excessive inflammatory reactions and long-term damage to neurological function. ACY1215 is a highly selective histone deacetylase 6 (HDAC6) inhibitor and reportedly has anti-inflammatory effects; however, its regulatory role in SCI has not been studied. The purpose of this study was to explore the role of ACY1215 in preventing inflammation, inhibiting astrogliosis, enhancing remyelination and preserving axons after spinal cord injury and further exploring the possible cellular signaling pathways involved. First, lipopolysaccharide (LPS) was utilized to stimulate rat astrocytes in vitro. Quantitative RT (qRT)-PCR and Western blotting showed that ACY1215 inhibited the expression of glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) in LPS-activated astrocytes. In addition, Western blotting results showed that ACY1215 could inhibit the signal transduction pathway of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). In vivo, ACY1215 could exert anti-inflammatory effects by inhibiting the expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Moreover, ACY1215 repaired spinal cord injury by reducing the formation of glial scars and promoting remyelination and nerve recovery. In summary, ACY1215 can inhibit the NF-κB and STAT3 signaling pathways in astrocytes, reduce inflammation and ameliorate SCI. Our results provide a novel strategy for the treatment of SCI.
脊髓损伤（SCI）是一种由机械损伤引起的公共卫生问题，导致继发性过度炎症反应和长期神经功能损害。ACY1215 是一种高度选择性的组蛋白去乙酰化酶 6（HDAC6）抑制剂，据报道具有抗炎作用；然而，其在 SCI 中的调节作用尚未得到研究。本研究旨在探讨 ACY1215 在预防炎症、抑制星形胶质细胞增生、增强髓鞘再生和保护轴突方面的作用，进一步探讨其涉及的可能细胞信号通路。首先，利用脂多糖（LPS）在体外刺激大鼠星形胶质细胞。定量 RT-PCR 和 Western blot 结果表明，ACY1215 抑制 LPS 激活的星形胶质细胞中神经胶质纤维酸性蛋白（GFAP）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNFα）的表达。此外，Western blot 结果表明，ACY1215 可以抑制核因子-κB（NF-κB）和信号转导子和转录激活子 3（STAT3）的信号转导通路。在体内，ACY1215 可以通过抑制炎症细胞因子（包括 IL-1β、IL-6 和 TNFα）的表达发挥抗炎作用。此外，ACY1215 通过减少胶质瘢痕的形成和促进髓鞘再生和神经恢复来修复脊髓损伤。总之，ACY1215 可以抑制星形胶质细胞中 NF-κB 和 STAT3 信号通路，减轻炎症反应，改善 SCI。我们的研究结果为 SCI 的治疗提供了一种新的策略。
