Nitidine对脊髓损伤后神经胶质疤痕形成的调控作用及其机制研究

Spinal cord injury (SCI) is a devastating form of trauma that results in permanent functional disability, and treatments that bring about meaningful improvements in patient outcomes remain elusive. The inhibitory extrinsic environment and a diminished intrinsic regenerative capacity of mature CNS neurons have been identified as essential contributors to the failure of axonal regeneration after SCI. Although a growing body progress has been made in understanding of the consequences of SCI and the reasons for failure of spontaneous repair, no satisfactory treatment is currently available..Reactive astrogliosis, characterized by distinctive morphological and biochemical features including cell hypertrophy, upregulation of intermediate filaments, and increased cell proliferation, is a common gradated continuum of glial response to all forms of CNS insult and disease depending upon the exact pathological context. Recent evidence indicates that reactive astrogliosis in the acute phase, as an adaptive process, exert essential beneficial functions such as uptake of excitotoxic glutamate and limiting the spread of inflammation and tissue damage. However, highly localized proliferative astroglial cells, an important component of overwhelming reactive astrogliosis can finally migrate towards the injured area to constitute a dense glial scar and release factors mediating the tissue inflammatory response, which has the potential to block the growth and maturation of neural progenitors and also impede neuroregeneration and neovascularization. In addition, microglia are the first cells to be activated after SCI, rapidly migrating to the injury site and initiating much of the further astrogliosis and communication with the immune system. Therefore, reducing the presence of sustained and excessive reactive astrogliosis, which is important for functional recovery, is a promising therapeutic strategy for SCI..Nitidine is a well-known benzophenanthridine alkaloid which has received considerable attention as a potent antitumor agent following the discovery of antimalarial activity in mice. Currently, nitidine has been reported as a tumor-selective cytotoxic agent by potentially inhibiting the proliferative activity of tumor cells in vitro an in vivo. An additional line of evidence has been provided that, as hydrocortisone, nitidine exhibited comparable anti-inflammatory effect. However, little is known about the effects of nitidine on the glial scar formation in the damaged adult spinal cord..In the present study, the effects of nitidine were tested on astroglial and microglial activation, glial scar formation, axonal regeneration, and functional recovery after SCI. This work based on the experimental mouse model of spinal cord crush injury will shed light on the potential therapeutic benefit of nitidine for SCI.

脊髓损伤一直是神经科学领域研究的一个重点和难点，目前尚无有效的治疗方法。脊髓损伤后导致神经组织破坏，在损伤处形成一个不利于神经再生的局部微环境。在这局部微环境中，星形胶质细胞和小胶质细胞活化并形成致密的胶质疤痕被认为是损伤后神经轴突不能再生并穿越损伤处的主要原因之一。为了寻找能够有效调控脊髓损伤后胶质疤痕形成并促进神经功能恢复，我们通过建立体外细胞模型，筛选中药单体化合物库，发现Nitidine能够明显地抑制星形胶质细胞和小胶质细胞活化，从而有效地减轻脊髓损伤后胶质疤痕形成。本研究将综合运用细胞生物学、分子生物学、形态学和行为学等技术手段，进一步深入研究Nitidine对星形胶质细胞和小胶质细胞活化及其引起的胶质疤痕形成的调控作用和相关分子机制，分析其在神经再生和神经功能恢复中的作用，以期为临床寻找能够有效治疗脊髓损伤的先导化合物药物提供重要的理论依据。

研究表明，胶质细胞反应参与了脑外伤和脊髓损伤的病理过程。小胶质细胞是中枢神经系统内的一种免疫细胞，尽管它能够清除神经损伤后产生的细胞碎片和毒性物质，但是过度激活的细胞胶质细胞会通过释放大量的炎症因子和细胞毒性介质而加重继发性损伤，从而影响中枢神经损伤修复。实际上，抑制小胶质细胞活化反应已成为治疗中枢神经损伤的一种有效策略。Nitidine（两面针碱）是从芸香科花椒属植物两面针中提取的一类苯并菲啶类生物碱。我们研究发现，Nitidine能够抑制小胶质细胞的活化，从而促进中枢神经损伤修复。在体外，Nitidine能够通过调节ERK和NF-κB信号通路抑制小胶质细胞的活化。在体内，Nitidine也能抑制小胶质细胞的活化，从而明显地促进神经元存活并保护神经组织。更重要的是，通过BMS评估和游泳测试等行为学分析，发现Nitidine能够明显地促进小鼠脊髓损伤后的功能修复。总之，这些实验结果表明，Nitidine能够抑制小胶质细胞反应性激活，从而促进中枢神经损伤后组织存活和神经功能修复，提示Nitidine可能有利于中枢神经损伤的治疗。