18kDa转运蛋白(TSPO)配体etifoxine对臂丛损伤神经元的保护及促其再生作用的研究

The high prevalence of brachial plexus injuries due to traffic accidents or shoulder dystocia and the permanent disability caused by these injuries stress the need for efficient therapeutic approaches. In our attempts to repair the motor nerve pathway, we have successfully bridged the avulsed cervical spinal ventral root to the cervical spinal cord through an implanted nerve graft in rats and primates (Liu et al. 1997; 1998). Whereas stress recovery is achievable to some extent, persisting sensory deficit limits functional benefits. We have recently developed a treatment method to repair sensory nerve pathway after spinal dorsal root injury. The method relies on microsurgical reconstruction combined with a neurotrophic factor therapy in order to promote regrowth of the sectioned spinal dorsal root into the spinal cord (Liu et al., 2009; 2011). This treatment provides means to reduce disability due to somatosensory defects after brachial plexus injury. Since numbers of regenerating axons and their speed of elongation towards the targets are the main limiting factors for functional reinnervation of the denervated target, an effective treatment to protect the injured neurons and stimulate endogenous capacity of their axonalregeneration is still needed in these repair models. We have recently assessed the potency of translocator protein 18 kDa (TSPO) ligand etifoxine, a clinically approved drug already used for the treatment of anxiety disorders, to promote axonal regeneration in rat after sciatic nerve injury (Girard et al., 2008). We found that etifoxine therapy resulted in acceleration of axonal regeneration in and downstream of the lesion, demonstrating that it is remarkably efficient in promoting peripheral nerve regeneration and functional recovery. In order to effectively treating plexus brachial injury, we design here to test the effects of TSPO ligand etifoxine on neuroprotection and axonal regeneration in a mouse spinal nerve injury model. This model is simple and reproducible, which induces important loss of both spinal motoneurons and primary sensory neurons in the same time. With the same model, we will also assess the mechanism of its effects on neuroprotection and axonal regeneration. Etifoxine, which can easily enter nervous tissues and regulates multiple functions in a concerted manner, offers a great hope of use in patients for the treatment of peripheral nerve injuries. It is expected that TSPO ligand treatment may lead to a rapid and effective functional reinnervation of the paralyzed targets by the spinal motoneurons or the primary sensory neurons after spinal nerve injury, thus providing proof-of-concept for further studies in humans.

研究证明神经损伤后受损神经元的成活数量及其轴突再生能力和速度是神经功能修复的关键，因此寻找能有效保护神经元和促进其轴突再生的方法是研究的重点。在前期研究中我们应用显微外科技术分别重建了脊髓运动前根和感觉背根使大鼠臂丛根性损伤后运动或感觉功能有了一定的恢复，但程度有限，其主要原因是损伤神经元成活的数量低及再生能力差。我们拟与法国巴黎十一大学混合实验室（UMR788）合作进行18kDa转运蛋白（TSPO）配体etifoxine对神经保护及促其再生作用的实验研究。etifoxine是临床上用于治疗焦虑症的药物，研究发现其具有促进周围神经再生和功能恢复的作用。我们设计了可同时引起脊髓前角运动神经元及背根节感觉神经元损伤凋亡的小鼠臂丛脊神经及背根损伤模型，拟在此模型上引入etifoxine治疗，观察其对损伤运动及感觉神经元的保护和促轴突再生作用，并探讨其作用机制，为神经损伤的治疗提供更有效的方法。

目的 证实孕酮的促进髓鞘再生和神经保护功能并研究etifoxine对臂丛神经损伤后的神经保护和促轴突再生的作用。 方法 将30只大鼠随机分为三组：A组（孕酮组）、B组（溶剂组）和C组（盐水组）。将大鼠制成臂丛损伤模型，术后两周每日每只大鼠腹腔注射药物，3个月后进行痛、温觉及电生理检测。 结果 术后3个月，大鼠痛觉检测结果显示A组与B组和C组比较均有显著差异（P<0.001）。大鼠温觉检测结果显示A组与B组比较有显著差异（P<0.01）。对大鼠进行运动传导电位及体感诱发电位检测，两者波幅结果显示A组的运动电位和体感电位波幅均高于B组及C组，但并无统计学差异（P>0.05）。 结论 孕酮对大鼠臂丛神经损伤后的功能恢复有促进作用，对促进大鼠损伤后的感觉功能恢复有明显作用。但术后长期电生理检测显示，孕酮无明显效果。进一步研究及检测还在进行。