Abstract：
Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27-3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy.
摘要：
脊髓损伤（SCI）是一种破坏性的神经系统创伤，可引起永久性的感觉和运动损伤以及自主神经生理功能的缺陷。黑皮质素受体4（MC4R）是一种G蛋白连接的受体，在神经系统中广泛表达并有助于抑制炎症，调节线粒体功能，并诱导程序性细胞死亡。然而,MC4R在氧化应激调节中的作用以及该机制是否与SCI中黑色素瘤2（AIM2）缺失的作用有关，目前尚未得到证实。在目前的研究中,我们证明，在创伤和细胞氧化刺激后，MC4R在脊髓神经元中显著增加。Further,RO27-3225对MC4R的活化有效地提高了功能恢复，抑制AIM2激活，维持线粒体稳态，抑制氧化应激，并阻止Drp1易位到线粒体。同时,治疗Drp1抑制剂将有利于减少AIM2激活，激活AIM2可以消除MC4R对神经元稳态的保护作用。总之,我们证明MC4R通过抑制线粒体功能障碍的新过程保护神经损伤，氧化应激，以及AIM2激活，可以作为SCI治疗的候选药物。
