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.