Body weight-supported treadmill training enhances motor recovery and ameliorates neuron injury through the MDK/LRP-1 signaling pathway in T10 incomplete spinal cord-injured rats

Midkine (MDK) could enhance neuron survival through its endocytosis receptor, lipoprotein receptor-related protein-1 (LRP-1). This study was designed to investigate whether body weight-supported treadmill training (BWSTT) promotes motor function and ameliorates neuronal injury following T10 incomplete contusive spinal cord injury (SCI) through the MDK/LRP-1 signaling pathway. T10 incomplete contusive SCI rats underwent two weeks of BWSTT. LRP-1-siRNA was utilized during the intervention to inhibit the MDK/LRP-1 signaling pathway. The Basso, Beattie, and Bresnahan (BBB) score, three-dimensional gait analysis, Nissl and NeuN staining of the spinal cord, and protein expression of MDK/LRP-1 were evaluated. Downstream activation of PI3K/Akt and BDNF expression was analyzed in vivo and in vitro. Two weeks of BWSTT significantly improved the BBB score after spinal cord injury (SCI) and ameliorated neuronal injury in the lumbar spinal cord. Immunofluorescence co-staining of MDK with NeuN indicates that BWSTT promoted the neuronal localization of MDK. The use of LRP-1-siRNA significantly inhibited the effectiveness of exercise training in enhancing motor function and ameliorating neuronal injury. Additionally, LRP-1-siRNA also hindered the neuronal localization of MDK following exercise training. Furthermore, exercise-induced Akt activation and BDNF upregulation were diminished in vivo by LRP-1-siRNA. In vitro results demonstrated that MDK activates Akt and BDNF, while RAP, an LRP-1 inhibitor, notably inhibited this effect. The neuroprotective effect of exercise training after SCI may be mediated, at least in part, through the MDK/LRP-1 signaling pathway, which promotes Akt activation and BDNF upregulation, contributing to neuronal survival and motor recovery after BWSTT in T10 incomplete spinal cord-injured rats.