Epidural Spinal Cord Stimulation Promotes the Expansion of Endogenous Neural Stem Cells and Neuroprotection via the PI3K/AKT/ mTOR Pathway after Spinal Cord Injury in Rats.

Spinal cord injury (SCI) often leads to severe motor and sensory dysfunction, yet no effective treatment currently exists. Epidural spinal cord stimulation (ESCS) is a treatment for chronic neuropathic pain in the trunk and extremities, and exerts a significant effect on the recovery of motor function, although the underlying mechanisms remain unclear. The present study aimed to investigate the effects of ESCS on the endogenous neural stem cells (eNSCs) proliferation and neuroprotection as well as the underlying mechanisms following SCI in rats. In the present study, results showed that ESCS improved hindlimb motor function and markedly increased the numbers of surviving ventral horn neurons of the spinal cord at 7 and 28 days after SCI. ESCS significantly reduced the apoptosis of anterior horn cells in the spinal cord on day 28 post-SCI. Moreover, ESCS remarkably increased the expressions of NSCs markers nestin and sox2, as well as the proportion of nestin/sox2/DAPI-double positive cells (eNSCs) at 7 days after SCI. Notably, ESCS induced only a negligible number of Sox2/NeuN/DAPI double-positive cells at 28 days after SCI. LY294002, a selective inhibitor of phosphoinositide 3-kinase (PI3K) markedly decreased the ratios of eNSCs and surviving ventral horn neurons after ESCS treatment. Finally, ESCS increased the protein levels of phosphorylated-protein kinase B (p-Akt) and phosphorylated-mammalian target of rapamycin (p-mTOR) at 7 days after SCI, and LY294002 significantly attenuated the effects of ESCS on p-Akt and p-mTOR. This report suggests that ESCS treatment after SCI enhances the expansion of eNSCs and neuroprotection via the PI3K/AKT/mTOR signaling pathway.