Effect Of Curcumin On Inducing Endogenous Neural Stem Cells To Promote Functional Recovery After Spinal Cord Injury

Spinal cord injury(SCI) is a severe traumatic disease in central nervous system(CNS) for which no satisfying treatment is available. Conventional wisdom suggested that the key problem of nerve functional recovery after spinal cord injury was that the nerve tissue and cells could not regenerate, which cause motor and sensory dysfunction below the damaged segment. The discovery of stem cells opened a new field of the research in nerve functional recovery after central nervous system injury. At present, cell replacement therapy is the focus area of the nerve functional recovery after SCI. The commonly used methods include exogenous stem cell transplantation and the activation and induction of endogenous neural stem cells.Compared with exogenous stem cells transplantation, there is no safety and ethical issues in activating and inducting endogenous neural stem cells after spinal cord injury, in that the new nerve cells are homologous integration with the host instead of rejection reaction. However, previous study showed that most of activated ENSCs differentiate into astrocytes after spinal cord injury rather than neurons to participate in the formation of glial scar, which obviously inhibited the regeneration of axon. How to give appropriate intervention after spinal cord injury to reduce the formation glial scar and the ratio of ENSCs differentiated into astrocytes. The research of SCI indicated that multiple approaches such as medication, surgery and rehabilitation could make the plasticity of endogenous neural stem cells play a great potential to improve nerve function after SCI.The polyphenol curcumin is extracted from the rhizome of curcuma longa, used in Traditional Chinese Medical in the treatment of diseases as various as rheumatism, fever, intestinal disorder, trauma, and amenorrhea. Modern research has attributed anti-inflammatory, immunomodulatory, antimalarial, and anticancer effects to this multitalented compound and has no side effect. The research on central nervous system injury in recent years revealed that curcumin had obvious protective effect, and it could stimulate the proliferation of embryonic neural precursor cells, also improved the adult neurogenesis in the hippocampus.In this study, we used curcumin as an intervention to the spinal cord compression model and observed the functional recovery of hind limbs. Additionally, we investigated the effect and mechanism of curcumin on inducting and differentiating of endogenous neural stem cells and the formation of glial scar.Objective:To investigate the effect of curcumin on functional recovery by influence the formation of glial scar and differentiation of endogenous neural stem cells (ENSCs) after spinal cord injury (SCI).Method:One hundred and thirty-eight male Sprague-Dawley (SD) rats were randomly divided into3groups including a sham group (n=12), a simple injury group (n=63), curcumin treatment group (n=63). The sham group was performed only laminectomy. The simple injury group and curcumin treatment group were introduced70g closing force aneurysm clip injury at T9-T10segment of spinal cord for lmin. The curcumin treatment group was given200mg/kg curcumin intraperitoneally30min after SCI while the simple injury group was given equivalent amount of normal saline. The Basso, Beattie and Bresnahan (BBB) locomotor rating scale and inclined plane test were used to evaluate rat behavioral consequences at the time points of lday,1,2,4,8week. Then rats were sacrificed and the spinal cord tissue samples were harvested to observe the the pathological changes of the injured region by HE staining and the expression of Nestin, Tuj1, GFAP/CSPG by immunofluorescence. The expression of Wnt3a protein and β-catenin were determined by Western blot.5%biotinylated dextran amine(BDA) was injected into the bilateral motor cortices at the time point of8week, the corticospinal tract(CST) fibers were traced3weeks later by immunofluorescence.Results:BBB locomotor rating scale and inclined plane test showed the functional recovery of curcumin treatment group was better than simple injury group at each time point from lweek after SCI (P<0.05). The formation of glia scar surrounding the cavity at the center of lesion site was defined at4week after SCI, the expression of GFAP and CSPG significant decrease in curcumin treatment group compared with simple injury group(P<0.05). The number of corticospinal tract(CST) fibers below the injured level in curcumin treatment group was increased compared with simple injury group(P<0.05). Immunofluorescence showed that Nestin positive cells could be seen at the vicinity of the lesion site1d after SCI, reached peak at1week, obviously decrease at2week. Tuj1labeled neurons were significant increase in curcumin treatment group compared with simple injury group(P<0.05). Western Blot showed that there was almost no expression of Wnt3a and β-catenin in sham group, significant up-regulated in curcumin treatment group compared with simple injury group(P<0.05).Conclusion:Our research suggested that curcumin may promote the functional recovery after SCI through inducing ENSCs more differentiated to neurons by the activation of Wnt/β-catenin signaling pathway and inhibiting glial scar formation.