Abstract
Spinal cord injury (SCI) is a traumatic injury to the central nervous system (CNS) with a high rate of disability and a low capability of self-recovery. Phosphatase and tensin homolog (PTEN) inhibition by pharmacological blockade with bisperoxovanadium (pic) (bpV(pic)) has been reported to increase AKT/mTOR activity and induce robust axonal elongation and regeneration. However, the therapeutic effect of bpV(pic) in treating SCI is limited due to the lack of efficient delivery approaches. In this study, a composite scaffold consisting of an acellular spinal cord (ASC) scaffold and incorporated bpV(pic) loaded poly (lactic-co-glycolic acid) (PLGA) microspheres was developed, in order to improve the therapeutic effect of bpV(pic) on SCI. The inhibition of PTEN activity and activation of the mTORC1/AKT pathway, the axonal regeneration and the markers of apoptosis were analyzed via western blot and immunofluorescence in vitro. The bpV(pic)/PLGA/ASC scaffolds showed excellent biocompatibility and promoted the viability of neural stem cells and axonal growth in vitro. Implantation of the composite scaffold into rats with hemi-sectioned SCI resulted in increased axonal regeneration and functional recovery in vivo. Besides, bpV(pic) inhibited the phosphorylation of PTEN and activated the PI3K/mTOR signaling pathway. The successful construction of the composite scaffold improves the therapeutic effect of bpV(pic) on SCI.
Highlights
Spinal cord injury (SCI), a serious traumatic injury to the spinal cord and central nervous system, is a major cause of motor disability and death.[1,2] It is associated with limited functional recovery, mainly due to the limited endogenous regeneration capacity of host spinal cord tissue.[3,4] SCI causes severance of axons and death of neurons, which lead to permanent functional impairments.[5,6] The pathophysiology of acute SCI consists of both primary and secondary injuries
Inhibiting the expression of Phosphatase and tensin homolog (PTEN) promotes neural stem cells (NSCs) differentiation and axonal growth To determine the potential role of PTEN in NSC differentiation, the level of PTEN expression during NSC differentiation (NSCs were incubated in neuronal differentiation induction medium (NIM)) was examined from day 0 to day 14, via western blot analysis
When NSCs were incubated with both NIM and bpV(pic), b-III-tubulin expression increased with increasing incubation time, which was examined using western blot analysis (Fig. 1f) and immuno uorescence staining analysis (Fig. 1g and h)
Summary
Spinal cord injury (SCI), a serious traumatic injury to the spinal cord and central nervous system, is a major cause of motor disability and death.[1,2] It is associated with limited functional recovery, mainly due to the limited endogenous regeneration capacity of host spinal cord tissue.[3,4] SCI causes severance of axons and death of neurons, which lead to permanent functional impairments.[5,6] The pathophysiology of acute SCI consists of both primary and secondary injuries. Secondary injury spreads from the primary injury site causing further tissue loss and dysfunction as well as a cascade of biological stress responses.[7] Restricting the development of secondary injury and enhancing the intrinsic growth ability of neurons, which naturally declines during development, bears the possibility to improve functional recovery a er SCI.[8,9] Current therapeutic strategies for SCI include surgical decompression and pharmacotherapy.[10,11,12] due to the limited understanding of the mechanisms involved in SCI progression, there is no effective strategy for treating this clinical challenge.
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