A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord

Abstract

Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

“…The possible mechanism implicated is the arrangement of intraspinal neural circuits by the local axons regenerated most probably from interneurons, which make signal relay and synaptic connections with regenerated descending axonal tracts as previously described. 36,37 Our findings confirmed preservation of lumbar motoneurons and their functional axons in Gal-1-treated mice. Finally, a compensatory response below the lesion site by these lumbar motoneurons was ruled out by retransection experiments, which demonstrated that the locomotor recovery was dependent on site-specific regeneration.…”

“…In this regard, previous studies showed expression of Sema3A within the transected spinal cord that was upregulated at the lesion site, peaking within 1 and 2 weeks after the injury. 36 Because of these particular kinetics, we propose that Gal-1 treatment should take place within a temporal window where its interactions with the NRP-1/PlexinA4 complex could lead to inhibition of Sema3A binding, allowing axonal regeneration of these tracts.…”

“…[2][3][4][46][47][48][49] During the past years, different therapies have been proposed that lead to axonal outgrowth after SCI such as SM-216289, 36 neurotrophic factors, 50 soluble Nogo receptors, 51 chondroitinase ABC 49 or cellular transplantation. 52 In particular, SM-216289, a small-molecule inhibitor, showed inhibition of Sema3A functions, including growth cone collapse and chemorepulsion of neurite extension.…”

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

“…Previous research focuses largely on improving neurological manifestations through the improvement of sensory function and locomotor function [1][2][3][4], but study of the bloodLi-Bing Ye and Xi-Chong Yu contributed equally to this work.…”

White matter inhibitors in CNS axon regeneration failure

“…In addition, the role of guidance molecules is not limited to those that are expressed by oligodendrocytes. A recent study indicates that administration of a small molecule inhibitor of Sema3A, a guidance molecule that is expressed by the fibroblast component of the scar tissue (De Winter et al, 2002), leads to multiple beneficial effects including enhanced regenerative response from axons (Kaneko et al, 2006). Thus, the potential role of axon guidance molecules in restricting axon regeneration after CNS injury is not limited to white matter or myelin (see the review by Smith and colleagues in the current issue).…”