Trimebutine, a small molecule mimetic agonist of adhesion molecule L1, contributes to functional recovery after spinal cord injury in mice.

Junping Xu,Qiong Jiang,Melitta Schachner,Chengliang Hu,Huifan Shen,Hongchao Pan

doi:10.1242/dmm.029801

Junping Xu, Qiong Jiang + Show 4 more

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https://doi.org/10.1242/dmm.029801

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Abstract

ABSTRACTCuring spinal cord injury (SCI) in mammals is a daunting task because of the lack of permissive mechanisms and strong inhibitory responses at and around the lesion. The neural cell adhesion molecule L1CAM (L1) has been shown to favor axonal regrowth and enhance neuronal survival and synaptic plasticity but delivery of full-length L1 or its extracellular domain could encounter difficulties in translation to therapy in humans. We have, therefore, identified several small organic compounds that bind to L1 and stimulate neuronal survival, neuronal migration and neurite outgrowth in an L1-dependent manner. Here, we assessed the functions of two L1 mimetics, trimebutine and honokiol, in regeneration following SCI in young adult mice. Using the Basso Mouse Scale (BMS) score, we found that ground locomotion in trimebutine-treated mice recovered better than honokiol-treated or vehicle-receiving mice. Enhanced hindlimb locomotor functions in the trimebutine group were observed at 6 weeks after SCI. Immunohistology of the spinal cords rostral and caudal to the lesion site showed reduced areas and intensities of glial fibrillary acidic protein immunoreactivity in both trimebutine and honokiol groups, whereas increased regrowth of axons was observed only in the trimebutine-treated group. Both L1- and L1 mimetic-mediated intracellular signaling cascades in the spinal cord lesion sites were activated by trimebutine and honokiol, with trimebutine being more effective than honokiol. These observations suggest that trimebutine and, to a lesser extent under the present experimental conditions, honokiol have a potential for therapy in regeneration of mammalian spinal cord injuries.

Highlights

Spinal cord injury (SCI) is a devastating neurological disease that can lead to life-long disability (Schwab et al, 2006; Silver and Miller, 2004)
Trimebutine and honokiol were tested in a mouse model of spinal cord injury (SCI), involving severe locomotor paralysis, to assess recovery through the Basso Mouse Scale (BMS) score
The values of foot-stepping angle and foot-stepping angle recovery index (RI) showed better recovery in mice treated with trimebutine (Fig. 1C, D), and the foot-stepping angle reached significance at 5 and 6 weeks (p=0.03 and p=0.048, respectively, versus the vehicle control) and foot-stepping angle RI at 5 weeks (p=0.036 versus the vehicle control), whereas honokiol-treated mice had no pronounced difference regarding vehicle control

Summary

Introduction

Spinal cord injury (SCI) is a devastating neurological disease that can lead to life-long disability (Schwab et al, 2006; Silver and Miller, 2004). L1 promotes axonal growth and myelination (Barbin et al, 2004; Mohajeri et al, 1996), prevents neuronal apoptosis (Chen et al, 1999), and enhances neuronal survival, axonal targeting, axonal regrowth/sprouting after injury and synaptic plasticity (Schafer and Frotscher, 2012; Zhang et al, 2008). A prior study has demonstrated that L1 conjugated to an Fc fragment (L1-Fc) facilitates locomotor recovery in rats after SCI (Roonprapunt et al, 2003), and L1-transfected embryonic stem cells enhance survival and support regrowth of corticospinal tract axons in mice post-SCI (Chen et al, 2005). In an in vivo study, duloxetine and piceid have been demonstrated to confer enhanced regeneration, correlating with enhanced survival, outgrowth and remyelination of motoneurons, attenuated astrocyte and microglia activation in a mouse model of SCI (Kataria et al, 2016)

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