Abstract
After spinal cord injury (SCI), reconstruction of neuronal tracts is very difficult because an inhibitory scar is formed at the lesion site, in which several axonal growth inhibitors, such as chondroitin sulfate proteoglycans (CSPG), accumulate. We previously found that matrine, a major alkaloid in Sophora flavescens, enhanced axonal growth in neurons seeded on CSPG coating. The aims of this study were to investigate therapeutic effects of matrine in SCI mice and to clarify the underlying mechanism. Matrine was orally administered to contusion SCI mice. In the matrine-treated mice, motor dysfunction of the hindlimbs was improved, and the density of 5-HT-positive tracts was increased in the injured spinal cord. We explored putative direct binding proteins of matrine in cultured neurons using drug affinity responsive target stability (DARTS). As a result, heat shock protein 90 (HSP90) was identified, and matrine enhanced HSP90 chaperon activity. We then presumed that extracellular HSP90 is a matrine-targeting signaling molecule, and found that specific blocking of extracellular HSP90 by a neutralizing antibody completely diminished matrine-induced axonal growth and SCI amelioration. Our results suggest that matrine enhances axonal growth and functional recovery in SCI mice by direct activation of extracellular HSP90. Matrine could be a significant candidate for therapeutic drugs for SCI with a novel mechanism.
Highlights
Spinal cord injury (SCI) is accompanied by refractory deficits of motor, sensory, and autonomic functions
We found that the water extract of dried roots of Sophora flavescens, a traditional medicine used in China, Korea, and Japan, enhanced axonal growth of cultured cortical neurons on a chondroitin sulfate proteoglycan (CSPG) coating (Tanabe et al, 2016)
High-dose matrine treatment led to a significant improvement in motor functions as measured by the Basso Mouse Scale (BMS) (Figure 1A) and the Toyama Mouse Score (TMS) (Figure 1B), while low-dose matrine treatment led to a slightly increased BMS score (Figure 1A)
Summary
Spinal cord injury (SCI) is accompanied by refractory deficits of motor, sensory, and autonomic functions. These dysfunctions are caused by disruptions of descending and/or ascending tracts. Reconstruction of the neuronal tracts is very difficult because an inhibitory environment, called a glial scar, is formed at the lesion site. The scar tissue contains several axonal growth inhibitors, such as chondroitin sulfate proteoglycan (CSPG) (Dyck and Karimi-Abdolrezaee, 2015).Currently, there are no drugs that are recommended in clinical guidelines as functional ameliorants for SCI (Walters et al, 2013). The development of novel clinical drugs effective for functional recovery in SCI is required and eagerly expected.
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