TY - JOUR
T1 - Matrine directly activates extracellular heat shock protein 90, resulting in axonal growth and functional recovery in spinal cord injured-mice
AU - Tanabe, Norio
AU - Kuboyama, Tomoharu
AU - Tohda, Chihiro
N1 - Publisher Copyright:
© 2018 Tanabe, Kuboyama and Tohda.
PY - 2018/5/7
Y1 - 2018/5/7
N2 - 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.
AB - 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.
KW - Axonal growth
KW - Chondroitin sulfate proteoglycan
KW - DARTS
KW - Extracellular HSP90
KW - HSP90 activator
KW - Heat shock protein 90
KW - Matrine
KW - Spinal cord injury
UR - http://www.scopus.com/inward/record.url?scp=85046663811&partnerID=8YFLogxK
U2 - 10.3389/fphar.2018.00446
DO - 10.3389/fphar.2018.00446
M3 - 学術論文
C2 - 29867458
AN - SCOPUS:85046663811
SN - 1663-9812
VL - 9
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
IS - MAY
M1 - 446
ER -