Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada.
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Biomolecules. 2021 Jul 1;11(7):972. doi: 10.3390/biom11070972.
Traumatic spinal cord injury (SCI) impairs neuronal function and introduces a complex cascade of secondary pathologies that limit recovery. Despite decades of preclinical and clinical research, there is a shortage of efficacious treatment options to modulate the secondary response to injury. Protein kinases are crucial signaling molecules that mediate the secondary SCI-induced cellular response and present promising therapeutic targets. The objective of this study was to examine the safety and efficacy of midostaurin-a clinically-approved multi-target protein kinase inhibitor-on cervical SCI pathogenesis. High-throughput analyses demonstrated that intraperitoneal midostaurin injection (25 mg/kg) in C6/7 injured Wistar rats altered the local inflammasome and downregulated adhesive and migratory genes at 24 h post-injury. Treated animals also exhibited enhanced recovery and restored coordination between forelimbs and hindlimbs after injury, indicating the synergistic impact of midostaurin and its dimethyl sulfoxide vehicle to improve functional recovery. Furthermore, histological analyses suggested improved tissue preservation and functionality in the treated animals during the chronic phase of injury. This study serves as a proof-of-concept experiment and demonstrates that systemic midostaurin administration is an effective strategy for mitigating cervical secondary SCI damage.
创伤性脊髓损伤 (SCI) 会损害神经元功能，并引发一系列复杂的继发性病变，从而限制康复。尽管经过几十年的临床前和临床研究，但仍缺乏有效的治疗选择来调节损伤后的继发性反应。蛋白激酶是介导继发性 SCI 诱导的细胞反应的关键信号分子，是有前途的治疗靶点。本研究旨在探讨米哚妥林（一种临床批准的多靶点蛋白激酶抑制剂）对颈 SCI 发病机制的安全性和疗效。高通量分析表明，在 C6/7 损伤的 Wistar 大鼠中腹腔内注射米哚妥林（25mg/kg）可改变局部炎症小体，并在损伤后 24 小时下调黏附和迁移基因。治疗动物在损伤后还表现出更好的恢复，以及前肢和后肢之间协调能力的恢复，表明米哚妥林及其二甲亚砜载体的协同作用可改善功能恢复。此外，组织学分析表明，在损伤的慢性阶段，治疗动物的组织保存和功能得到改善。这项研究是一个概念验证实验，表明全身给予米哚妥林是减轻颈发性 SCI 损伤的有效策略。
