Abstract
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.
Highlights
Transcriptional, histological, and neurobehavioral readouts, we report that midostaurin treatment is associated with a significant beneficial impact in a translationally relevant model of cervical Spinal cord injury (SCI)
The local molecular impact of midostaurin was examined at 24 h after cervical SCI
Western blotting revealed lower levels of phosphorylated GSK3β and Signal Transducer and Activator of Transcription 3 (STAT3) in the midostaurin-treated group (Supplementary Figure S2). These are multirole signal transducer molecules downstream of protein kinases that validate the impact of midostaurin on local enzymatic activity
Summary
Spinal cord injury (SCI) is a life-threatening and multifaceted condition that impairs the local neural circuitry responsible for both sensorimotor and autonomic functions [1]. The laceration, compression, and contusion of the spinal cord damages the local neuronal, glial, and vascular cells, which introduces toxic cellular debris and disrupts the vital vasculature network [6]. These events lead to a secondary pathology cascade, evident by early signs of hypoxia, microglial activation, reactive immune cell infiltration, and astrocytic response [7]. Over the course of the secondary injury, a non-neuronal lesion core characterized by cavitation and fibrotic scarring is formed at the injury epicenter [8]
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