The Protein Kinase Inhibitor Midostaurin Improves Functional Neurological Recovery and Attenuates Inflammatory Changes Following Traumatic Cervical Spinal Cord Injury

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.

Efficacy of NHP66 Bioactive Cage on Patients with Cervical Spine Injury in Short-Track Speed Skating

“…NHP66 has a similar structure to human cortical bone, with marvelous toughness, stress strength, and fusion with bone [ 13 ]. Studies have shown that NHP66 can also form an antibacterial and anti-inflammatory biological scaffold with antimicrobial titanium, which has a certain adjuvant therapeutic effect on infected bone defects or osteomyelitis [ 14 ]. For short-track speed skaters, they need not only to restore the height of the injured vertebrae and reconstruct the normal sequence of cervical vertebrae but also more stable internal fixation and a higher rate of intervertebral fusion.…”

Experimental Treatments for Oedema in Spinal Cord Injury: A Systematic Review and Meta-Analysis

“…However, kinase inhibitors are often non-specific; hence, there may be other off-target effects of TFP which we have not considered. For example, Midostaurin, a small-molecule inhibitor of multiple kinases such as PKC, caused a significant number of kinomic changes in a cervical SCI model [38]. Nonetheless, we showed that the inhibition of D2 and PKC increased spinal cord water content, demonstrating that the direct and specific inhibition of CaM and PKA is responsible for attenuating SCI-induced oedema after TFP treatment [20].…”

The MAPK Signaling Pathway Presents Novel Molecular Targets for Therapeutic Intervention after Traumatic Spinal Cord Injury: A Comparative Cross-Species Transcriptional Analysis

“…Furthermore, the proliferation of perivascular fibroblast-derived stromal cells, meningeal fibroblasts, and pericytes leads to scar formation and modifications within the spinal ECM [ 7 ]. Treatment strategies targeting these early processes can have a lasting effect on functional recovery and chronic preservation of neural tissue [ 5 , 34 ], hence the present study aimed to further investigate therapeutic targets during the early subacute phase of injury.…”

“…The incidence rate of traumatic SCI varies according to geographic location [ 2 ], but in the United States alone, it is estimated that there are approximately 17,900 new cases per year [ 3 , 4 ]. Traumatic SCI results from sudden mechanical damage to spinal neuronal, glial, and vascular cells due to an external force, and leads to a cascade of secondary molecular changes that further damage the spinal cord [ 5 ]. This secondary response is characterized mainly by early hypoxia, hemorrhage, and inflammation, which over-time results in cavitation and scar formation [ 6 , 7 ].…”

“…The objective of this study is to identify and characterize both common and inconsistent SCI-induced differentially expressed genes (DEGs) across species to explore therapeutic targets with a higher chance of clinical translation. Given the importance of early intervention on the progression of secondary injury [ 5 , 25 , 26 ], this study will focus on the early subacute injury-time point (between 3/4-days post-SCI).…”