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Imatinib enhances functional outcome after spinal cord injury.

ABSTRACT: We investigated whether imatinib (Gleevec®, Novartis), a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondroitin sulfate proteoglycans, and increased tissue preservation. These improvements were associated with enhanced vascular integrity and reduced inflammation. Our results show that imatinib improves recovery in spinal cord injury by preserving axons and other spinal cord tissue components. The rapid time course of these beneficial effects suggests that the effects of imatinib are neuroprotective rather than neurorestorative. The positive effects on experimental spinal cord injury, obtained by oral delivery of a clinically used drug, makes imatinib an interesting candidate drug for clinical trials in spinal cord injury.

SUBMITTER: Abrams MB

PROVIDER: S-EPMC3378614 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Imatinib enhances functional outcome after spinal cord injury.

Abrams Mathew B MB Nilsson Ingrid I Lewandowski Sebastian A SA Kjell Jacob J Codeluppi Simone S Olson Lars L Eriksson Ulf U

PloS one 20120619 6

We investigated whether imatinib (Gleevec®, Novartis), a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondro ...[more]

PMID: 22723886

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Project description:ObjectiveWe aimed to construct a nonlinear regression model through Extreme Gradient Boost (XGBoost) to predict functional outcome 1 year after surgical decompression for patients with acute spinal cord injury (SCI) and explored the importance of predictors in predicting the functional outcome.MethodsWe prospectively enrolled 249 patients with acute SCI from 5 primary orthopedic centers from June 1, 2016, to June 1, 2020. We identified a total of 6 predictors with three aspects: (1) clinical characteristics, including age, American Spinal Injury Association (ASIA) Impairment Scale (AIS) at admission, level of injury and baseline ASIA motor score (AMS); (2) MR imaging, mainly including Brain and Spinal Injury Center (BASIC) score; (3) surgical timing, specifically comparing whether surgical decompression was received within 24 h or not. We assessed the SCIM score at 1 year after the operation as the functional outcome index. XGBoost was used to build a nonlinear regression prediction model through the method of boosting integrated learning.ResultsWe successfully constructed a nonlinear regression prediction model through XGBoost and verified the credibility. There is no significant difference between actual SCIM and nonlinear prediction model (t = 0.86, P = 0.394; Mean ± SD: 3.31 ± 2.8). The nonlinear model is superior to the traditional linear model (t = 6.57, P < 0.001). AMS and age played the most important roles in constructing predictive models. There is an obvious correlation between AIS, AMS and BASIC score.ConclusionWe verified the feasibility of using XGBoost to construct a nonlinear regression prediction model for the functional outcome of patients with acute SCI, and proved that the predictive performance of the nonlinear model is better than the traditional linear regression prediction model. Age and baseline AMS play the most important role in predicting the functional outcome. We also found a significant correlation between AIS at admission, baseline AMS and BASIC score.Trial registrationClinicalTrials.gov identifier: NCT03103516.

Project description:Microtubule stabilization through epothilones is a promising preclinical therapy for functional recovery following spinal cord injury that stimulates axon regeneration, reduces growth-inhibitory molecule deposition and promotes functional improvements. Rehabilitation therapy is the only clinically validated approach to promote functional improvements following spinal cord injury. However, whether microtubule stabilization can augment the beneficial effects of rehabilitation therapy or act in concert with it to further promote repair remains unknown. Here, we investigated the pharmacokinetic, histological and functional efficacies of epothilone D, epothilone B and ixabepilone alone or in combination with rehabilitation following a moderate contusive spinal cord injury. Pharmacokinetic analysis revealed that ixabepilone only weakly crossed the blood-brain barrier and was subsequently excluded from further investigations. In contrast, epothilones B and D rapidly distributed to CNS compartments displaying similar profiles after either subcutaneous or intraperitoneal injections. Following injury and subcutaneous administration of epothilone B or D, rats were subjected to 7 weeks of sequential bipedal and quadrupedal training. For all outcome measures, epothilone B was efficacious compared with epothilone D. Specifically, epothilone B decreased fibrotic scaring which was associated with a retention of fibronectin localized to perivascular cells in sections distal to the lesion. This corresponded to a decreased number of cells present within the intralesional space, resulting in less axons within the lesion. Instead, epothilone B increased serotonergic fibre regeneration and vesicular glutamate transporter 1 expression caudal to the lesion, which was not affected by rehabilitation. Multiparametric behavioural analyses consisting of open-field locomotor scoring, horizontal ladder, catwalk gait analysis and hindlimb kinematics revealed that rehabilitation and epothilone B both improved several aspects of locomotion. Specifically, rehabilitation improved open-field locomotor and ladder scores, as well as improving the gait parameters of limb coupling, limb support, stride length and limb speed; epothilone B improved these same gait parameters but also hindlimb kinematic profiles. Functional improvements by epothilone B and rehabilitation acted complementarily on gait parameters leading to an enhanced recovery in the combination group. As a result, principal component analysis of gait showed the greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting.

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Imatinib enhances functional outcome after spinal cord injury.

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Imatinib enhances functional outcome after spinal cord injury.

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