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.
Highlights
Traumatic injury to the spinal cord results in irreversible locomotor, sensory, and autonomic dysfunctions for which there is currently no effective pharmacologic treatment
Imatinib Enhances Functional Outcome We investigated the effects of a 5-day treatment course with either imatinib (250 mg/kg/day orally) or PBS beginning 30 minutes after injury on functional outcome measures in rats subjected to a contusion injury to the spinal cord (25 mm weight drop)
Imatinib Enhances Blood-spinal Cord-barrier Integrity To determine the effects of imatinib on blood-spinal cordbarrier (BSCB) integrity, we evaluated the expression of claudin-5, an endothelial cell tight junction protein at day 5 after injury
Summary
Traumatic injury to the spinal cord results in irreversible locomotor, sensory, and autonomic dysfunctions for which there is currently no effective pharmacologic treatment. The functional losses are due to the initial physical disruption of spinal cord tissue and vascular changes, and to a cascade of secondary events triggered by the initial insult, which results in further damage to the spinal cord at and around the site of injury [1] These detrimental secondary events include the loss of microcirculation, edema, hemorrhage, and local inflammation [2,3], [3,4]. Imatinib has been reported to modulate tyrosine kinase signaling cascades involved in local inflammation, such as c-Kit, c-Fms, and LCK [5], [6]. Imatinib has been reported to inhibit PDGF signaling [8], [9], [10] and, in an experimental model of ischemic stroke, to reduce edema and hemorrhage [8],
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