The goal of this project is to demonstrate that inhibition of the toxic polyol pathway, which is activated by injury, can oppose irreversible loss of locomotor function and spinal cord tissue due to spinal cord injury (SCI). Presently, only methylprednisolone has been shown to have efficacy for SCI. However, recovery is modest and megadoses are used which can cause hyperglycemia, muscle atrophy and impaired immunological function. Because of these limitations, additional or alternative countermeasures that can be used in spinal cord-injured patients are needed. The proposed studies are an outgrowth of previous work, in which we demonstrated that SCI activates polyol synthesis from glucose leading to axonal degeneration and subsequent paralysis. Therefore inhibition of the rate-limiting enzyme of the polyol pathway, aldose reductase, by direct enzyme inhibition with sorbinil should reverse paralysis and spare spinal cord tissue following SCI. Sorbinil, an aldose reductase inhibitor, that has been shown to be clinically safe and effective for diabetic neuropathy, is a potentially superior treatment for SCI that is available, but requires a demonstration of efficacy in an appropriate animal model of SCI before use in patient trials. We will determine the efficacy of sorbinil for treating SCI with regard to dosage, onset and duration of the therapeutic time-window and in combination therapy with methylprednisolone with an established model of SCI developed by the Multicenter Animal Spinal Cord Injury Study (MASCIS). Optimization of aldose reductase inhibition may lead to a therapeutic modality for reduction of traumatic injury to the nervous system. The purpose of these studies is to provide proof of principle that AR inhibitors as a class of compounds are effective for treating spinal cord injury which will be patented for commercial application and licensing.
Public Health Relevance: Presently, only methylprednisolone has been shown to have efficacy in humans for spinal cord injury (SCI), although recovery is modest and muscle atrophy and suppression of immunological function may result. Recently we demonstrated that SCI activates a toxic biochemical pathway leading to nervous tissue degeneration and subsequent paralysis. Therefore inhibition of the rate-limiting enzyme of this pathway should reverse paralysis and spare spinal cord tissue following SCI. The proposed studies will determine the efficacy of a novel treatment for spinal cord contusion injury with regard to dosage, therapeutic time-window and use together with methylprednisolone in combination therapy with an established model of SCI.
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