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MRI evidence that glibenclamide reduces acute lesion expansion in a rat model of spinal cord injury.

ABSTRACT: Experimental, controlled, animal study.To use non-invasive magnetic resonance imaging (MRI) to corroborate invasive studies showing progressive expansion of a hemorrhagic lesion during the early hours after spinal cord trauma and to assess the effect of glibenclamide, which blocks Sur1-Trpm4 channels implicated in post-traumatic capillary fragmentation, on lesion expansion.Baltimore.Adult female Long-Evans rats underwent unilateral impact trauma to the spinal cord at C7, which produced ipsilateral but not contralateral primary hemorrhage. In series 1 (six control rats and six administered glibenclamide), hemorrhagic lesion expansion was characterized using MRI at 1 and 24?h after trauma. In series 2, hemorrhagic lesion size was characterized on coronal tissue sections at 15?min (eight rats) and at 24?h after trauma (eight control rats and eight administered glibenclamide).MRI (T2 hypodensity) showed that lesions expanded 2.3±0.33-fold (P<0.001) during the first 24?h in control rats, but only 1.2±0.07-fold (P>0.05) in glibenclamide-treated rats. Measuring the areas of hemorrhagic contusion on tissue sections at the epicenter showed that lesions expanded 2.2±0.12-fold (P<0.001) during the first 24?h in control rats, but only 1.1±0.05-fold (P>0.05) in glibenclamide-treated rats. Glibenclamide treatment was associated with significantly better neurological function (unilateral BBB scores) at 24?h in both the ipsilateral (median scores, 9 vs 0; P<0.001) and contralateral (median scores, 12 vs 2; P<0.001) hindlimbs.MRI is an accurate non-invasive imaging biomarker of lesion expansion and is a sensitive measure of the ability of glibenclamide to reduce lesion expansion.

SUBMITTER: Simard JM

PROVIDER: S-EPMC4076111 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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MRI evidence that glibenclamide reduces acute lesion expansion in a rat model of spinal cord injury.

Simard J M JM Popovich P G PG Tsymbalyuk O O Caridi J J Gullapalli R P RP Kilbourne M J MJ Gerzanich V V

Spinal cord 20130917 11

<h4>Study design</h4>Experimental, controlled, animal study.<h4>Objectives</h4>To use non-invasive magnetic resonance imaging (MRI) to corroborate invasive studies showing progressive expansion of a hemorrhagic lesion during the early hours after spinal cord trauma and to assess the effect of glibenclamide, which blocks Sur1-Trpm4 channels implicated in post-traumatic capillary fragmentation, on lesion expansion.<h4>Setting</h4>Baltimore.<h4>Methods</h4>Adult female Long-Evans rats underwent uni ...[more]

PMID: 24042989

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Project description:Lesion-induced scarring is a major impediment for regeneration of injured axons in the central nervous system (CNS). The collagen-rich glial-fibrous scar contains numerous axon growth inhibitory factors forming a regeneration-barrier for axons. We demonstrated previously that the combination of the iron chelator 2,2'-bipyridine-5,5'-decarboxylic acid (BPY-DCA) and 8-Br-cyclic AMP (cAMP) inhibits scar formation and collagen deposition, leading to enhanced axon regeneration and partial functional recovery after spinal cord injury. While BPY-DCA is not a clinical drug, the clinically approved iron chelator deferoxamine mesylate (DFO) may be a suitable alternative for anti-scarring treatment (AST). In order to prove the scar-suppressing efficacy of DFO we modified a recently published in vitro model for CNS scarring. The model comprises a co-culture system of cerebral astrocytes and meningeal fibroblasts, which form scar-like clusters when stimulated with transforming growth factor-β (TGF-β). We studied the mechanisms of TGF-β-induced CNS scarring and compared the efficiency of different putative pharmacological scar-reducing treatments, including BPY-DCA, DFO and cAMP as well as combinations thereof. We observed modulation of TGF-β-induced scarring at the level of fibroblast proliferation and contraction as well as specific changes in the expression of extracellular matrix molecules and axon growth inhibitory proteins. The individual and combinatorial pharmacological treatments had distinct effects on the cellular and molecular aspects of in vitro scarring. DFO could be identified as a putative anti-scarring treatment for CNS trauma. We subsequently validated this by local application of DFO to a dorsal hemisection in the rat thoracic spinal cord. DFO treatment led to significant reduction of scarring, slightly increased regeneration of corticospinal tract as well as ascending CGRP-positive axons and moderately improved locomotion. We conclude that the in vitro model for CNS scarring is suitable for efficient pre-screening and identification of putative scar-suppressing agents prior to in vivo application and validation, thus saving costs, time and laboratory animals.

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MRI evidence that glibenclamide reduces acute lesion expansion in a rat model of spinal cord injury.

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MRI evidence that glibenclamide reduces acute lesion expansion in a rat model of spinal cord injury.

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