Purpose: To evaluate the therapeutic efficacy of S-nitrosoglutathione (GSNO) in spinal cord injury (SCI) using in vivo MRI in combination with neuorobehavioral testing and postmortem tissue analysis. Materials and Methods:Sixteen female rats were mildly injured at the vertebral T10 level and randomized into control (n ¼ 8) and GSNO-treatment (n ¼ 8) groups. GSNO was delivered at 0.05 mg/kg dose in saline by means of tail vein at 1 hr postinjury and then given orally on the following days. On postinjury days 1, 3, 7, and 28, the rats were tested behaviorally, then scanned using sagittal T2-weighted MRI for the quantification of lesion, edema, and hemorrhagic regions at the injury site. Excised cords were analyzed using histology and immunohistochemistry.Results: Treatment with GSNO was feasible in rats with SCI. On the average, the GSNO group at each scan day 1, 3, 7, and 28 exhibited better functional recovery as indicated by the behavioral performance of 52%, 33%, 19%, and 18%, and had smaller lesions of À4%, À16%, À20%, and À17% compared with the controls, respectively. Edema trend was parallel to the lesion volumes in both groups. Ex vivo data demonstrated that GSNO plays a role in neuronal tissue preservation and sparing. Conclusion:The data collectively provided the preliminary evidence that the injured rats responded favorably to GSNO treatment. Longitudinal MRI provides critical quantitative information regarding the changes in lesion properties, which helps evaluating the efficacy of an exogenous intervention in SCI. POTENTIAL NEW THERAPIES for spinal cord injury (SCI) are currently being developed and tested in animal models (1-4). Evaluating the efficacy of a pharmacological therapy depends on accurately quantifying the drug-induced improvements in injured spinal cord (SC). Such quantification is possible with measurable data obtained from in vivo neuroimaging (5-9). To date, MRI in preclinical SCI research has primarily been used to understand the progression of pathobiology and to characterize lesion properties with anatomical, structural, and functional information about the underlying neurovascular tissue (10-12). Recent studies have expanded this capability further and applied MRI to rapidly screen the effects of a promising treatment in live animal models of SCI (13-16).Blood spinal cord barrier (BSCB) is responsible for regulating the transport of blood constituents across the vessel walls into the SC. Trauma damages the SC tissue and alters the permeability of BSCB. This compromise in neurovasculature activates inflammatory response that leads to immune cell infiltration, oxidative stress, neuronal/glial cell death, and demyelination. An ideal strategy to treat SCI would be to simultaneously protect the blood vessels, neurons, and other non-neuronal support cells in the injured cord. Oxidative mediators, including reactive oxygen and reactive nitrogen species, are recognized among the causative factors in secondary injuries. Reducing the level of oxidative stress by means of modulation of redox...

BackgroundIn vivo preclinical imaging of spinal cord injury (SCI) in rodent models provides clinically relevant information in translational research. This paper uses multimodal magnetic resonance imaging (MRI) to investigate neurovascular pathology and changes in blood spinal cord barrier (BSCB) permeability following SCI in a mouse model of SCI.MethodsC57BL/6 female mice (n = 5) were subjected to contusive injury at the thoracic T11 level and scanned on post injury days 1 and 3 using anatomical, dynamic contrast-enhanced (DCE-MRI) and diffusion tensor imaging (DTI). The injured cords were evaluated postmortem with histopathological stains specific to neurovascular changes. A computational model was implemented to map local changes in barrier function from the contrast enhancement. The area and volume of spinal cord tissue with dysfunctional barrier were determined using semi-automatic segmentation.ResultsQuantitative maps derived from the acquired DCE-MRI data depicted the degree of BSCB permeability variations in injured spinal cords. At the injury sites, the damaged barriers occupied about 70% of the total cross section and 48% of the total volume on day 1, but the corresponding measurements were reduced to 55% and 25%, respectively on day 3. These changes implied spatio-temporal remodeling of microvasculature and its architecture in injured SC. Diffusion computations included longitudinal and transverse diffusivities and fractional anisotropy index. Comparison of permeability and diffusion measurements indicated regions of injured cords with dysfunctional barriers had structural changes in the form of greater axonal loss and demyelination, as supported by histopathologic assessments.ConclusionThe results from this study collectively demonstrated the feasibility of quantitatively mapping regional BSCB dysfunction in injured cord in mouse and obtaining complementary information about its structural integrity using in vivo DCE-MRI and DTI protocols. This capability is expected to play an important role in characterizing the neurovascular changes and reorganization following SCI in longitudinal preclinical experiments, but with potential clinical implications.