ABSTRACT
The spinal cord injury (SCI) research community has experienced great advances in discovery research, technology development, and promising clinical interventions in the past decade. To build upon these advances and maximize the benefit to persons with SCI, the National Institutes of Health (NIH) hosted a conference February 12-13, 2019 titled "SCI 2020: Launching a Decade of Disruption in Spinal Cord Injury Research." The purpose of the conference was to bring together a broad range of stakeholders, including researchers, clinicians and healthcare professionals, persons with SCI, industry partners, regulators, and funding agency representatives to break down existing communication silos. Invited speakers were asked to summarize the state of the science, assess areas of technological and community readiness, and build collaborations that could change the trajectory of research and clinical options for people with SCI. In this report, we summarize the state of the science in each of five key domains and identify the gaps in the scientific literature that need to be addressed to move the field forward.
Subject(s)
Biomedical Research/trends , Congresses as Topic/trends , National Institute of Neurological Disorders and Stroke (U.S.)/trends , Spinal Cord Injuries/therapy , Biomedical Research/methods , Exoskeleton Device/trends , Humans , Maryland , Spinal Cord Injuries/epidemiology , Transcutaneous Electric Nerve Stimulation/methods , Transcutaneous Electric Nerve Stimulation/trends , United States/epidemiologyABSTRACT
Matrix metalloproteinase (MMP)-2 knockout (KO) mice show impaired neurological recovery after spinal cord injury (SCI), suggesting that this proteinase is critical to recovery processes. However, this finding in the KO has been confounded by a compensatory increase in MMP-9. We synthesized the thiirane mechanism-based inhibitor ND-378 and document that it is a potent (nanomolar) and selective slow-binding inhibitor of MMP-2 that does not inhibit the closely related MMP-9 and MMP-14. ND-378 crosses the blood-spinal cord barrier, achieving therapeutic concentrations in the injured spinal cord. Spinal-cord injured mice treated with ND-378 showed no change in long-term neurological outcomes, suggesting that MMP-2 is not a key determinant of locomotor recovery.
Subject(s)
Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Phenyl Ethers/pharmacology , Recovery of Function/physiology , Spinal Cord Injuries/enzymology , Spinal Cord/enzymology , Sulfones/pharmacology , Animals , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Male , Matrix Metalloproteinase 14/metabolism , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Mice , Mice, Knockout , Molecular Docking Simulation , Molecular Structure , Motor Activity/drug effects , Motor Activity/physiology , Phenyl Ethers/chemical synthesis , Phenyl Ethers/pharmacokinetics , Recovery of Function/drug effects , Spinal Cord/drug effects , Spinal Cord Injuries/drug therapy , Sulfones/chemical synthesis , Sulfones/pharmacokineticsABSTRACT
Clinical evidence suggests that the cerebellum is damaged after traumatic brain injury (TBI) and experimental studies have validated these observations. We have previously shown cerebellar vulnerability, as demonstrated by Purkinje cell loss and microglial activation, after fluid percussion brain injury. In this study, we examine the effect of graded controlled cortical impact (CCI) injury on the cerebellum in the context of physiologic and anatomical parameters that have been shown by others to be sensitive to injury severity. Adult male rats received mild, moderate, or severe CCI and were euthanized 7 days later. We first validated the severity of the initial injury using physiologic criteria, including apnea and blood pressure, during the immediate postinjury period. Increasing injury severity was associated with an increased incidence of apnea and higher mortality. Severe injury also induced transient hypertension followed by hypotension, while lower grade injuries produced an immediate and sustained hypotension. We next evaluated the pattern of subcortical neuronal loss in response to graded injuries. There was significant neuronal loss in the ipsilateral cortex, hippocampal CA2/CA3, and laterodorsal thalamus that was injury severity-dependent and that paralleled microglial activation. Similarly, there was a distinctive pattern of Purkinje cell loss and microglial activation in the cerebellar vermis that varied with injury severity. Together, these findings emphasize the vulnerability of the cerebellum to TBI. That a selective pattern of Purkinje cell loss occurs regardless of the type of injury suggests a generalized response that is a likely determinant of recovery and a target for therapeutic intervention.