Journal of neurotrauma
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Journal of neurotrauma · May 2019
Clinical TrialFurosemide Unmasks Inhibitory Dysfunction after Spinal Cord Injury in Humans: Implications for Spasticity.
Spasticity after spinal cord injury has considerable quality of life implications, impacts on rehabilitation efforts and necessitates long-term multi-disciplinary pharmacological and non-pharmacological management. The potassium chloride co-transporter (KCC2) plays a central role in intracellular chloride homeostasis and the inhibitory function of mature neurons. Animal studies consistently have demonstrated a downregulation of KCC2 activity after spinal cord transection, causing a shift from the inhibitory action of gamma-aminobutyric acid and glycine to an excitatory effect. ⋯ The lack of furosemide effect after spinal cord injury suggests KCC2 dysfunction in humans, resulting in reduced inhibitory synaptic transmission in spinal neurons. Our findings suggest that KCC2 dysfunction may be an important etiological factor in hyperreflexia after spinal cord injury. These observations may pave the way to novel therapeutic strategies against spasticity centered on chloride homeostasis.
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Journal of neurotrauma · May 2019
Development of Cardiovascular Dysfunction in a Rat Spinal Cord Crush Model and Responses to Serotonergic Interventions.
Selection of a proper spinal cord injury (SCI) rat model to study therapeutic effects of cell transplantation is imperative for research in cardiovascular functional recovery, due to the local harsh milieu inhibiting cell growth. We recently found that a crushed spinal cord lesion can minimize fibrotic scarring and grafted cell death compared with open-dura injuries. To determine if this SCI model is applicable for studying cardiovascular recovery, we examined hemodynamic consequences following crushed SCI and tested cardiovascular responses to serotonin (5-HT) or dopamine (DA) receptor agonists. ⋯ During CRD-induced autonomic dysreflexia, systemic administration of DOI alleviated the severity of bradycardia responsive to episodic hypertension. In contrast, selective stimulation of 5-HT1A receptors with 8-OH-DPAT or non-selective activation of DA receptors with apomorphine did not affect cardiovascular performance. Thus, crush injuries induce cardiovascular abnormalities in rats that are sensitive to 5-HT2A receptor stimulation, indicating a reliable SCI model to study how cell-based approaches impact the severity of autonomic dysreflexia and identify a possible target for pharmacological interventions.
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Journal of neurotrauma · May 2019
Multi-Potent Adult Progenitor Cells, but not Tissue Inhibitor of Matrix Metalloproteinase-3, Increase Tissue Sparing and Reduce Urological Complications following Spinal Cord Injury.
Following spinal cord injury (SCI), inflammation amplifies damage beyond the initial insult, providing an opportunity for targeted treatments. An ideal protective therapy would reduce both edema within the lesion area and the activation/infiltration of detrimental immune cells. Previous investigations demonstrated the efficacy of intravenous injection of multipotent adult progenitor cells (MAPC®) to modulate immune response following SCI, leading to significant improvements in tissue sparing, locomotor and urological functions. ⋯ The results suggest that intravenous delivery of MAPC cell therapy 1 day following acute SCI significantly improves tissue sparing and impacts functional recovery. TIMP3 treatment provided no significant benefit, and further, when co-administered with MAPC cells, it abrogated the therapeutic effects of MAPC cell therapy. Importantly, this study demonstrated for the first time that acute treatment of SCI with MAPC cells can significantly reduce the incidence of urinary tract infection (UTI) and the use of antibiotics for UTI treatment.
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Journal of neurotrauma · May 2019
Predictors of response to 4-aminopyridine in chronic canine spinal cord injury.
4-Aminopyridine (4AP), a potassium channel antagonist, can improve hindlimb motor function in dogs with chronic thoracolumbar spinal cord injury (SCI); however, individual response is variable. We hypothesized that injury characteristics would differ between dogs that do and do not respond to 4AP. Our objective was to compare clinical, electrodiagnostic, gait, and imaging variables between dogs that do and do not respond to 4AP, to identify predictors of response. ⋯ MEPs were more common post-4AP than pre-4AP (10 vs. 6 dogs) and 4AP decreased H-reflex threshold and increased spasticity in responders. 4-AP impacts central conduction and motor neuron pool excitability in dogs with chronic SCI. Severity of spasticity and H-reflex threshold might allow prediction of response. Further exploration of electrodiagnostic and imaging characteristics might elucidate additional factors contributing to response or non-response.