reparixin and Spinal-Cord-Injuries

Female Wistar rats (225 g) underwent spinal cord injury (SCI) at the T4 segment and were assigned to one of the three groups treated with: (1) saline; (2) 7.5 mg kg(-1) Reparixin; or (3) 15 mg kg(-1) Reparixin. Reparixin is a small molecule, allosteric noncompetitive inhibitor of CXCR1 and CXCR2 chemokine receptors involved in inflammation.. Spinal cord homogenates at 12 and 72 h post-SCI were assayed for tumor necrosis factor α (TNF-α) and cytokine-induced neutrophil chemoattractant (CINC)-1 using enzyme-linked immunosorbant assay (ELISA). Myeloperoxidase activity and western blots for CD68, Fas and p75 content were used to assess inflammation and death receptor ligands, respectively. Histopathology and neurological outcomes were assessed by immunohistochemistry, locomotion scoring and cardiovascular measurement of autonomic dysreflexia 4 weeks post-SCI.. Both 7.5 and 15 mg kg(-1) doses of Reparixin reduced levels of TNF-α and CINC-1 72 h post-SCI and decreased macrophage (CD68) content in the spinal cord lesion. Only 15 mg kg(-1) Reparixin reduced both Fas and p75 levels in the spinal cord compared with untreated SCI. We observed a reduced lesion area and increased neuron number in the gray matter of Reparixin-treated rats. Hindlimb motor scores at 7 and 28 days post-SCI were improved by 15 mg kg(-1) Reparixin treatment. Both 7.5 and 15 mg kg(-1) Reparixin reduced development of autonomic dysreflexia 4 weeks post-SCI. The change in mean arterial pressure, induced by cutaneous or visceral stimulation, was reduced by 40-50%.. Acute treatment with 15 mg kg(-1) Reparixin reduces acute inflammation and is associated with minor improvements in motor function and a significant reduction in the severity of autonomic dysreflexia.

Topics: Acute Disease; Animals; Autonomic Dysreflexia; Disease Models, Animal; Female; Inflammation Mediators; Nerve Degeneration; Rats; Rats, Wistar; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Spinal Cord Injuries; Sulfonamides

It has been shown that the blockade of CXCR1 and CXCR2 receptors prevents ischemia/reperfusion damage in several types of vascular beds. Reparixin is a recently described inhibitor of human CXCR1/R2 and rat CXCR2 receptor activation. We applied reparixin in rats following traumatic spinal cord injury and determined therapeutic temporal and dosages windows. Treatment with reparixin significantly counteracts secondary degeneration by reducing oligodendrocyte apoptosis, migration to the injury site of neutrophils and ED-1-positive cells. The observed preservation of the white matter might also be secondary to the enhanced proliferation of NG2-positive cells. The expression of macrophage-inflammatory protein-2, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1 beta was also counteracted, and the proliferation of glial fibrillary acidic protein-positive cells was markedly reduced. These effects resulted in a smaller post-traumatic cavity and in a significantly improved recovery of hind limb function. The best beneficial outcome of reparixin treatment required 7-day administration either by i.p. route (15 mg/kg) or subcutaneous infusion via osmotic pumps (10 mg/kg), reaching a steady blood level of 8 microg/ml. Methylprednisolone was used as a reference drug; such treatment reduced cytokine production but failed to affect the rate of hind limb recovery.

Topics: Animals; Cell Movement; Cell Proliferation; Cytokines; Dose-Response Relationship, Drug; Inflammation; Lower Extremity; Male; Oligodendroglia; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-8B; Spinal Cord Injuries; Sulfonamides