Reparixin, an Inhibitor of CXCR2 Function, Attenuates Inflammatory Responses and Promotes Recovery of Function after Traumatic Lesion to the Spinal Cord

Abstract

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-␣, interleukin (IL)-6, and IL-1␤ 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 g/ml. Methylprednisolone was used as a reference drug; such treatment reduced cytokine production but failed to affect the rate of hind limb recovery.

Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury

“…Our results expand upon a 7-day regimen of Reparixin treatment of rats that also demonstrated improved motor function and reduced inflammation after SCI. 7 We report the novel finding that Reparixin treatment reduced the expression of Fas and p75 in the SCI lesion to levels comparable to uninjured spinal cord (Figures 3a and b). Both Fas and p75 receptors are implicated in apoptosis and contain intracytoplasmic death domains that activate caspases after SCI.…”

“…5,15 Previously, neutralization of the Fas receptor ligand by antibody 6 or by soluble Fas receptor infusion 5 has been shown to reduce apoptosis, promote regeneration and improve neurological recovery after dorsal column transection or spinal cord clip-compression, respectively. Although the mechanism Reparixin diminished the expression of Fas and p75 receptors is unknown, the inhibited oligodendrocyte apoptosis and preservation of the white matter around the SCI lesion 7 could be attributed to reduced levels of Fas and p75. In this paper, we also observed that Reparixin treatment reduced the area of the spinal cord lesion, but also report a neuroprotective benefit as neurons were more abundant near the SCI lesion of Reparixin-treated rats, compared with saline-treated rats (Figure 4).…”

“…1 Recently, treatment strategies designed to selectively reduce inflammation and cell death after SCI have demonstrated increased axonal sparing, neuroprotection and improved neurological outcomes after SCI. [2][3][4][5][6] Targets have included chemokine receptors, 3,4,7 cell adhesion integrins, 2,8 and cytokines and death receptors 5,6 that are upregulated after SCI.…”

“…10 Recently, Reparixin treatment has also been shown to attenuate the inflammatory response, reduce gliosis, promote white matter sparing and improve hindlimb locomotor recovery in rats after spinal cord contusion injury. 7 Although the development of autonomic dysreflexia after SCI has been demonstrated to be sensitive to antiinflammatory treatment 2,8 and associated with the severity of injury and tissue sparing, 2,11 the effects of Reparixin treatment on sensory or autonomic function have not been investigated. 7 Autonomic dysreflexia, a condition that develops in 50-90% of patients with upper thoracic and cervical SCI, is characterized by symptoms that include episodic hypertension, debilitating headaches and profuse sweating.…”

“…7 Although the development of autonomic dysreflexia after SCI has been demonstrated to be sensitive to antiinflammatory treatment 2,8 and associated with the severity of injury and tissue sparing, 2,11 the effects of Reparixin treatment on sensory or autonomic function have not been investigated. 7 Autonomic dysreflexia, a condition that develops in 50-90% of patients with upper thoracic and cervical SCI, is characterized by symptoms that include episodic hypertension, debilitating headaches and profuse sweating. 12,13 The rapid increase in arterial pressure can lead to cardiac arrhythmias, seizures and hemorrhagic strokes.…”