Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of function after traumatic lesion to the spinal cord.
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.
Gorio
Alfredo
A
Pharmacological Laboratories, Department of Medicine, Surgery and Dentistry, via A. Di Rudinì 8, 20142 Milano, Italy. alfredo.gorio@unimi.it
Madaschi
Laura
L
Zadra
Giorgia
G
Marfia
Giovanni
G
Cavalieri
Barbara
B
Bertini
Riccardo
R
Di Giulio
Anna Maria
AM
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000188:drug therapy*; D035002:Lower Extremity / Q000503:physiopathology; D008297:Male; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D016207:Cytokines; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; C490707:reparixin