Effect of cyclopentanone prostaglandin 15-deoxy-delta12,14PGJ2 on early functional recovery from experimental spinal cord injury.
Peroxisome proliferator-activated receptor (PPAR) gamma is a member of the nuclear-receptor superfamily that binds to DNA with retinoid X receptors as PPAR-retinoid X receptor heterodimers. Recent evidence also suggests that the cyclopentenone prostaglandin 15-deoxy-DeltaPGJ2 (15d-PGJ2), which is a metabolite of the prostaglandin D2, functions as an endogenous ligand for PPAR-gamma We postulated that 15d-PGJ2 would attenuate inflammation, investigating the effects on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Furthermore, 15d-PGJ2 reduced (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nuclear factor-kappaB activation, (4) expression of iNOS, nitrotyrosine and TNF-alpha, and (5) apoptosis (terminal deoxynucleotidyltransferase-mediated uridine triphosphate end labeling staining, Bax, Bcl-2, and FAS-L expression). In a separate set of experiments, 15d-PGJ2 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). To elucidate whether the protective effects of 15d-PGJ2 are related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, GW 9662, on the protective effects of 15d-PGJ2. GW9662 (1 mg/kg administered i.p. 30 min before treatment with 15d-PGJ2) significantly antagonized the effect of the PPAR-gamma agonist and, thus, abolished the protective effect. Taken together, our results clearly demonstrate that treatment with 15d-PGJ2 reduces the development of inflammation and tissue injury associated with spinal cord trauma.
Genovese
Tiziana
T
IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Esposito
Emanuela
E
Mazzon
Emanuela
E
Di Paola
Rosanna
R
Muià
Carmelo
C
Meli
Rosaria
R
Bramanti
Placido
P
Cuzzocrea
Salvatore
S
D000818:Animals; D003500:Cyclization; D003517:Cyclopentanes / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D012720:Severity of Illness Index; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D003517:Cyclopentanes; D018836:Inflammation Mediators; D008024:Ligands; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; C013905:cyclopentenone; D015230:Prostaglandin D2