Reduction of Pathological and Behavioral Deficits Following Spinal Cord Contusion Injury with the Selective Cyclooxygenase-2 Inhibitor NS-398

Abstract

Spinal cord injury (SCI) results in loss of locomotor function and development of abnormal chronic pain syndromes (mechanical allodynia, thermal hyperalgesia). Following injury, secondary mechanisms including release of excitatory amino acids, inflammation and lipid peroxidation damage neural cells through release of cytotoxic free radicals. We hypothesized that selective inhibition of cyclooxygenase-2 (COX-2), an inducible inflammatory mediator, would decrease tissue damage and subsequently reduce locomotor deficits and development of chronic central pain syndromes after injury. Fifteen minutes prior to receiving T13 spinal segment spinal cord contusion injury, 200-225-g male Sprague-Dawley rats received either vehicle (0.5 ml 1:1 v/v DMSO/saline, i.p., n = 20) or the selective COX-2 inhibitor NS-398 (5 mg/kg in DMSO/saline v/v, i.p., n = 20). Locomotor function via the BBB scale, and nociceptive behaviors measured by paw withdrawals to von Frey filaments and radiant heat stimuli were tested for 4 weeks postinjury. Histological examination and volumetric analysis of spinal cord tissue were performed concomitantly. Spinally contused animals receiving NS-398 demonstrated significantly (p < 0.05) reduced locomotor alteration and reductions in both fore- and hindlimb mechanical allodynia and thermal hyperalgesia when compared to vehicle controls. Histological examination of spinal segments at the lesion segment demonstrated reduced lesion extent and increased viable tissue when compared to vehicle controls. Prostaglandin E2 levels were significantly lowered in NS-398-treated but not vehicle-treated animals 12 h after injury. These results support the role of COX-2 in reducing pathological and behavioral deficits after spinal cord injury.

Extracellular Signal-Regulated Kinase-Regulated Microglia–Neuron Signaling by Prostaglandin E2Contributes to Pain after Spinal Cord Injury

“…Drugs were administered from days 31 to 33, followed by 2 additional days of testing (until day 35). On the first day of behavioral testing after SCI, motor performance of rats with SCI recovered well enough to yield reliable withdrawal reflex measures, as shown in previous studies (Hains et al, 2001).…”

“…Microglial PGE 2 may therefore play an important role in the generation of central sensitization after SCI. Reductions in behavioral indicators of pain after SCI are possible through inhibition of COX-2-mediated PGE 2 production (Hains et al, 2001). COX-mediated PGE 2 release may be possible through a number of cell types.…”

“…Given evidence that inhibition of PGE 2 release can reduce behavioral signs of pain after SCI (Hains et al, 2001) and peripheral nerve injury , we tested the hypothesis that activated microglia modulate the activity of dorsal horn sensory neurons through a PGE 2 signaling mechanism and that PGE 2 synthesis is regulated by an ERK1/2-dependent mechanism after SCI. Here, we identify a putative microglia-neuron signaling pathway involving PGE 2 that contributes to chronic pain after SCI and show that microglial PGE 2 release is dependent on activation of an upstream ERK1/2 mitogen-activated protein kinase (MAPK) cascade.…”

Differences in forebrain activation in two strains of rat at rest and after spinal cord injury

“…For example, Christensen and colleagues reported that unilateral hemisection at T13 produced mechanical and thermal allodynia and hyperalgesia in both the ipsilateral and contralateral forelimbs and hindlimbs (Christensen et al, 1996). Since that study, there have been several reports of hyperresponsiveness of the forelimbs following SCI (Hulsebosch et al, 1998;Bennett et al, 2000a,b;Hains et al, 2000Hains et al, , 2001. Therefore, it is possible that our animals may also experience a hyperresponsiveness to stimulation of the face and whisker barrels.…”

Immediate administration of COX inhibitors in spinal cord contusion injury and a current review of COX Therapy

“…Consequently, functional improvement in hind limbs, using a selective COX-2 inhibitor, SC58125 (1-[4-methylsufonyl) phenyl]-3-tri-fluro-methyl-5-[(4-fluro) phenyl] prazole were observed [7]. Pain profile improvements following application of COX-2 inhibitors reducing PGE2 production in numerous studies have been reported [19][20][21][22]. Because SCI may cause a relatively immediate increase in PGE2 levels, it is important to consider the possible role of COX-2 induction in the onset of SCI-induced NP.…”