Effect of kynurenate on functional deficits resulting from traumatic spinal cord injury

Abstract

The potential role of excitatory amino acid (EAA) receptors in spinal cord trauma was examined in a standardized rat model of contusive injury. EAA antagonists were administered in a split-dose protocol with half given 5 min prior to and the remainder 15 min after contusion produced at the T8 vertebral level. Hindlimb function was assessed using a battery of tests of reflex and more complex behaviors at 1 day after injury and weekly thereafter through 4–8 weeks. Functional deficits were compared for groups administered intravenous MK 801 (1 mg/kg), dextromethorphan (10 mg/kg) and kynurenate (300 mg/kg) or the vehicle, saline, alone. In addition, possible effect of the drugs themselves on hindlimb function were assessed in uninjured controls. None of the drugs produced more than transient effect on uninjured rats. In contused rats, only kynurenate produced significant reductions in functional deficits as compared to saline controls. Significant improvement of hindlimb function was also observed when the thoracic cord was locally perfused with kynurenate via intrathecal cannulas and when kynurenate was directly infused into the contusive injury site by stereotaxic microinjection. Using the latter route of administration, a dose-dependent effect of kynurenate (100, 200 and 400 nmol) on the ability of contused rats to use their hindlimbs in locomotion was demonstrated. The highest dose also resulted in a significant reduction in overall functional deficits from 1 week through 1 month and at 2 months after injury. Our results support the hypothesis that EAA receptors at or near the injury site are involved in producing a proportion of the overall functional deficits stemming from traumatic injury. In addition, the efficacy of the broad spectrum antagonist of EAA receptors, kynurenate, and the absence of effect of the NMDA receptor antagonists, MK 801 or dextromethorphan, suggests than non-NMDA receptors may play a hitherto unappreciated role in secondary injury after spinal cord contusion.