Regulation of interleukin-1β by the interleukin-1 receptor antagonist in the glutamate-injured spinal cord:: Endogenous neuroprotection

Elevation of extracellular glutamate contributes to cell death and functional impairments generated by spinal cord injury (SCI), in part through the activation of the neurotoxic cytokine interleukin-1 beta (IL-1 beta). This study examines the participation of IL-1 beta and its regulation by the endogenous interleukin-1 receptor antagonist (IL-1ra) in glutamate toxicity following SCI Glutamate, glutamatergic agonists and SCI had similar effects on levels of IL-1 beta and IL-1ra. Following spinal cord contusion or exposure to elevated glutamate, concentrations of IL-1 beta first increased as IL-1ra decreased, and both then changed in the opposite directions. Applying the glutamate agonists NMDA and S-AMPA to the spinal cord caused changes in IL-1 beta and IL-1ra levels very similar to those produced by contusion and glutamate. The glutamate antagonists MK801 and NBQX blocked the glutamate-induced changes in IL-1 beta and IL-1ra levels. Administering IL-1 beta elevated IL-1ra, and administering IL-1ra depressed IL-1 beta levels. Infusing IL-beta into the spinal cord impaired locomotion, and infusing IL-1ra improved recovery from glutamate-induced motor impairments. We hypothesize that elevating IL-1ra opposes the damage caused by IL-1 beta in SCI by reducing IL-1 beta levels as well as by blocking binding of IL-1 beta to its receptor. Our results demonstrate that IL-1 beta contributes to glutamate damage following SCI; blocking IL-1 beta may usefully counteract glutamate toxicity. (C) 2008 Elsevier B.V. All rights reserved.