[Glutamate neurotoxicity during spinal cord ischemia--the neuroprotective effects of adenosine]

Evidence is accumulating that glutamate, a major neurotransmitter, exerts potent neurotoxic activity during ischemia. In our laboratory, a delayed-onset paraplegia model using rabbits has been developed and described. The severity of the ischemic event in this model, i.e., extracellular glutamate overload, is believed to influence the etiology of this delayed neuronal dysfunction. Adenosine, an endogenous neuromodulator, is released after acute ischemic insult and provides neuroprotection by actions on neuronal and glial cells in the still viable border zone of the ischemic focus. We hypothesized that the neuroprotective action of adenosine is associated with inhibition of glutamate neurotoxicity following ischemia. Infrarenal aortic segments from 11 New Zealand white rabbits were isolated for 5 minutes and infused at a rate of 2 ml/min. Group I (n = 6) received normothermic L-glutamate (20 mM). Group II (n = 5) received 75 mg of adenosine and normothermic L-glutamate (20 mM). Neurologic function was assessed at 6, 24, and 48 hours after surgery according to the modified Tarlov scale, After 48 hours, the rabbits were euthanized and their spinal cords were harvested for histologic examination. The neurologic function of three rabbits in group I showed acute paraplegia and the other three showed delayed-onset paraplegia, whereas all group II animals and nearly intact neurologic function. Histologic examination of spinal cords from rabbits in group I showed evidence of moderate spinal cord injury with central gray matter and adjacent white matter necrosis and axonal swelling, whereas spinal cords from group II revealed no evidence of cord injury. Adenosine A1-receptor activation is suspected to reduce excitatory amino acids by controlling the activation of the voltage-dependent NMDA receptor. These results indicate that the neuroprotective effect of adenosine is associated with inhibition of glutamate neurotoxicity, which initiates a deleterious cascade of biochemical events that ultimately result in delayed-onset paraplegia.