The role of glucose uptake and metabolism in hyperglycemic exacerbation of neurological deficit in the paraplegic rat.

Previous studies indicate that hyperglycemia, particularly that induced by exogenous glucose administration, exacerbates neurological deficits in the rat spinal cord ischemic model. The effect of inhibition of glucose uptake (glucose transporter) and initial metabolism (hexokinase) on neurological outcome was evaluated in the present investigation using the competitive inhibitors 2-deoxyglucose (2-DG) and 3-O-methylglucose (3-OMG). Sprague-Dawley rats, weighing 200 to 300 gm each, received either 0.25, 1, or 2 gm/kg 2-DG; 2 gm/kg 3-OMG; 2 gm/kg glucose; or an equivalent volume of 0.9% saline intraperitoneally. Rats were intubated and ventilated with 1% to 1.5% halothane. The aortic arch was exposed and snares were placed on the right and left subclavian arteries and the aorta distal to the left subclavian artery. The three vessels were occluded for 10, 11, 12, or 13 minutes. Lower-extremity neurological deficits were evaluated at 1, 4, 18, and 24 hours postocclusion based on a 15-point scale (normal = 0, severe deficit = 15). Lower-extremity neurological deficits were significantly less severe in the groups treated with 2-DG (0.25 and 1 gm/kg) at 18 and 24 hours postocclusion (p less than 0.05 for 0.25 gm/kg and p less than 0.005 for 1 gm/kg, Student's t-test with Bonferroni correction). The lower 2-DG dose of 0.25 gm/kg did not significantly increase the plasma glucose level, suggesting that the glucose transporter was not markedly inhibited, and that the improved neurological outcome was more likely due to inhibition of hexokinase. The higher 2-DG dose of 1 gm/kg afforded protection despite significantly increasing the plasma glucose level, implying a strong inhibition of both the glucose transporter and hexokinase. Administration of 3-OMG, which only inhibits glucose uptake and not hexokinase, actually worsened the neurological deficit in a manner similar to that observed in rats treated with glucose. The authors conclude that the activity of the glucose transporter by itself does not significantly contribute to hyperglycemic exacerbation of neurological deficits. In contrast, the hexokinase step, at least in combination with the transporter and possibly alone, plays a significant role in hyperglycemic exacerbation of the lower-extremity neurological deficit in the paraplegic rat.