Prevention of Severe Hypoglycemia-Induced Brain Damage and Cognitive Impairment With Verapamil.

Abstract

People with insulin-treated diabetes are uniquely at risk for severe hypoglycemia-induced brain damage. Because calcium influx may mediate brain damage, we tested the hypothesis that the calcium-channel blocker, verapamil, would significantly reduce brain damage and cognitive impairment caused by severe hypoglycemia. Sprague-Dawley rats (10 weeks old) were randomly assigned to one of three treatments: 1) control hyperinsulinemic (200 mU ⋅ kg-1 ⋅ min-1)-euglycemic (80-100 mg/dL) clamps (n = 14), 2) hyperinsulinemic-hypoglycemic (10-15 mg/dL) clamps (n = 16), or 3) hyperinsulinemic-hypoglycemic clamps, followed by a single treatment with verapamil (20 mg/kg) (n = 11). Compared with euglycemic controls, hypoglycemia markedly increased dead/dying neurons in the hippocampus by 16-fold and cortex by 14-fold. Verapamil treatment strikingly decreased hypoglycemia-induced hippocampal and cortical damage, by 87% and 94%, respectively. Morris Water Maze probe trial results demonstrated that hypoglycemia induced a retention, but not encoding, memory deficit (noted by both abolished target quadrant preference and reduced target quadrant time). Verapamil treatment significantly rescued spatial memory as noted by restoration of target quadrant preference and target quadrant time. In summary, a one-time treatment with verapamil after severe hypoglycemia prevented neural damage and memory impairment caused by severe hypoglycemia. For people with insulin-treated diabetes, verapamil may be a useful drug to prevent hypoglycemia-induced brain damage.