minocycline and Hypoglycemia

Diabetic patients who attempt strict management of blood glucose levels frequently experience hypoglycemia. Severe and prolonged hypoglycemia causes neuronal death and cognitive impairment. There is no effective tool for prevention of these unwanted clinical sequelae. Minocycline, a second-generation tetracycline derivative, has been recognized as an anti-inflammatory and neuroprotective agent in several animal models such as stroke and traumatic brain injury. In the present study, we tested whether minocycline also has protective effects on hypoglycemia-induced neuronal death and cognitive impairment. To test our hypothesis we used an animal model of insulin-induced acute hypoglycemia. Minocycline was injected intraperitoneally at 6 hours after hypoglycemia/glucose reperfusion and injected once per day for the following 1 week. Histological evaluation for neuronal death and microglial activation was performed from 1 day to 1 week after hypoglycemia. Cognitive evaluation was conducted 6 weeks after hypoglycemia. Microglial activation began to be evident in the hippocampal area at 1 day after hypoglycemia and persisted for 1 week. Minocycline injection significantly reduced hypoglycemia-induced microglial activation and myeloperoxidase (MPO) immunoreactivity. Neuronal death was significantly reduced by minocycline treatment when evaluated at 1 week after hypoglycemia. Hypoglycemia-induced cognitive impairment is also significantly prevented by the same minocycline regimen when subjects were evaluated at 6 weeks after hypoglycemia. Therefore, these results suggest that delayed treatment (6 hours post-insult) with minocycline protects against microglial activation, neuronal death and cognitive impairment caused by severe hypoglycemia. The present study suggests that minocycline has therapeutic potential to prevent hypoglycemia-induced brain injury in diabetic patients.

Topics: Analysis of Variance; Animals; Blood Glucose; Blood Pressure; Brain Injuries; CD11b Antigen; Cell Death; Disease Models, Animal; Exploratory Behavior; Fluoresceins; Hippocampus; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Microglia; Minocycline; Movement; Neurons; Neutrophil Infiltration; Organic Chemicals; Peroxidase; Rats; Rats, Sprague-Dawley

Hypoglycemia is an important complication of insulin treatment in diabetic children and may contribute to lasting cognitive impairment. Previous studies demonstrated that 21-day-old rats (P21) subjected to brief, repetitive episodes of hypoglycemia sustain cortical neuronal death. The developing brain is capable of utilizing alternative energy substrates acetoacetate and beta-hydroxybutyrate. In these studies we tested the hypothesis that the developing brain adapted to ketone utilization and provided with ketones during hypoglycemia by eating a ketogenic diet would sustain less brain injury compared to littermates fed a standard diet. Supporting this hypothesis, P21 rats weaned to a ketogenic diet and subjected to insulin-induced hypoglycemia at P25 had significantly less neuronal death than rats on a standard diet. This animal model may provide insight into the determinants influencing the brain's susceptibility to hypoglycemic injury.

Topics: Animals; Anti-Bacterial Agents; Brain; Cell Death; Diet; Hypoglycemia; Hypoglycemic Agents; Insulin; Ketones; Minocycline; Neurons; Rats; Rats, Sprague-Dawley