Abstract
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.
Highlights
Hypoglycemia occurs in type 1 and type 2 diabetic patients who attempt strict management of their blood glucose levels with insulin or other glucose-lowering drugs [1,2,3]
A substantial degree of microglial activation was detected in the hippocampus, striatum and cerebral cortex 5 days after hypoglycemia (Figure 1)
The present study shows that delayed treatment with minocycline reduces microglial activation and neuronal death in the hippocampus after hypoglycemia
Summary
Hypoglycemia occurs in type 1 and type 2 diabetic patients who attempt strict management of their blood glucose levels with insulin or other glucose-lowering drugs [1,2,3]. Hypoglycemia unawareness may lead to prolonged nocturnal hypoglycemia, causing convulsions result of activating cell death-related signaling pathways such as glutamate receptor activation, reactive oxygen species (ROS) production and extracellular zinc release [1012]. The exact circumstances under which microglial activation is harmful or beneficial are still controversial [15], some evidence indicates that early phase inflammation caused by acute brain injury can contribute to neuronal death. We showed that hypoglycemic injury-induced microglial activation is affected by body temperature [18]. It is unknown whether microglial activation is a major contributing factor in hypoglycemiainduced neuronal death
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