Prevention of hypoglycemia-induced neuronal death by minocycline
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Won et al. Journal of Neuroinflammation 2012, 9:225 http://www.jneuroinflammation.com/content/9/1/225
RESEARCH
Open Access
Prevention of hypoglycemia-induced neuronal death by minocycline Seok Joon Won1, Jin Hee Kim6, Byung Hoon Yoo1,3, Min Sohn4, Tiina M Kauppinen1, Man-Seong Park5, Hyung-Joo Kwon5, Jialing Liu2* and Sang Won Suh1,6*
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. Keywords: Hypoglycemia, Minocycline, Neuronal death, Microglia
Introduction 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 [1-3]. Hypoglycemia causes recurrent morbidity in patients, and sometimes results in mortality [4,5]. Frequent low blood glucose levels in type 1 diabetic patients can lead to the development of hypoglycemia unawareness, which desensitizes patients to symptoms of low blood glucose [6]. Hypoglycemia unawareness may lead to prolonged nocturnal hypoglycemia, causing convulsions * Correspondence: [email protected]; [email protected] 2 Department of Neurological Surgery, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA
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