title: Prevention of hypoglycemia-induced neuronal death by minocycline.
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.
authors.affiliation: Department of Neurology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Byung Hoon
authors.initials: BH
authors.lastname: Yoo
authors.forename: Min
authors.initials: M
authors.lastname: Sohn
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Kauppinen
authors.forename: Man-Seong
authors.initials: MS
authors.lastname: Park
authors.forename: Hyung-Joo
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Jialing
authors.initials: J
authors.lastname: Liu
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001930:Brain Injuries / Q000209:etiology* / Q000517:prevention & control*; D039481:CD11b Antigen / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005452:Fluoresceins; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007003:Hypoglycemia / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D007004:Hypoglycemic Agents / Q000633:toxicity; D007328:Insulin / Q000633:toxicity; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008911:Minocycline / Q000627:therapeutic use*; D009068:Movement / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009930:Organic Chemicals; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D039481:CD11b Antigen; D005452:Fluoresceins; D007004:Hypoglycemic Agents; D007328:Insulin; D009930:Organic Chemicals; C435731:fluoro jade; D009195:Peroxidase; D008911:Minocycline