title: Diazoxide reduces status epilepticus neuron damage in diabetes.
abstract: Diabetic hyperglycemia is associated with seizure severity and may aggravate brain damage after status epilepticus. Our earlier studies suggest the involvement of ATP-sensitive potassium channels (K(ATP)) in glucose-related neuroexcitability. We aimed to determine whether K(ATP) agonist protects against status epilepticus-induced brain damage. Adult male Sprague-Dawley rats were divided into two groups: the streptozotocin (STZ)-induced diabetes (STZ) group and the normal saline (NS) group. Both groups were treated with either diazoxide (15 mg/kg, i.v.) (STZ + DZX, NS + DZX) or vehicle (STZ + V, NS + V) before lithium-pilocarpine-induced status epilepticus. We evaluated seizure susceptibility, severity, and mortality. The rats underwent Morris water-maze tests and hippocampal histopathology analyses 24 h post-status epilepticus. A multi-electrode recording system was used to study field excitatory postsynaptic synaptic potentials (fEPSP). RNA interference (RNAi) to knockdown Kir 6.2 in a hippocampal cell line was used to evaluate the effect of diazoxide in the presence of high concentration of ATP. Seizures were less severe (P < 0.01), post-status epilepticus learning and memory were better (P < 0.05), and neuron loss in the hippocampal CA3 area was lower (P < 0.05) in the STZ + DZX than the STZ + V group. In contrast, seizure severity, post-status epilepticus learning and memory, and hippocampal CA3 neuron loss were comparable in the NS + DZX and NS + V groups. fEPSP was lower in the STZ + DZX but not in the NS + DZX group. The RNAi study confirmed that diazoxide, with its K(ATP)-opening effects, could counteract the K(ATP)-closing effect by high dose ATP. We conclude that, by opening K(ATP), diazoxide protects against status epilepticus-induced neuron damage during diabetic hyperglycemia.
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan. huangped@mail.ncku.edu.tw
authors.forename: Chin-Wei
authors.initials: CW
authors.lastname: Huang
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
authors.forename: Juei-Tang
authors.initials: JT
authors.lastname: Cheng
authors.forename: Jing-Jane
authors.initials: JJ
authors.lastname: Tsai
authors.forename: Chao-Ching
authors.initials: CC
authors.lastname: Huang
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002461:Cell Line, Transformed; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003981:Diazoxide / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D018021:Lithium Chloride; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D014162:Transfection / Q000379:methods; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D001786:Blood Glucose; D003981:Diazoxide; D018021:Lithium Chloride; D024661:Potassium Channels, Inwardly Rectifying; D034741:RNA, Small Interfering; D014665:Vasodilator Agents; D000099161:Kcnj11 Channel