title: Pregabalin attenuates excitotoxicity in diabetes.
abstract: Diabetes can exacerbate seizures and worsen seizure-related brain damage. In the present study, we aimed to determine whether the standard antiepileptic drug pregabalin (PGB) protects against pilocarpine-induced seizures and excitotoxicity in diabetes. Adult male Sprague-Dawley rats were divided into either a streptozotocin (STZ)-induced diabetes group or a normal saline (NS) group. Both groups were further divided into subgroups that were treated intravenously with either PGB (15 mg/kg) or a vehicle; all groups were treated with subcutaneous pilocarpine (60 mg/kg) to induce seizures. To evaluate spontaneous recurrent seizures (SRS), PGB-pretreated rats were fed rat chow containing oral PGB (450 mg) for 28 consecutive days; vehicle-pretreated rats were fed regular chow. SRS frequency was monitored for 2 weeks from post-status epilepticus day 15. We evaluated both acute neuronal loss and chronic mossy fiber sprouting in the CA3 area. In addition, we performed patch clamp recordings to study evoked excitatory postsynaptic currents (eEPSCs) in hippocampal CA1 neurons for both vehicle-treated rats with SRS. Finally, we used an RNA interference knockdown method for Kir6.2 in a hippocampal cell line to evaluate PGB's effects in the presence of high-dose ATP. We found that compared to vehicle-treated rats, PGB-treated rats showed less severe acute seizure activity, reduced acute neuronal loss, and chronic mossy fiber sprouting. In the vehicle-treated STZ rats, eEPSC amplitude was significantly lower after PGB administration, but glibenclamide reversed this effect. The RNA interference study confirmed that PGB could counteract the ATP-sensitive potassium channel (KATP)-closing effect of high-dose ATP. By opening KATP, PGB protects against neuronal excitotoxicity, and is therefore a potential antiepileptogenic in diabetes. These findings might help develop a clinical algorithm for treating patients with epilepsy and comorbid metabolic disorders.
authors.affiliation: Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. huangcw@mail.ncku.edu.tw
authors.forename: Chin-Wei
authors.initials: CW
authors.lastname: Huang
authors.forename: Ming-Chi
authors.initials: MC
authors.lastname: Lai
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
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose; D002460:Cell Line; D003929:Diabetic Neuropathies / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010862:Pilocarpine / Q000009:adverse effects; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D000069583:Pregabalin; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D013311:Streptozocin / Q000009:adverse effects; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D000927:Anticonvulsants; D001786:Blood Glucose; D005905:Glyburide; D054086:KATP Channels; D010862:Pilocarpine; D024661:Potassium Channels, Inwardly Rectifying; D000069583:Pregabalin; D013311:Streptozocin; D005680:gamma-Aminobutyric Acid; D000099161:Kcnj11 Channel