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.
Highlights
In modern societies, more than one-third of the adult populations develops metabolic syndrome (MS) [1]
We examined whether PGB, a standard antiepileptic drugs (AEDs) with KATP agonist properties, protected diabetic rats against pilocarpineinduced seizures and excitotoxicity
We found that PGB (1) reduced acute seizure severity and status epilepticus-related mortality, (2) reduced chronic seizure frequency, (3) ameliorated neuronal damage induced by pilocarpine-induced epilepsy and hyperexcitability, and (4) positively opened KATP in the presence of a high concentration of ATP
Summary
More than one-third of the adult populations develops metabolic syndrome (MS) [1]. Due to its major role in MS, diabetes and its complications deserve attention [2]. Both clinical and laboratory studies [3,4,5] report that MS and diabetes increase seizure severity, which can significantly affect neurological outcome. Kir6.2 mRNA is found in cells distributed throughout the brain [9] and overlaps considerably with SUR1 mRNA. These observations indicate the Kir6.2/ SUR1 complex is an ideal candidate for studying KATP function in the brain [10,11]
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