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Diazoxide Reduces Status Epilepticus Neuron Damage in Diabetes

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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 (KATP) in glucose-related neuroexcitability. We aimed to determine whether KATP 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 KATP-opening effects, could counteract the KATP-closing effect by high dose ATP. We conclude that, by opening KATP, diazoxide protects against status epilepticus-induced neuron damage during diabetic hyperglycemia.

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Acknowledgments

This work was partly supported by grants NSC-96-2314-B-006-059 from the National Science Council and NCKUH-9701015 from National Cheng Kung University Hospital, Taiwan. We thank Dr. Ming-Wei Lin for technical assistance and Bill Franke for editorial assistance.

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Authors and Affiliations

  1. Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan

    Chin-Wei Huang & Chao-Ching Huang

  2. Department of Neurology, National Cheng Kung University College of Medicine, Tainan, Taiwan

    Chin-Wei Huang & Jing-Jane Tsai

  3. Department of Physiology, National Cheng Kung University College of Medicine, Tainan, Taiwan

    Sheng-Nan Wu

  4. Department of Pharmacology, National Cheng Kung University College of Medicine, Tainan, Taiwan

    Juei-Tang Cheng

  5. Department of Pediatrics, Institute of Clinical Medicine, National Cheng Kung University College of Medicine, 138 Sheng-Li Road, Tainan, 70428, Taiwan

    Chao-Ching Huang

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  1. Chin-Wei Huang
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Correspondence to Chao-Ching Huang.

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Huang, CW., Wu, SN., Cheng, JT. et al. Diazoxide Reduces Status Epilepticus Neuron Damage in Diabetes. Neurotox Res 17, 305–316 (2010). https://doi.org/10.1007/s12640-009-9104-3

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