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Mol Brain. 2019 May 15;12(1):50. doi: 10.1186/s13041-019-0465-0.

Gluconate suppresses seizure activity in developing brains by inhibiting CLC-3 chloride channels.

Author information

1
Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
2
School of Life Sciences, South China Normal University, Guangzhou, 510631, China.
3
South China Research Center for Acupuncture-Moxibustion, Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou Univ Chinese Med, Guangzhou, 510006, China.
4
Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
5
Bio-X Institutes, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
6
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
7
Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. gongchen@psu.edu.

Abstract

Neonatal seizures are different from adult seizures, and many antiepileptic drugs that are effective in adults often fail to treat neonates. Here, we report that gluconate inhibits neonatal seizure by inhibiting CLC-3 chloride channels. We detect a voltage-dependent outward rectifying Cl- current mediated by CLC-3 Cl- channels in early developing brains but not adult mouse brains. Blocking CLC-3 Cl- channels by gluconate inhibits seizure activity both in neonatal brain slices and in neonatal animals with in vivo EEG recordings. Consistently, neonatal neurons of CLC-3 knockout mice lack the outward rectifying Cl- current and show reduced epileptiform activity upon stimulation. Mechanistically, we demonstrate that activation of CLC-3 Cl- channels alters intracellular Cl- homeostasis and enhances GABA excitatory activity. Our studies suggest that gluconate can suppress neonatal seizure activities through inhibiting CLC-3 Cl- channels in developing brains.

KEYWORDS:

Anticonvulsant; CLC-3; Chloride channels; Epilepsy; GABA; Gluconate; Neonatal seizure

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