Furosemide prevents membrane KCC2 downregulation during convulsant stimulation in the hippocampus

Lulan Chen; Jiangning Yu; Li Wan; Zheng Wu; Guoxiang Wang; Zihan Hu; Liang Ren; Jing Zhou; Binbin Qian; Xuan Zhao; Jinwei Zhang; Xu Liu; Yun Wang

IBRO Neuroscience Reports (Jun 2022)

Furosemide prevents membrane KCC2 downregulation during convulsant stimulation in the hippocampus

Lulan Chen,
Jiangning Yu,
Li Wan,
Zheng Wu,
Guoxiang Wang,
Zihan Hu,
Liang Ren,
Jing Zhou,
Binbin Qian,
Xuan Zhao,
Jinwei Zhang,
Xu Liu,
Yun Wang

Affiliations

Lulan Chen: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Jiangning Yu: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Li Wan: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Rehabilitation Center, Shenzhen Second People's Hospital/ the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, China Institute of
Zheng Wu: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Guoxiang Wang: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Zihan Hu: Department of Anesthesiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
Liang Ren: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Jing Zhou: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Rehabilitation Center, Shenzhen Second People's Hospital/ the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, China Institute of
Binbin Qian: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Xuan Zhao: Department of Anesthesiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China; Correspondence to: Department of Anesthesiology, Shanghai Tenth People’s Hospital, China.
Jinwei Zhang: Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK
Xu Liu: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Correspondence to: Department of Neurology, Zhongshan Hospital, Fudan University, China.
Yun Wang: Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Correspondence to: Institutes of Brain Science, Fudan University, Shanghai 200032, China.

Journal volume & issue: Vol. 12
pp. 355 – 365

Abstract

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In adults, γ-aminobutyric acid (GABA) type A receptor (GABAAR)-mediated inhibition depends on the maintenance of low intracellular chloride anion concentration through neuron-specific potassium-chloride cotransporter-2 (KCC2). KCC2 has been widely reported to have a plasticity change during the course of epilepsy development, with an early downregulation and late recovery in neuronal cell membranes after epileptic stimulation, which facilitates epileptiform burst activity. Furosemide is a clinical loop diuretic that inhibits KCC2. Here, we first confirmed that furosemide pretreatment could effectively prevented convulsant stimulation-induced neuronal membrane KCC2 downregulation in the hippocampus in both in vivo and in vitro cyclothiazide-induced seizure model. Second, we verified that furosemide pretreatment rescued KCC2 function deficits, as indicated by EGABA depolarizing shift and GABAAR inhibitory function impairment induced via cyclothiazide treatment. Further, we demonstrated that furosemide also suppressed cyclothiazide-induced epileptiform burst activity in cultured hippocampal neurons and lowered the mortality rate during acute seizure induction. Overall, furosemide prevents membrane KCC2 downregulation during acute seizure induction, restores KCC2-mediated GABA inhibition, and interrupts the progression from acute seizure to epileptogenesis.

Published in IBRO Neuroscience Reports

ISSN: 2667-2421 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/ibro-neuroscience-reports

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