Activation of Kir2.3 Channels by Tenidap Suppresses Epileptiform Burst Discharges in Cultured Hippocampal Neurons

Author(s): Xunyi Wu*, Zhiyun Chen, Wanbing Sun, Guoxiang Wang, Lu Zhang, Yuwen Zhang, Kai Zang, Yun Wang*.

Journal Name: CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)

Volume 18 , Issue 8 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background & Objective: Tenidap, a selective human inwardly rectifying potassium (Kir) 2.3 channel opener, has been reported to have antiepileptic effect in the pilocarpine temporal lobe epilepsy rat model in our previous study. However, the effect of tenidap on neurons and its relationship with the epileptiform bursting charges in neuron is still required to be explored.

Methods: In this study, cyclothiazide (CTZ) induced cultured hippocampal neuron epileptic model was used to study the antiepileptic effect of tenidap and the relationship between Kir2.3 channel and the neuronal epileptiform burst.

Results: Patch clamp recording showed that both acute (2h) and chronic (48h) CTZ pre-treatment all significantly induced robust epileptiform burst activities in cultured hippocampal neurons, and tenidap acutely application inhibited this highly synchronized abnormal activities. The effect of tenidap is likely due to increased activity of Kir2.3 channels, since tenidap significantly enhanced kir current recorded from those neurons. In addition, neurons overexpressing Kir2.3 channels, by transfection with Kir2.3 plasmid, showed a significant large increase of the Kir current, prevented CTZ treatment to induce epileptiform burst discharge.

Conclusion: Our current study demonstrated that over activation of Kir2.3 channel in hippocampal neurons could positively interference with epileptiform burst activities, and tenidap, as a selective Kir2.3 channel opener, could be a potential candidate for seizure therapy.

Keywords: Tenidap, potassium channel, Kir2.3, epilepsy, neurological disorder, epileptiform burst firing.

[1]
Ali A, Ahmad FJ, Pillai KK, Vohora D. Evidence of the antiepileptic potential of amiloride with neuropharmacological benefits in rodent models of epilepsy and behavior. Epilepsy Behav 2004; 5: 322-8.
[2]
Deng X, Xie Y, Chen Y. Effect of neuroinflammation on ABC transporters. Possible contribution to refractory epilepsy. CNS Neurol Disord Drug Targets 2018; 17: 728-35.
[3]
Ying X, Wang Y, Liang J, et al. Angiopep-conjugated electro-responsive hydrogel nanoparticles: Therapeutic potential for epilepsy. Angew Chem Int Ed Engl 2014; 53: 12436-40.
[4]
Shuzhang Z, Yudan Z, Zhiping Z, Jie T, Yong-Hua J. Understanding genotypes and phenotypes of the mutations in voltage- gated sodium channel α subunits in epilepsy. CNS Neurol Disord Drug Targets 2018; 17: 1-7.
[5]
Ohno Y, Tokudome K. Therapeutic role of Synaptic Vesicle glycoprotein 2A (SV2A) in modulating epileptogenesis. CNS Neurol Disord Drug Targets 2017; 16: 463-71.
[6]
Witkin JM, Schober DA, Gleason SD, et al. Targeted Blockade of TARP-γ8-associated AMPA receptors: Anticonvulsant activity with the selective antagonist LY3130481 (CERC-611). CNS Neurol Disord Drug Targets 2017; 16: 1099-110.
[7]
Shiha AA, de la Rosa RF, Delgado M, Pozo MA, García-García L. Subacute fluoxetine reduces signs of hippocampal damage induced by a single convulsant dose of 4-aminopyridine in rats. CNS Neurol Disord Drug Targets 2017; 16: 694-704.
[8]
Lerche H, Shah M, Beck H, Noebels J, Johnston D, Vincent A. Ion channels in genetic and acquired forms of epilepsy. J Physiol 2013; 591: 753-64.
[9]
Zhu Y, Zhang S, Feng Y, Xiao Q, Cheng J, Tao J. The Yin and Yang of BK channels in epilepsy. CNS Neurol Disord Drug Targets 2018; 17: 272-9.
[10]
Zang K, Zhang Y, Hu J, Wang Y. The large conductance calcium- and voltage-activated potassium channel (BK) and epilepsy. CNS Neurol Disord Drug Targets 2018; 17: 248-54.
[11]
Pruss H, Derst C, Lommel R, Veh RW. Differential distribution of individual subunits of strongly inwardly rectifying potassium channels (Kir2 family) in rat brain. Brain Res Mol Brain Res 2005; 139: 63-79.
[12]
Bedner P, Steinhauser C. Altered Kir and gap junction channels in temporal lobe epilepsy. Neurochem Int 2013; 63: 682-7.
[13]
Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels, their structure, function, and physiological roles. Physiol Rev 2010; 90: 291-366.
[14]
de Boer TP, Houtman MJ, Compier M, van der Heyden MA. The mammalian K(IR)2.x inward rectifier ion channel family, expression pattern and pathophysiology. Acta Physiol (Oxf) 2010; 199: 243-56.
[15]
Murata Y, Yasaka T, Takano M, Ishihara K. Neuronal and glial expression of inward rectifier potassium channel subunits Kir2.x in rat dorsal root ganglion and spinal cord. Neurosci Lett 2016; 617: 59-65.
[16]
Xu L, Hao Y, Wu X, Yu P, Zhu G, Hong Z. Tenidap, an agonist of the inwardly rectifying K+ channel Kir2.3, delays the onset of cortical epileptiform activity in a model of chronic temporal lobe epilepsy. Neurol Res 2013; 35: 561-7.
[17]
Madhok R Tenidap. Lancet 1995; 346(8973): 481-5.
[18]
Liu Y, Liu D, Printzenhoff D, Coghlan MJ, Harris R, Krafte DS. Tenidap, a novel anti-inflammatory agent, is an opener of the inwardly rectifying K+ channel hKir2.3. Eur J Pharmacol 2002; 435: 153-60.
[19]
Chen B, Jiang M, Zhou M, et al. Both NMDA and non-NMDA receptors mediate glutamate stimulation induced cofilin rod formation in cultured hippocampal neurons. Brain Res 2012; 1486: 1-13.
[20]
Chen L, Wan L, Wu Z, et al. KCC2 downregulation facilitates epileptic seizures. Sci Rep 2017; 7: 156.
[21]
Sun Y, Wu Z, Kong S, et al. Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors. Mol Brain 2013; 6: 21.
[22]
Qi J, Wang Y, Jiang M, Warren P, Chen G. Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo. J Physiol 2006; 571: 605-18.
[23]
Stafstrom CE, Carmant L. Seizures and epilepsy: An overview for neuroscientists. Cold Spring Harb Perspect Med 2015; 5pii: a022426
[24]
Naseer MI, Rasool M, Chaudhary AG, et al. Chromosomal micro-aberration in a Saudi family with juvenile myoclonic epilepsy. CNS Neurol Disord Drug Targets 2017; 16: 1010-7.
[25]
Jiang XW, Lu HY, Xu Z, et al. In Silicoanalyses for key genes and molecular genetic mechanism in epilepsy and Alzheimer’s disease. CNS Neurol Disord Drug Targets 2018; 17: 608-17.
[26]
Hille B. Ionic channels in excitable membranes. Current problems and biophysical approaches. Biophys J 1978; 22: 283-94.
[27]
Perier F, Radeke CM, Vandenberg CA. Primary structure and. characterization of a small-conductance inwardly rectifying potassium channel from human hippocampus. Proc Natl Acad Sci USA 1994; 91: 6240-4.
[28]
Tang XH, Wu XY, Xu L, et al. Tenidap is neuroprotective in a pilocarpine rat model of temporal lobe epilepsy. Chin Med J (Engl) 2013; 126: 1900-5.
[29]
Zhang S, Zhu Y, Zhang Z, Tao J, Ji Y. Understanding genotypes and phenotypes of voltage-gated sodium channel mutations in epilepsy. CNS Neurol Disord Drug Targets 2018; 18(4): 266-72.
[30]
Leo A, Citraro R, Marra R, et al. The sphingosine 1-phosphate signaling pathway in epilepsy. A possible role for the immunomodulator drug fingolimod in epilepsy treatment. CNS Neurol Disord Drug Targets 2017; 16: 311-25.
[31]
Ruppersberg JP. Intracellular regulation of inward rectifier K+ channels. Pflugers Arch 2000; 441: 1-11.
[32]
Wang WH. Regulation of the hyperpolarization-activated K+ channel in the lateral membrane of the cortical collecting duct. J Gen Physiol 1995; 106: 25-43.
[33]
Fisher RS, Pedley TA, Moody WJ Jr, Prince DA. The role of extracellular potassium in hippocampal epilepsy. Arch Neurol 1976; 33: 76-83.
[34]
Lothman EW, Somjen GG. Functions of primary afferents and responses of extracellular K+ during spinal epileptiform seizures. Electroencephalogr Clin Neurophysiol 1976; 41: 253-67.
[35]
Traynelis SF, Dingledine R. Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J Neurophysiol 1988; 59: 259-76.
[36]
Best L, Brown PD, Sener A, Malaisse WJ. Opposing effects of tenidap on the volume-regulated anion channel and K(ATP) channel activity in rat pancreatic beta-cells. Eur J Pharmacol 2010; 629: 159-63.
[37]
Cleveland PL, Millard PJ, Showell HJ, Fewtrell CM. Tenidap, a novel inhibitor of calcium influx in a mast cell line. Cell Calcium 1993; 14: 1-16.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 8
Year: 2019
Page: [621 - 630]
Pages: 10
DOI: 10.2174/1871527318666190807122623
Price: $65

Article Metrics

PDF: 27
HTML: 4