Zonisamide-induced inhibition of the firing of APs in hippocampal neurons (Huang et al. 2007)

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Zonisamide (ZNS), a synthetic benzisoxazole derivative, has been used as an alternative choice in the treatment of epilepsy with a better efficacy and safety profile. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. The ZNS (30 uM) reversibly increased the amplitude of K+ outward currents and paxilline (1 uM) was effective in suppressing ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 uM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+-activated K+ (BKCa) channels primarily by decreasing mean closed time. The EC50 value for ZNS-stimulated BKCa channels was 34 uM. This drug caused a left shift in the activation curve of BKCa channels with no change in the gating charge of these channels. ZNS at a concentration greater than 100 uM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that in hippocampal neurons, during the exposure to ZNS, the ZNS-mediated effects on BKCa channels and IA could be one of the ionic mechanisms through which it affects neuronal excitability.
Reference:
1 . Huang CW, Huang CC, Wu SN (2007) Activation by Zonisamide, a Newer Anti-Epileptic Drug, of Large-Conductance Calcium-Activated Potassium Channel in Differentiated Hippocampal Neuron-Derived H19-7 Cells. J Pharmacol Exp Ther [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell;
Brain Region(s)/Organism:
Cell Type(s): Hippocampus CA3 pyramidal cell;
Channel(s): I K,Ca; I Sodium;
Gap Junctions:
Receptor(s):
Gene(s):
Transmitter(s):
Simulation Environment: XPP;
Model Concept(s): Ion Channel Kinetics; Axonal Action Potentials; Epilepsy;
Implementer(s): Wu, Sheng-Nan [snwu at mail.ncku.edu.tw]; Huang, Chin-Wei;
Search NeuronDB for information about:  Hippocampus CA3 pyramidal cell; I K,Ca; I Sodium;
  
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Neuron_ZNS
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Huang CW, Huang CC, Wu SN (2007) Activation by Zonisamide, a Newer Anti-Epileptic Drug, of Large-Conductance Calcium-Activated Potassium Channel in Differentiated Hippocampal Neuron-Derived H19-7 Cells. J Pharmacol Exp Ther[PubMed]

References and models cited by this paper

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Bailey MA, Cantone A, Yan Q, MacGregor GG, Leng Q, Amorim JB, Wang T, Hebert SC, Giebisch G, (2006) Maxi-K channels contribute to urinary potassium excretion in the ROMK-deficient mouse model of Type II Bartter's syndrome and in adaptation to a high-K diet. Kidney Int 70:51-9 [PubMed]

Baulac M (2006) Introduction to zonisamide. Epilepsy Res 68 Suppl 2:S3-9

Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L (1993) mSlo, a complex mouse gene encoding "maxi" calcium-activated potassium channels. Science 261:221-4 [PubMed]

Castro PA, Cooper EC, Lowenstein DH, Baraban SC (2001) Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy. J Neurosci 21:6626-34 [PubMed]

Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang L, Kotagal P, Luders HO, Shi J, Cui (2005) Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 37:733-8 [PubMed]

Ermentrout GB (2002) Simulating, Analyzing, and Animating Dynamical System: A Guide to XPPAUT for Researchers and Students Society for Industrial and Applied Mathematics (SIAM)

Ghaemi SN, Zablotsky B, Filkowski MM, Dunn RT, Pardo TB, Isenstein E, Baldassano CF (2006) An open prospective study of zonisamide in acute bipolar depression. J Clin Psychopharmacol 26:385-8 [PubMed]

Ghatta S, Nimmagadda D, Xu X, O'Rourke ST (2006) Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol Ther 110:103-16 [PubMed]

Gribkoff VK, Starrett JE, Dworetzky SI, Hewawasam P, Boissard CG, Cook DA, Frantz SW, Heman K (2001) Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat Med 7:471-7 [PubMed]

Hong KW, Kim KY, Shin HK, Lee JH, Choi JM, Kwak YG, Kim CD, Lee WS, Rhim BY (2003) Cilostazol prevents tumor necrosis factor-alpha-induced cell death by suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and activation of Akt-cyclic AMP response element-binding protein phosphorylation. J Pharmacol Exp Ther 306:1182-90 [PubMed]

Huang CW, Huang CC, Liu YC, Wu SN (2004) Inhibitory effect of lamotrigine on A-type potassium current in hippocampal neuron-derived H19-7 cells. Epilepsia 45:729-36 [PubMed]

Huang CW, Huang CC, Wu SN (2006) The opening effect of pregabalin on ATP-sensitive potassium channels in differentiated hippocampal neuron-derived H19-7 cells. Epilepsia 47:720-6 [PubMed]

Huang CW, Ueno S, Okada M, Kaneko S (2006) Zonisamide at clinically relevant concentrations inhibits field EPSP but not presynaptic fiber volley in rat frontal cortex. Epilepsy Res 67:51-60 [PubMed]

Jang IS, Nakamura M, Ito Y, Akaike N (2006) Presynaptic GABAA receptors facilitate spontaneous glutamate release from presynaptic terminals on mechanically dissociated rat CA3 pyramidal neurons. Neuroscience 138:25-35

Kim B, Leventhal PS, Saltiel AR, Feldman EL (1997) Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation. J Biol Chem 272:21268-73 [PubMed]

Knaus HG, McManus OB, Lee SH, Schmalhofer WA, Garcia-Calvo M, Helms LM, Sanchez M, Giangiacom (1994) Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry 33:5819-28 [PubMed]

Laumonnier F, Roger S, Guerin P, Molinari F, M'rad R, Cahard D, Belhadj A, Halayem M, Persico (2006) Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am J Psychiatry 163:1622-9 [PubMed]

Leppik IE (2004) Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure 13 Suppl 1:S5-9; discussion S10

Morita S, Miwa H, Kondo T (2005) Effect of zonisamide on essential tremor: a pilot crossover study in comparison with arotinolol. Parkinsonism Relat Disord 11:101-3

Morrione A, Romano G, Navarro M, Reiss K, Valentinis B, Dews M, Eves E, Rosner MR, Baserga R (2000) Insulin-like growth factor I receptor signaling in differentiation of neuronal H19-7 cells. Cancer Res 60:2263-72 [PubMed]

Ondo WG (2006) Essential tremor: treatment options. Curr Treat Options Neurol 8:256-67

Oommen KJ, Mathews S (2004) Zonisamide: a new antiepileptic drug. Clin Neuropharmacol 22:192-200

Ortiz MI, Castaneda-Hernandez G, Granados-Soto V (2003) Possible involvement of potassium channels in peripheral antinociception induced by metamizol: lack of participation of ATP-sensitive K+ channels. Pharmacol Biochem Behav 74:465-70

Ortiz MI, Castaneda-Hernandez G, Granados-Soto V (2005) Pharmacological evidence for the activation of Ca2+-activated K+ channels by meloxicam in the formalin test. Pharmacol Biochem Behav 81:725-31 [PubMed]

Peters DH, Sorkin EM (1993) Zonisamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 45:760-87

Pinsky PF, Rinzel J (1994) Intrinsic and network rhythmogenesis in a reduced Traub model for CA3 neurons. J Comput Neurosci 1:39-60 [Journal] [PubMed]

   CA3 pyramidal cell: rhythmogenesis in a reduced Traub model (Pinsky, Rinzel 1994) [Model]

Rock DM, Macdonald RL, Taylor CP (2003) Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD 810, CI 912), a novel anticonvulsant. Epilepsy Res 3:138-43 [PubMed]

Schauf CL (1987) Zonisamide enhances slow sodium inactivation in Myxicola. Brain Res 413:185-8

Shao LR, Halvorsrud R, Borg-Graham L, Storm JF (1999) The role of BK-type Ca2+-dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells. J Physiol 521 Pt 1:135-46 [PubMed]

Smith BL, McLeay LM, Embling PP (2003) Effect of the mycotoxins penitrem, paxilline and lolitrem B on the electromyographic activity of skeletal and gastrointestinal smooth muscle of sheep. Res Vet Sci 62:111-6 [PubMed]

Storm JF (1990) Potassium currents in hippocampal pyramidal cells. Prog Brain Res 83:161-87 [PubMed]

Suzuki S, Kawakami K, Nishimura S, Watanabe Y, Yagi K, Seino M, Miyamoto K (1992) Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex. Epilepsy Res 12:21-7 [PubMed]

Tanabe M, Sakaue A, Takasu K, Honda M, Ono H (2005) Centrally mediated antihyperalgesic and antiallodynic effects of zonisamide following partial nerve injury in the mouse. Naunyn Schmiedebergs Arch Pharmacol 372:107-14 [PubMed]

Tasaki K, Minami T, Ieiri I, Ohtsubo K, Hirakawa Y, Ueda K, Higuchi S (2006) Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding. Brain Dev 17:182-5 [PubMed]

Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC (2004) Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J 18:760-1 [PubMed]

Wu SN, Chang HD (2005) Diethyl pyrocarbonate, a histidine-modifying agent, directly stimulates activity of ATP-sensitive potassium channels in pituitary GH(3) cells. Biochem Pharmacol [Journal] [PubMed]

   A model for pituitary GH(3) lactotroph (Wu and Chang 2005) [Model]

Wu SN, Li HF (1999) Characterization of riluzole-induced stimulation of large-conductance calcium-activated potassium channels in rat pituitary GH3 cells. J Investig Med 47:484-95 [PubMed]

Wu SN, Liu SI, Huang MH (2004) Cilostazol, an inhibitor of type 3 phosphodiesterase, stimulates large-conductance, calcium-activated potassium channels in pituitary GH3 cells and pheochromocytoma PC12 cells. Endocrinology 145:1175-84 [PubMed]

Wu SN, Wu AZ, Lin MW (2006) Pharmacological roles of the large-conductance calcium-activated potassium channel. Curr Top Med Chem 6:1025-30 [PubMed]

Yoshida S, Okada M, Zhu G, Kaneko S (2005) Effects of zonisamide on neurotransmitter exocytosis associated with ryanodine receptors. Epilepsy Res 67:153-62

Huang CW, Tsai JJ, Huang CC, Wu SN (2009) Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (Kv3.1): contribution to the firing of action potentials J Physiol Pharmacol 60(4):37-47 [Journal] [PubMed]

   Simulation studies on mechanisms of levetiracetam-mediated inhibition of IK(DR) (Huang et al. 2009) [Model]

Huang CW, Huang CC, Lin MW, Tsai JJ, Wu SN (2008) The synergistic inhibitory actions of oxcarbazepine on voltage-gated sodium and potassium currents in differentiated NG108-15 neuronal cells and model neurons. Int J Neuropsychopharmacol 11:597-610 [Journal] [PubMed]

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