Skip to main content
SpringerLink
Log in

Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model

  • Basic Neurosciences, Genetics and Immunology - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Accumulating evidence indicates that amiloride (a potassium-sparing diuretic) exerts the anticonvulsant action in various in vivo and in vitro experiments. Therefore, the objective of this study was to assess the influence of amiloride on the protective action of numerous conventional and second-generation antiepileptic drugs [AEDs: carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), topiramate (TPM), and valproate (VPA)] against maximal electroshock (MES)-induced seizures in mice. Results indicate that amiloride [up to 100 mg/kg, intraperitoneally (i.p.), at 30, 60, and 120 min before the test] neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice. Moreover, amiloride (75 and 100 mg/kg, i.p., 120 min prior to the test) significantly enhanced the anticonvulsant effects of all studied AEDs, except for LTG, by reducing their ED50 values in the MES test. In contrast, amiloride at 50 mg/kg (i.p.) had no significant effect on the antielectroshock action of the tested AEDs in mice. Estimation of total brain AED concentrations revealed that amiloride (75 mg/kg) significantly increased total brain concentrations of CBZ, OXC, and PB, but not those of LTG, TPM, and VPA in mice. In conclusion, one can ascertain that the potentiation of the antiseizure action of TPM and VPA by amiloride in the MES test and lack of any pharmacokinetic interactions between drugs, make the combinations of amiloride with TPM and VPA of pivotal importance for epileptic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Akaike N, Ueno S (1994) Proton-induced current in neuronal cells. Prog Neurobiol 43:73–83

    Article  PubMed  CAS  Google Scholar 

  • Ali A, Ahmad FJ, Pillai KK, Vohora D (2004) Evidence of the antiepileptic potential of amiloride with neuropharmacological benefits in rodent models of epilepsy and behavior. Epilepsy Behav 5:322–328

    Article  PubMed  Google Scholar 

  • Ali A, Ahmad FJ, Pillai KK, Vohora D (2005) Amiloride protects against pentylenetetrazole-induced kindling in mice. Br J Pharmacol 145:880–884

    Article  PubMed  CAS  Google Scholar 

  • Ali A, Pillai KP, Ahmad FJ, Dua Y, Vohora D (2006) Anticonvulsant effect of amiloride in pentetrazole-induced status epilepticus in mice. Pharmacol Rep 58:242–245

    PubMed  CAS  Google Scholar 

  • Ali A, Pillai KK, Ahmad FJ, Dua Y, Khan ZI, Vohora D (2007) Comparative efficacy of liposome-entrapped amiloride and free amiloride in animal models of seizures and serum potassium in mice. Eur Neuropsychopharmacol 17:227–229

    Article  PubMed  CAS  Google Scholar 

  • Andreeva N, Khodorov B, Stelmashook E, Sokolova S, Cragoe E Jr, Victorov I (1992) 5-(N-ethyl-N-isopropyl)-amiloride and mild acidosis protect cultured cerebellar granule cells against glutamate-induced delayed neuronal death. Neuroscience 49:175–181

    Article  PubMed  CAS  Google Scholar 

  • Angehagen M, Ben-Menachem E, Shank R, Ronnback L, Hansson E (2004) Topiramate modulation of kainate-induced calcium currents is inversely related to channel phosphorylation level. J Neurochem 88:320–325

    Article  PubMed  CAS  Google Scholar 

  • Aram JA, Lodge D (1987) Epileptiform activity induced by alkalosis in rat neocortical slices: block by antagonists of N-methyl-d-aspartate. Neurosci Lett 83:345–350

    Article  PubMed  CAS  Google Scholar 

  • Attaphitaya S, Park K, Melvin JE (1999) Molecular cloning and functional expression of a rat Na+/H+ exchanger (NHE5) highly expressed in brain. J Biol Chem 274:4383–4388

    Article  PubMed  CAS  Google Scholar 

  • Boissier JR, Tardy J, Diverres JC (1960) Une nouvelle méthode simple pour explorer l’action tranquilisante: le test de la cheminée. Med Exp (Basel) 3:81–84

    Article  CAS  Google Scholar 

  • Bonnet U, Bingmann D, Wiemann M (2000) Intracellular pH modulates spontaneous and epileptiform bioelectric activity of hippocampal CA3-neurones. Eur Neuropsychopharmacol 10:97–103

    Article  PubMed  CAS  Google Scholar 

  • Cadart M, Marchand S, Pariat C, Bouquet S, Couet W (2002) Ignoring pharmacokinetics may lead to isoboles misinterpretation: illustration with the norfloxacin-theophylline convulsant interaction in rats. Pharm Res 19:209–214

    Article  PubMed  CAS  Google Scholar 

  • Chesler M, Kaila K (1992) Modulation of pH by neuronal activity. Trends Neurosci 15:396–402

    Article  PubMed  CAS  Google Scholar 

  • Czapinski P, Blaszczyk B, Czuczwar SJ (2005) Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 5:3–14

    Article  PubMed  CAS  Google Scholar 

  • Giffard RG, Monyer H, Choi DW (1990a) Selective vulnerability of cultured cortical glia to injury by extracellular acidosis. Brain Res 530:138–141

    Article  PubMed  CAS  Google Scholar 

  • Giffard RG, Monyer H, Christine CW, Choi DW (1990b) Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 506:339–342

    Article  PubMed  CAS  Google Scholar 

  • Gillessen T, Alzheimer C (1997) Amplification of EPSPs by low Ni(2+)- and amiloride-sensitive Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J Neurophysiol 77:1639–1643

    PubMed  CAS  Google Scholar 

  • Higashima M, Kinoshita H, Koshino Y (1998) Contribution of T-type calcium channels to afterdischarge generation in rat hippocampal slices. Brain Res 781:127–134

    Article  PubMed  CAS  Google Scholar 

  • Hinton CF, Eaton DC (1989) Expression of amiloride-blockable sodium channels in Xenopus oocytes. Am J Physiol 257:C825–C829

    PubMed  CAS  Google Scholar 

  • Horisberger JD, Giebisch G (1987) Potassium-sparing diuretics. Ren Physiol 10:198–220

    Article  PubMed  CAS  Google Scholar 

  • Inomata N, Ishihara T, Akaike N (1988) Effects of diuretics on GABA-gated chloride current in frog isolated sensory neurones. Br J Pharmacol 93:679–683

    PubMed  CAS  Google Scholar 

  • Jang IS, Brodwick MS, Wang ZM, Jeong HJ, Choi BJ, Akaike N (2006) The Na(+)/H(+) exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons. J Neurochem 99:1224–1236

    Article  PubMed  CAS  Google Scholar 

  • Kalaria RN, Premkumar DR, Lin CW, Kroon SN, Bae JY, Sayre LM, LaManna JC (1998) Identification and expression of the Na+/H+ exchanger in mammalian cerebrovascular and choroidal tissues: characterization by amiloride-sensitive [3H]MIA binding and RT-PCR analysis. Brain Res Mol Brain Res 58:178–187

    Article  PubMed  CAS  Google Scholar 

  • Kang TC, An SJ, Park SK, Hwang IK, Suh JG, Oh YS, Bae JC, Won MH (2002) Alterations in Na+/H+ exchanger and Na+/HCO3-cotransporter immunoreactivities within the gerbil hippocampus following seizure. Brain Res Mol Brain Res 109:226–232

    Article  PubMed  CAS  Google Scholar 

  • Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113

    PubMed  CAS  Google Scholar 

  • Löscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16:669–694

    Article  PubMed  Google Scholar 

  • Löscher W, Fassbender CP, Nolting B (1991) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res 8:79–94

    Article  PubMed  Google Scholar 

  • Luo J, Sun D (2007) Physiology and pathophysiology of Na(+)/H(+) exchange isoform 1 in the central nervous system. Curr Neurovasc Res 4:205–215

    Article  PubMed  CAS  Google Scholar 

  • Luszczki JJ, Czuczwar SJ (2004) Preclinical profile of combinations of some second-generation antiepileptic drugs: an isobolographic analysis. Epilepsia 45:895–907

    Article  PubMed  CAS  Google Scholar 

  • Luszczki JJ, Swiader M, Czuczwar M, Kis J, Czuczwar SJ (2003) Interactions of tiagabine with some antiepileptics in the maximal electroshock in mice. Pharmacol Biochem Behav 75:319–327

    Article  PubMed  CAS  Google Scholar 

  • Luszczki JJ, Wojcik-Cwikla J, Andres MM, Czuczwar SJ (2005) Pharmacological and behavioral characteristics of interactions between vigabatrin and conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: an isobolographic analysis. Neuropsychopharmacology 30:958–973

    Article  PubMed  CAS  Google Scholar 

  • Luszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ (2006) Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol 373:169–181

    Article  PubMed  CAS  Google Scholar 

  • Luszczki JJ, Czernecki R, Wojtal K, Borowicz KK, Czuczwar SJ (2008a) Agmatine enhances the anticonvulsant action of phenobarbital and valproate in the mouse maximal electroshock seizure model. J Neural Transm 115:1485–1494

    Google Scholar 

  • Luszczki JJ, Wu JZ, Raszewski G, Czuczwar SJ (2008b) Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol doi: 10.1007/s00210-008-0349-9

  • Ma E, Haddad GG (1997) Expression and localization of Na+/H+ exchangers in rat central nervous system. Neuroscience 79:591–603

    Article  PubMed  CAS  Google Scholar 

  • Manev H, Bertolino M, DeErausquin G (1990) Amiloride blocks glutamate-operated cationic channels and protects neurons in culture from glutamate-induced death. Neuropharmacology 29:1103–1110

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto Y, Yamamoto S, Suzuki Y, Tsuboi T, Terakawa S, Ohashi N, Umemura K (2004) Na+/H+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons. Stroke 35:185–190

    Article  PubMed  CAS  Google Scholar 

  • N’Gouemo P (2008) Amiloride delays the onset of pilocarpine-induced seizures in rats. Brain Res 1222:230–232

    Article  PubMed  CAS  Google Scholar 

  • Raley-Susman KM, Cragoe EJ, Sapolsky RM, Kopito RR (1991) Regulation of intracellular pH in cultured hippocampal neurons by an amiloride-insensitive Na+/H+ exchanger. J Biol Chem 266:2739–2745

    PubMed  CAS  Google Scholar 

  • Ritter M, Fuerst J, Wöll E, Chwatal S, Gschwentner M, Lang F, Deetjen P, Paulmichl M (2001) Na(+)/H(+)exchangers: linking osmotic dysequilibrium to modified cell function. Cell Physiol Biochem 11:1–18

    Article  PubMed  CAS  Google Scholar 

  • Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE (2000) An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 41(Suppl 1):S3–S9

    Article  PubMed  CAS  Google Scholar 

  • Shank RP, Doose DR, Streeter AJ, Bialer M (2005) Plasma and whole blood pharmacokinetics of topiramate: the role of carbonic anhydrase. Epilepsy Res 63:103–112

    Article  PubMed  CAS  Google Scholar 

  • Slepkov ER, Rainey JK, Sykes BD, Fliegel L (2007) Structural and functional analysis of the Na+/H+ exchanger. Biochem J 401:623–633

    Article  PubMed  CAS  Google Scholar 

  • Venault P, Chapouthier G, de Carvalho LP, Simiand J, Morre M, Dodd RH, Rossier J (1986) Benzodiazepine impairs and beta-carboline enhances performance in learning and memory tasks. Nature 321:864–866

    Article  PubMed  CAS  Google Scholar 

  • Wakabayashi S, Fafournoux P, Sardet C, Pouyssegur J (1992) The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls “H(+)-sensing”. Proc Natl Acad Sci U S A 89:2424–2428

    Article  PubMed  CAS  Google Scholar 

  • Whittingham TS, Warman E, Assaf H, Sick TJ, LaManna JC (1989) Manipulating the intracellular environment of hippocampal slices: pH and high-energy phosphates. J Neurosci Methods 28:83–91

    Article  PubMed  CAS  Google Scholar 

  • Xia Y, Zhao P, Xue J, Gu XQ, Sun X, Yao H, Haddad GG (2003) Na+ channel expression and neuronal function in the Na+/H+ exchanger 1 null mutant mouse. J Neurophysiol 89:229–236

    Article  PubMed  CAS  Google Scholar 

  • Xiong ZQ, Saggau P, Stringer JL (2000) Activity-dependent intracellular acidification correlates with the duration of seizure activity. J Neurosci 20:1290–1296

    PubMed  CAS  Google Scholar 

  • Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP (2008) Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol 8:25–32

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Velumian AA, Jones OT, Carlen PL (2000) Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 41(Suppl 1):S52–S60

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from Medical University of Lublin (DS 474/2007-2008 and PW 555/2008). The authors are grateful for the generous gifts of VPA from ICN-Polfa S.A. (Rzeszow, Poland) and CBZ from Polpharma S.A. (Starogard, Poland). The authors express their thanks to Mr W. Zgrajka and Mr G. Raszewski (Institute of Agricultural Medicine, Lublin, Poland) for the skilful determination of the brain concentrations of oxcarbazepine and lamotrigine with HPLC.

Author information

Authors and Affiliations

  1. Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland

    Jarogniew J. Luszczki, Katarzyna M. Sawicka, Justyna Kozinska, Monika Dudra-Jastrzebska & Stanislaw J. Czuczwar

  2. Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950, Lublin, Poland

    Jarogniew J. Luszczki, Monika Dudra-Jastrzebska & Stanislaw J. Czuczwar

Authors
  1. Jarogniew J. Luszczki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katarzyna M. Sawicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Justyna Kozinska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monika Dudra-Jastrzebska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stanislaw J. Czuczwar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jarogniew J. Luszczki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luszczki, J.J., Sawicka, K.M., Kozinska, J. et al. Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model. J Neural Transm 116, 57–66 (2009). https://doi.org/10.1007/s00702-008-0152-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-008-0152-2

Keywords

Search

Navigation