Skip to main content
SpringerLink
Log in

Effects of Retigabine on the Neurodegeneration and Extracellular Glutamate Changes Induced by 4-Aminopyridine in Rat Hippocampus In Vivo

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

We have previously shown that microdialysis perfusion of the K+ channel blocker 4-aminopyridine (4-AP) in rat hippocampus induces convulsions and neurodegeneration, due to the stimulation of glutamate release from synaptic terminals. Retigabine is an opener of the KCNQ2/Q3-type K+ channel that possesses antiepileptic action and may be neuroprotective, and we have therefore studied its effect on the hyperexcitation, the neuronal damage and the changes in extracellular glutamate induced by 4-AP. Retigabine and 4-AP were co-administered by microdialysis in the hippocampus of anesthetized rats, with simultaneous recording of the EEG, and the extracellular concentration of glutamate was measured in the microdialysis fractions. In 70–80% of the rats tested retigabine reduced the 4-AP-induced stimulation of glutamate release and prevented the neuronal damage observed at 24 h in the CA1 hippocampal region. However, retigabine did not block the EEG epileptic discharges and their duration was reduced in only 20–25% of the tested animals. We conclude that the neuroprotective action of retigabine is probably due to the blockade of the 4-AP-induced stimulation of glutamate release. This inhibition, however, was not sufficient to block the epileptic activity.

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

Similar content being viewed by others

References

  1. R. Tapia L. Medina-Ceja F. Peña (1999) ArticleTitleOn the relationships between extracellular glutamate, hyperexcitation and neurodegeneration, in vivo Neurochem. Int. 34 23–31 Occurrence Handle10100193 Occurrence Handle10.1016/S0197-0186(98)00061-8 Occurrence Handle1:CAS:528:DyaK1MXhslChu74%3D

    Article  PubMed  CAS  Google Scholar 

  2. F. Peña R. Tapia (1999) ArticleTitleRelationships among seizures, extracellular amino acid changes, and neurodegeneration induced by 4-aminopyridine in rat hippocampus: A microdialysis and electroencephalographic study J. Neurochem. 72 2006–2014 Occurrence Handle10217278

    PubMed  Google Scholar 

  3. R. Tapia M. Sitges (1982) ArticleTitleEffect of 4-aminopyridine on transmitter release in synaptosomes Brain Res. 250 291–299 Occurrence Handle6129030 Occurrence Handle10.1016/0006-8993(82)90423-1 Occurrence Handle1:CAS:528:DyaL38XmtV2hsrs%3D

    Article  PubMed  CAS  Google Scholar 

  4. R. Tapia M. Sitges E. Morales (1985) ArticleTitleMechanism of the calcium-dependent stimulation of transmitter release by 4-aminopyridine in synaptosomes Brain Res. 361 373–382 Occurrence Handle2867810 Occurrence Handle10.1016/0006-8993(85)91307-1 Occurrence Handle1:CAS:528:DyaL28XmtF2rsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  5. D. H. G. Versteeg F. M. J. Heemskerk H. A. Spierenburg P. N. E. Graan Particlede L. H. Schrama (1995) ArticleTitle4-Aminopyridine differentially affects the spontaneous release of radiolabelled transmitters from rat brain slices in vitro Brain Res. 686 233–238 Occurrence Handle7583288 Occurrence Handle10.1016/0006-8993(95)00515-R Occurrence Handle1:CAS:528:DyaK2MXmvF2ntrk%3D

    Article  PubMed  CAS  Google Scholar 

  6. Y. Gu S. Y. Ge D. Y. Ruan (2004) ArticleTitleEffect of 4-aminopyridine on synaptic transmission in rat hippocampal slices Brain Res. 1006 225–232 Occurrence Handle15051526 Occurrence Handle10.1016/j.brainres.2004.02.008 Occurrence Handle1:CAS:528:DC%2BD2cXisF2iu7o%3D

    Article  PubMed  CAS  Google Scholar 

  7. P. Perreault M. Avoli (1991) ArticleTitlePhysiology and pharmacology of epileptiform activity induced by 4-aminopyridine in rat hippocampal slices J. Neurophysiol. 65 771–785 Occurrence Handle1675671 Occurrence Handle1:STN:280:DyaK3M3mvVyksw%3D%3D

    PubMed  CAS  Google Scholar 

  8. W. D. Yonekawa I. M. Kapetanovic H. J. Kupferberg (1995) ArticleTitleThe effects of anticonvulsant agents on 4-aminopyridine induced epileptiform activity in rat hippocampus in vitro Epilepsy Res. 20 137–150 Occurrence Handle7750510 Occurrence Handle10.1016/0920-1211(94)00077-A Occurrence Handle1:STN:280:DyaK2M3mvFOgsA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  9. C. Brückner U. Heinemann (2000) ArticleTitleEffects of standard anticonvulsant drugs on different patterns of epileptiform discharges induced by 4-aminopyridine in combined entorhinal cortex–hippocampal slices Brain Res. 859 15–20 Occurrence Handle10720610

    PubMed  Google Scholar 

  10. P. Salazar R. Tapia M. A. Rogawski (2003) ArticleTitleEffects of neurosteroids on epileptiform activity induced by 4-aminopyridine in the rat hippocampal slice Epilepsy Res. 55 71–82 Occurrence Handle12948618 Occurrence Handle10.1016/S0920-1211(03)00112-8 Occurrence Handle1:CAS:528:DC%2BD3sXms1yrsr4%3D

    Article  PubMed  CAS  Google Scholar 

  11. F. Peña J. Bargas R. Tapia (2002) ArticleTitlePaired pulse facilitation is turned into paired pulse depression in hippocampal slices after epilepsy induced by 4-aminopyridine in vivo Neuropharmacology 42 807–812 Occurrence Handle12015207

    PubMed  Google Scholar 

  12. E. W. Schafer R. B. Brunton D. J. Cunningham (1973) ArticleTitleA summary of acute toxicity of 4-aminopyridine to birds and mammals Toxicol. Appl. Pharmacol. 26 532–538 Occurrence Handle4771602 Occurrence Handle1:CAS:528:DyaE2cXls1Wmsw%3D%3D

    PubMed  CAS  Google Scholar 

  13. D. A. Spyker C. Lynch J. Shabanowitz J. A. Sinn (1980) ArticleTitlePoisoning with 4-aminopyridine: Report of three cases Clin. Toxicol. 16 487–497 Occurrence Handle6250762 Occurrence Handle1:STN:280:DyaL3M%2Fgt1OlsA%3D%3D Occurrence Handle10.3109/15563658008989978

    Article  PubMed  CAS  Google Scholar 

  14. J. Fragoso-Veloz L. Massieu R. Alvarado R. Tapia (1990) ArticleTitleSeizures and wet-dog shakes induced by 4-aminopyridine, and their potentiation by nifedipine Eur. J. Pharmacol. 178 275–284 Occurrence Handle2340861 Occurrence Handle1:CAS:528:DyaK3cXktVSntrs%3D

    PubMed  CAS  Google Scholar 

  15. S. Yamaguchi M. A. Rogawski (1992) ArticleTitleEffects of anticonvulsant drugs on 4-aminopyridine induced seizures in mice Epilepsy Res. 11 9–16 Occurrence Handle1563341 Occurrence Handle10.1016/0920-1211(92)90016-M Occurrence Handle1:CAS:528:DyaK38Xkt1Sgsrk%3D

    Article  PubMed  CAS  Google Scholar 

  16. F. Peña R. Tapia (2000) ArticleTitleSeizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: Role of glutamate and GABA-mediated neurotransmission and of ion channels Neuroscience 101 547–561 Occurrence Handle11113304

    PubMed  Google Scholar 

  17. G. X. Ayala R. Tapia (2003) ArticleTitleExpression of heat shock protein 70 induced by 4-aminopyridine through glutamate-mediated excitotoxic stress in rat hippocampus in vivo Neuropharmacology 45 649–660 Occurrence Handle12941378 Occurrence Handle10.1016/S0028-3908(03)00230-2 Occurrence Handle1:CAS:528:DC%2BD3sXms1Ort7Y%3D

    Article  PubMed  CAS  Google Scholar 

  18. A. D. Wickenden (2002) ArticleTitlePotassium channels as anti-epileptic drugs targets Neuropharmacology 43 1055–1060 Occurrence Handle12504910 Occurrence Handle10.1016/S0028-3908(02)00237-X Occurrence Handle1:CAS:528:DC%2BD38Xps12mu7o%3D

    Article  PubMed  CAS  Google Scholar 

  19. B. Rudy et al. (1999) ArticleTitleContributions of Kv3 channels to neuronal excitability Ann. N.Y. Acad. Sci. 868 304–343 Occurrence Handle10414303 Occurrence Handle1:CAS:528:DyaK1MXjvFKitLg%3D

    PubMed  CAS  Google Scholar 

  20. O. Pongs et al. (1999) ArticleTitleFunctional and molecular aspects of voltage-gated K+ channel β units Ann. N.Y. Acad. Sci. 868 344–355 Occurrence Handle10414304 Occurrence Handle1:CAS:528:DyaK1MXjvFKitLk%3D

    PubMed  CAS  Google Scholar 

  21. T. J. Jentsch (2000) ArticleTitleNeuronal KCNQ potassium channels: Physiology and role in disease Nat. Rev. Neurosci. 1 21–30 Occurrence Handle11252765 Occurrence Handle10.1038/35036198 Occurrence Handle1:CAS:528:DC%2BD3MXivVSjsro%3D

    Article  PubMed  CAS  Google Scholar 

  22. M. A. Rogawski (2000) ArticleTitleKCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy Trends Neurosci. 23 393–398 Occurrence Handle10941184 Occurrence Handle10.1016/S0166-2236(00)01629-5 Occurrence Handle1:CAS:528:DC%2BD3cXlvFSqu74%3D

    Article  PubMed  CAS  Google Scholar 

  23. C. Biervert B. C. Schroeder C. Kubisch S. F. Berkovic P. Proopping T. J. Jentsch O. K. Steinlein (1998) ArticleTitleA potassium channel mutation in neonatal human epilepsy Science 279 403–406 Occurrence Handle9430594 Occurrence Handle10.1126/science.279.5349.403 Occurrence Handle1:CAS:528:DyaK1cXmsVSitQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  24. M. Leppert N. Singh (1999) ArticleTitleBenign familial neonatal epilepsy with mutations in two potassium channel genes Curr. Opin. Neurol. 12 143–147 Occurrence Handle10226745 Occurrence Handle10.1097/00019052-199904000-00003 Occurrence Handle1:STN:280:DyaK1M3ktlegsA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  25. B. S. Brown S. P. Yu (2000) ArticleTitleModulation and genetic identification of the M channel Prog. Biophys. Mol. Biol. 73 135–166 Occurrence Handle10958929 Occurrence Handle1:CAS:528:DC%2BD3cXlvV2rs7s%3D

    PubMed  CAS  Google Scholar 

  26. H. S. Wang Z. Pan W. Shi B. S. Brown R. S. Wymore I. S. Cohen J. E. Dixon D. Mckinnon (1998) ArticleTitleKCNQ2 and KCNQ3 potassium channel subunits: Molecular correlates of M-channel Science 282 1890–1893 Occurrence Handle9836639 Occurrence Handle1:CAS:528:DyaK1cXotVWisb4%3D

    PubMed  CAS  Google Scholar 

  27. C. Rundfeldt (1997) ArticleTitleThe new anticonvulsant retigabine (D-23129) acts as an opener of K+ channel in neuronal cells Eur. J. Pharmacol. 336 243–249 Occurrence Handle9384239 Occurrence Handle10.1016/S0014-2999(97)01249-1 Occurrence Handle1:CAS:528:DyaK2sXmsVKmtb8%3D

    Article  PubMed  CAS  Google Scholar 

  28. C. Rundfeldt (1999) ArticleTitleCharacterization of the K+ channel opening effect of the anticonvulsant retigabine in PC12 cells Epilepsy Res. 35 99–107 Occurrence Handle10372563 Occurrence Handle10.1016/S0920-1211(98)00131-4 Occurrence Handle1:CAS:528:DyaK1MXis1eisbk%3D

    Article  PubMed  CAS  Google Scholar 

  29. C. Rundfeldt R. Netzer (2000) ArticleTitleThe novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary cells transfected with human KCNQ2/3 subunits Neurosci. Lett. 282 73–76 Occurrence Handle10713399 Occurrence Handle10.1016/S0304-3940(00)00866-1 Occurrence Handle1:CAS:528:DC%2BD3cXhsFGrs7o%3D

    Article  PubMed  CAS  Google Scholar 

  30. M. Main J. E. Cryan J. Dupere B. Cox J. Clare S. Burbidge (2000) ArticleTitleModulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine Mol. Pharmacol. 58 253–262 Occurrence Handle10908292 Occurrence Handle1:CAS:528:DC%2BD3cXlsVyms7s%3D

    PubMed  CAS  Google Scholar 

  31. L. Tatulian P. Delmas F. C. Abogadie D. A. Brown (2001) ArticleTitleActivation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine J. Neurosci. 21 5535–5545 Occurrence Handle11466425 Occurrence Handle1:CAS:528:DC%2BD3MXlsV2gtr8%3D

    PubMed  CAS  Google Scholar 

  32. A. D. Wickenden W. Yu A. Zou T. Jegla P.␣K. Wagoner (2000) ArticleTitleRetigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels Mol. Pharmacol. 58 591–600 Occurrence Handle10953053 Occurrence Handle1:CAS:528:DC%2BD3cXmtFCqtb4%3D

    PubMed  CAS  Google Scholar 

  33. I. M. Kapetanovic C. Rundfeldt (1996) ArticleTitleD-23129: A new anticonvulsant compound CNS Drug Rev. 2 308–321 Occurrence Handle1:CAS:528:DyaK28XnsV2rsbY%3D

    CAS  Google Scholar 

  34. C. Tober A. Rostock C. Rundfeldt R. Bartsch (1996) ArticleTitleD-23129: A potent anticonvulsant in the amygdala kindling model of complex partial seizures Eur. J. Pharmacol. 303 163–169 Occurrence Handle8813562 Occurrence Handle10.1016/0014-2999(96)00073-8 Occurrence Handle1:CAS:528:DyaK28XjsVOlurY%3D

    Article  PubMed  CAS  Google Scholar 

  35. A. Rostock C. Tober C. Rundfeldt R. Bartsch J. Engel E. E. Polymeropoulos B. Kutscher W. Löscher D. Hönack H. S. White H. H. Wolf (1996) ArticleTitleD-23129: A new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures Epilepsy Res. 23 211–223 Occurrence Handle8739124 Occurrence Handle10.1016/0920-1211(95)00101-8 Occurrence Handle1:CAS:528:DyaK28XjslCmsr0%3D

    Article  PubMed  CAS  Google Scholar 

  36. J. W. Dailey J. H. Cheong K. H. Ko L. E. Adams-Curtis P. C. Jobe (1995) ArticleTitleAnticonvulsant properties of D-20443 in genetically epilepsy-prone rats: Prediction of clinical response Neurosci. Lett. 195 77–80 Occurrence Handle7478272 Occurrence Handle10.1016/0304-3940(95)11783-S Occurrence Handle1:CAS:528:DyaK2MXntl2mu74%3D

    Article  PubMed  CAS  Google Scholar 

  37. G. Sarro ParticleDe E. D. Di Paola G. Conte M. P. Pasculli A. Sarro ParticleDe (2001) ArticleTitleInfluence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice Naunyn Schimiedeberg's Arch. Pharmacol. 363 330–336

    Google Scholar 

  38. R. Dost C. Rundfeldt (2000) ArticleTitleThe anticonvulsant retigabine potently suppresses epileptiform discharges in the low Ca++ and low Mg++ model in the hippocampal slice preparation Epilepsy Res. 38 53–66 Occurrence Handle10604606 Occurrence Handle1:CAS:528:DC%2BD3cXisVOlsQ%3D%3D

    PubMed  CAS  Google Scholar 

  39. V. Armand C. Rundfeldt U. Heineman (1999) ArticleTitleEffects of retigabine (D-23129) on different patterns of epileptiform activity induced by 4-aminopyridine in rat entorhinal cortex hippocampal slices Naunyn Schmiedeberg’s Arch. Pharmacol. 359 33–39 Occurrence Handle1:CAS:528:DyaK1cXnvFaksr0%3D

    CAS  Google Scholar 

  40. R. Hetka C. Rundfeldt U. Heinemann D. Schmitz (1999) ArticleTitleRetigabine strongly reduces repetitive firing in rat entorhinal cortex Eur. J. Pharmacol. 386 165–171 Occurrence Handle10618466 Occurrence Handle10.1016/S0014-2999(99)00786-4 Occurrence Handle1:CAS:528:DC%2BD3cXotlel

    Article  PubMed  CAS  Google Scholar 

  41. N. Ramírez-Munguía G. Vera R. Tapia (2003) ArticleTitleEpilepsy, neurodegeneration and extracellular glutamate in the hippocampus of awake and anesthetized rats treated with okadaic acid Neurochem. Res. 28 1517–1524 Occurrence Handle14570396

    PubMed  Google Scholar 

  42. G. Paxinos C. Watson (1982) The Rat Brain in Stereotaxic Coordinates Academic Press Sidney

    Google Scholar 

  43. G. Sills C. Rundfeldt E. Butler G. Forrest G. Thompson M. Brodie (2000) ArticleTitleA neurochemical study of the novel antiepileptic drug retigabine in mouse brain Pharmacol. Res. 42 553–557 Occurrence Handle11058408 Occurrence Handle10.1006/phrs.2000.0738 Occurrence Handle1:CAS:528:DC%2BD3MXhtlantQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  44. P. Salazar T. Montiel S. Brailowsky R. Tapia (1994) ArticleTitleDecrease of glutamate decarboxylase activity after in vivo cortical infusion of γ-aminobutyric acid Neurochem. Int. 24 363–368 Occurrence Handle8061600 Occurrence Handle10.1016/0197-0186(94)90114-7 Occurrence Handle1:CAS:528:DyaK2cXktlans7k%3D

    Article  PubMed  CAS  Google Scholar 

  45. L. Massieu A. Morales-Villagrán R. Tapia (1995) ArticleTitleAccumulation of extracellular glutamate by inhibition of its uptake is not sufficient for inducing neuronal damage: An in vivo microdialysis study J. Neurochem. 64 2262–2272 Occurrence Handle7722511 Occurrence Handle1:CAS:528:DyaK2MXltFygu70%3D

    PubMed  CAS  Google Scholar 

  46. L. Massieu R. Tapia (1997) ArticleTitleGlutamate uptake impairment and neuronal damage in young and aged rats in vivo J. Neurochem. 69 1151–1160 Occurrence Handle9282938 Occurrence Handle1:CAS:528:DyaK2sXls1Chtb4%3D

    PubMed  CAS  Google Scholar 

  47. A. Morales-Villagrán R. Tapia (1996) ArticleTitlePreferential stimulation of glutamate release by 4-aminopyridine in rat striatum in vivo Neurochem. Int. 28 35–40 Occurrence Handle8746762

    PubMed  Google Scholar 

  48. U. Ebert C. Brandt W. Löscher (2002) ArticleTitleDelayed sclerosis, neuroprotection, and limbic epileptogenesis after status epilepticus in the rat Epilepsia 43 IssueIDSuppl. 5 86–95 Occurrence Handle12121301

    PubMed  Google Scholar 

  49. Ayala, G. X. and Tapia, R. 2006. Late NMDA receptor blockade rescues hippocampal neurons from excitotoxic stress and death after 4-aminopyridine-induced epilepsy. Eur. J. Neurosci. (in press)

  50. M. Martire P. Castaldo M. D'Amico P. Preziosi L. Annunziato M. Taglialatela (2004) ArticleTitleM Channels containing KCNQ2 subunits modulate norepinephrine, aspartate and GABA release from hippocampal nerve terminals J. Neurosci. 24 592–597 Occurrence Handle14736843 Occurrence Handle10.1523/JNEUROSCI.3143-03.2004 Occurrence Handle1:CAS:528:DC%2BD2cXht1Cjtb0%3D

    Article  PubMed  CAS  Google Scholar 

  51. J. Seyfried B. O. Evert C. Rundfeldt J. Schulz K.␣A. Kovar T. Klockgether U. Wüllner (2000) ArticleTitleFlupirtine and retigabine prevent l-glutamate toxicity in rat pheochromocytoma PC 12 cells Eur. J. Pharmacol. 400 155–166 Occurrence Handle10988329 Occurrence Handle10.1016/S0014-2999(00)00397-6 Occurrence Handle1:CAS:528:DC%2BD3cXkvFSmu7Y%3D

    Article  PubMed  CAS  Google Scholar 

  52. I. M. Kapetanovic W. D. Yonekawa H. J. Kupferberg (1995) ArticleTitleThe effects of d-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippocampus in vitro Epilepsy Res. 22 167–173 Occurrence Handle8991783 Occurrence Handle10.1016/0920-1211(95)00050-X Occurrence Handle1:CAS:528:DyaK28XptlWlsw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  53. C. Rundfeldt R. Netzer (2000) ArticleTitleInvestigations into the mechanism of action of the new anticonvulsant retigabine. Interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels Arzneimittelforschung 50 1063–1070 Occurrence Handle11190770 Occurrence Handle1:CAS:528:DC%2BD3MXisV2hsg%3D%3D

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510, México, D. F., México

    Gabriela Mora & Ricardo Tapia

Authors
  1. Gabriela Mora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ricardo Tapia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo Tapia.

Additional information

Special issue dedicated to Dr. Simo S. Oja

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mora, G., Tapia, R. Effects of Retigabine on the Neurodegeneration and Extracellular Glutamate Changes Induced by 4-Aminopyridine in Rat Hippocampus In Vivo . Neurochem Res 30, 1557–1565 (2005). https://doi.org/10.1007/s11064-005-8834-8

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-005-8834-8

Keywords

Search

Navigation