The tricyclic antidepressant desipramine inhibited the neurotoxic, kainate-induced [Ca2+]i increases in CA1 pyramidal cells in acute hippocampal slices

István Koncz, Bernadett K. Szász, Szilárd I. Szabó, János P. Kiss, A. Mike, Balázs Lendvai, E. Vízi, T. Zelles

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Kainate (KA), used for modelling neurodegenerative diseases, evokes excitotoxicity. However, the precise mechanism of KA-evoked [Ca2+]i increase is unexplored, especially in acute brain slice preparations. We used [Ca2+]i imaging and patch clamp electrophysiology to decipher the mechanism of KA-evoked [Ca2+]i rise and its inhibition by the tricyclic antidepressant desipramine (DMI) in CA1 pyramidal cells in rat hippocampal slices and in cultured hippocampal cells. The effect of KA was dose-dependent and relied totally on extracellular Ca2+. The lack of effect of dl-2-amino-5-phosphonopentanoic acid (AP-5) and abolishment of the response by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) suggested the involvement of non-N-methyl-d-aspartate receptors (non-NMDARs). The predominant role of the Ca2+-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the initiation of the Ca2+ response was supported by the inhibitory effect of the selective AMPAR antagonist GYKI 53655 and the ineffectiveness of 1-naphthyl acetylspermine (NASPM), an inhibitor of the Ca2+-permeable AMPARs. The voltage-gated Ca2+ channels (VGCC), blocked by ω-Conotoxin MVIIC+nifedipine+NiCl2, contributed to the [Ca2+]i rise. VGCCs were also involved, similarly to AMPAR current, in the KA-evoked depolarisation. Inhibition of voltage-gated Na+ channels (VGSCs; tetrodotoxin, TTX) did not affect the depolarisation of pyramidal cells but blocked the depolarisation-evoked action potential bursts and reduced the Ca2+ response. The tricyclic antidepressant DMI inhibited the KA-evoked [Ca2+]i rise in a dose-dependent manner. It directly attenuated the AMPA-/KAR current, but its more potent inhibition on the Ca2+ response supports additional effect on VGCCs, VGSCs and Na+/Ca2+ exchangers. The multitarget action on decisive players of excitotoxicity holds out more promise in clinical therapy of neurodegenerative diseases.

Original languageEnglish
Pages (from-to)42-51
Number of pages10
JournalBrain Research Bulletin
Volume104
DOIs
Publication statusPublished - 2014

Fingerprint

Desipramine
Pyramidal Cells
Tricyclic Antidepressive Agents
Kainic Acid
GYKI 53655
Neurodegenerative Diseases
Conotoxins
6-Cyano-7-nitroquinoxaline-2,3-dione
2-Amino-5-phosphonovalerate
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Electrophysiology
Tetrodotoxin
Nifedipine
Evoked Potentials
Action Potentials
Cultured Cells
Brain

Keywords

  • AMPA receptors
  • CA1 pyramidal cells
  • Desipramine
  • Kainic acid
  • Rat hippocampal slices

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

The tricyclic antidepressant desipramine inhibited the neurotoxic, kainate-induced [Ca2+]i increases in CA1 pyramidal cells in acute hippocampal slices. / Koncz, István; Szász, Bernadett K.; Szabó, Szilárd I.; Kiss, János P.; Mike, A.; Lendvai, Balázs; Vízi, E.; Zelles, T.

In: Brain Research Bulletin, Vol. 104, 2014, p. 42-51.

Research output: Contribution to journalArticle

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abstract = "Kainate (KA), used for modelling neurodegenerative diseases, evokes excitotoxicity. However, the precise mechanism of KA-evoked [Ca2+]i increase is unexplored, especially in acute brain slice preparations. We used [Ca2+]i imaging and patch clamp electrophysiology to decipher the mechanism of KA-evoked [Ca2+]i rise and its inhibition by the tricyclic antidepressant desipramine (DMI) in CA1 pyramidal cells in rat hippocampal slices and in cultured hippocampal cells. The effect of KA was dose-dependent and relied totally on extracellular Ca2+. The lack of effect of dl-2-amino-5-phosphonopentanoic acid (AP-5) and abolishment of the response by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) suggested the involvement of non-N-methyl-d-aspartate receptors (non-NMDARs). The predominant role of the Ca2+-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the initiation of the Ca2+ response was supported by the inhibitory effect of the selective AMPAR antagonist GYKI 53655 and the ineffectiveness of 1-naphthyl acetylspermine (NASPM), an inhibitor of the Ca2+-permeable AMPARs. The voltage-gated Ca2+ channels (VGCC), blocked by ω-Conotoxin MVIIC+nifedipine+NiCl2, contributed to the [Ca2+]i rise. VGCCs were also involved, similarly to AMPAR current, in the KA-evoked depolarisation. Inhibition of voltage-gated Na+ channels (VGSCs; tetrodotoxin, TTX) did not affect the depolarisation of pyramidal cells but blocked the depolarisation-evoked action potential bursts and reduced the Ca2+ response. The tricyclic antidepressant DMI inhibited the KA-evoked [Ca2+]i rise in a dose-dependent manner. It directly attenuated the AMPA-/KAR current, but its more potent inhibition on the Ca2+ response supports additional effect on VGCCs, VGSCs and Na+/Ca2+ exchangers. The multitarget action on decisive players of excitotoxicity holds out more promise in clinical therapy of neurodegenerative diseases.",
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AU - Szász, Bernadett K.

AU - Szabó, Szilárd I.

AU - Kiss, János P.

AU - Mike, A.

AU - Lendvai, Balázs

AU - Vízi, E.

AU - Zelles, T.

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