title: The tricyclic antidepressant desipramine inhibited the neurotoxic, kainate-induced [Ca(2+)]i increases in CA1 pyramidal cells in acute hippocampal slices.
abstract: Kainate (KA), used for modelling neurodegenerative diseases, evokes excitotoxicity. However, the precise mechanism of KA-evoked [Ca(2+)]i increase is unexplored, especially in acute brain slice preparations. We used [Ca(2+)]i imaging and patch clamp electrophysiology to decipher the mechanism of KA-evoked [Ca(2+)]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 Ca(2+). 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 Ca(2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the initiation of the Ca(2+) 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 Ca(2+)-permeable AMPARs. The voltage-gated Ca(2+) channels (VGCC), blocked by ω-Conotoxin MVIIC+nifedipine+NiCl2, contributed to the [Ca(2+)]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 Ca(2+) response. The tricyclic antidepressant DMI inhibited the KA-evoked [Ca(2+)]i rise in a dose-dependent manner. It directly attenuated the AMPA-/KAR current, but its more potent inhibition on the Ca(2+) response supports additional effect on VGCCs, VGSCs and Na(+)/Ca(2+) exchangers. The multitarget action on decisive players of excitotoxicity holds out more promise in clinical therapy of neurodegenerative diseases.
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Bernadett K
authors.initials: BK
authors.lastname: Szász
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Szilárd I
authors.initials: SI
authors.lastname: Szabó
authors.affiliation: Servier, Budapest, Hungary.
authors.forename: János P
authors.initials: JP
authors.lastname: Kiss
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Arpád
authors.initials: A
authors.lastname: Mike
authors.affiliation: Gedeon Richter Plc., Pharmacology and Drug Safety Department, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Lendvai
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: E
authors.initials: E
authors.lastname: Sylvester Vizi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: zelles.tibor@med.semmelweis-univ.hu.
authors.forename: Tibor
authors.initials: T
authors.lastname: Zelles
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007608:Kainic Acid / Q000633:toxicity*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000929:Antidepressive Agents, Tricyclic; D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D002118:Calcium; D003891:Desipramine
keywords: AMPA receptors; CA1 pyramidal cells; Desipramine; Kainic acid; Rat hippocampal slices; [Ca(2+)](i)