Koncz, Istvan and Szasz, Bernadett K. and Szabo, Szilard I. and Kiss, János P. and Mike, Árpád and Vizi, E. Szilveszter (2014) The tricyclic antidepressant desipramine inhibited the neurotoxic, kainate-induced [Ca] increases in CA1 pyramidal cells in acute hippocampal slices. BRAIN RESEARCH BULLETIN, 104. pp. 42-51. ISSN 0361-9230
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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 alpha-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 omega-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.
Item Type: | Article |
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Subjects: | R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan |
SWORD Depositor: | MTMT SWORD |
Depositing User: | MTMT SWORD |
Date Deposited: | 23 May 2014 08:04 |
Last Modified: | 13 Apr 2015 12:06 |
URI: | http://real.mtak.hu/id/eprint/12866 |
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