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SHR Neuro Cancer Cardio Lipid Metab Microb
Koncz, I; Szász, BK; Szabó, SI; Kiss, JP; Mike, A; Lendvai, B; Sylvester, Vizi, E; Zelles, T.
The tricyclic antidepressant desipramine inhibited the neurotoxic, kainate-induced [Ca(2+)]i increases in CA1 pyramidal cells in acute hippocampal slices.
Brain Res Bull. 2014; 104: 42-51.
Doi: 10.1016/j.brainresbull.2014.04.003
Web of Science
PubMed
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- Co-authors Med Uni Graz
- Szabo Szilard
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Antidepressive Agents, Tricyclic - pharmacology
- CA1 Region, Hippocampal - drug effects, metabolism
- Calcium - metabolism
- Desipramine - pharmacology
- Excitatory Amino Acid Agonists - toxicity
- Kainic Acid - toxicity
- Pyramidal Cells - drug effects, metabolism
- Rats - administration & dosage
- Rats, Wistar - administration & dosage
- Find related publications in this database (Keywords)
- Kainic acid
- AMPA receptors
- CA1 pyramidal cells
- Rat hippocampal slices
- [Ca2+](i)
- Desipramine