Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 16-25 |
| Number of pages | 10 |
| Journal | European Journal Of Pharmacology |
| Volume | 634 |
| Issue number | 1-3 |
| DOIs | |
| Publication status | Published - 2010 |
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Keywords
- Acetylcholinesterase inhibitor
- Alzheimer's disease
- Galantamine
- Hippocampus
- Neuroblastoma
- Voltage-clamp artefact
- galantamine
- voltage gated potassium channel
- potassium channel
- potassium channel blocking agent
- animal cell
- animal experiment
- article
- cell differentiation
- controlled study
- dose response
- electrophysiology
- hippocampus
- mouse
- nerve cell
- nerve cell excitability
- neuroblastoma cell
- nonhuman
- potassium current
- priority journal
- pyramidal nerve cell
- rat
- steady state
- voltage clamp
- action potential
- animal
- comparative study
- cytology
- drug effects
- hippocampal CA1 region
- physiology
- tumor cell line
- Action Potentials
- Animals
- CA1 Region, Hippocampal
- Cell Differentiation
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Mice
- Neurons
- Potassium Channel Blockers
- Potassium Channels
- Rats
Cite this
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Galantamine inhibits slowly inactivating K+ currents with a dual dose-response relationship in differentiated N1E-115 cells and in CA1 neurones. / Vicente, M.I.; Costa, P.F.; Lima, P.A.
In: European Journal Of Pharmacology, Vol. 634, No. 1-3, 2010, p. 16-25.Research output: Contribution to journal › Article
TY - JOUR
T1 - Galantamine inhibits slowly inactivating K+ currents with a dual dose-response relationship in differentiated N1E-115 cells and in CA1 neurones
AU - Vicente, M.I.
AU - Costa, P.F.
AU - Lima, P.A.
PY - 2010
Y1 - 2010
N2 - Galantamine, one of the major drugs used in Alzheimer's disease therapy, is a relatively weak acetylcholinesterase inhibitor and an allosteric potentiating ligand of nicotinic acetylcholine receptors. However, a role in the control of excitability has also been attributed to galantamine via modulation of K+ currents in central neurones. To further investigate the effect of galantamine on voltage-activated K+ currents, we performed whole-cell voltage-clamp recordings in differentiated neuroblastoma N1E-115 cells and in dissociated rat CA1 neurones. In both cell models, one can identify two main voltage-activated K+ current components: a relatively fast inactivating component (Ifast; time constant~hundred milliseconds) and a slowly inactivating one (Islow; time constant~1s). We show that galantamine (1pM-300μM) inhibits selectively Islow, exhibiting a dual dose-response relationship, in both differentiated N1E-115 cells and CA1 neurones. We also demonstrate that, in contrast with what was previously reported, galantamine-induced inhibition is not due to a shift on the steady-state inactivation and activation curves. Additionally, we characterized a methodological artefact that affects voltage-dependence as a function of time in whole-cell configuration, observed in both cell models. By resolving an inhibitory role on K+ currents in a non-central neuronal system and in hippocampal neurones, we are attributing a widespread role of galantamine on the modulation of cell excitability. The present results are relevant in the clinical context, since the effects at low dosages suggest that galantamine-induced K+ current inhibition may contribute to the efficiency of galantamine in the treatment of Alzheimer's disease. © 2010 Elsevier B.V.
AB - Galantamine, one of the major drugs used in Alzheimer's disease therapy, is a relatively weak acetylcholinesterase inhibitor and an allosteric potentiating ligand of nicotinic acetylcholine receptors. However, a role in the control of excitability has also been attributed to galantamine via modulation of K+ currents in central neurones. To further investigate the effect of galantamine on voltage-activated K+ currents, we performed whole-cell voltage-clamp recordings in differentiated neuroblastoma N1E-115 cells and in dissociated rat CA1 neurones. In both cell models, one can identify two main voltage-activated K+ current components: a relatively fast inactivating component (Ifast; time constant~hundred milliseconds) and a slowly inactivating one (Islow; time constant~1s). We show that galantamine (1pM-300μM) inhibits selectively Islow, exhibiting a dual dose-response relationship, in both differentiated N1E-115 cells and CA1 neurones. We also demonstrate that, in contrast with what was previously reported, galantamine-induced inhibition is not due to a shift on the steady-state inactivation and activation curves. Additionally, we characterized a methodological artefact that affects voltage-dependence as a function of time in whole-cell configuration, observed in both cell models. By resolving an inhibitory role on K+ currents in a non-central neuronal system and in hippocampal neurones, we are attributing a widespread role of galantamine on the modulation of cell excitability. The present results are relevant in the clinical context, since the effects at low dosages suggest that galantamine-induced K+ current inhibition may contribute to the efficiency of galantamine in the treatment of Alzheimer's disease. © 2010 Elsevier B.V.
KW - Acetylcholinesterase inhibitor
KW - Alzheimer's disease
KW - Galantamine
KW - Hippocampus
KW - Neuroblastoma
KW - Voltage-clamp artefact
KW - galantamine
KW - voltage gated potassium channel
KW - potassium channel
KW - potassium channel blocking agent
KW - animal cell
KW - animal experiment
KW - article
KW - cell differentiation
KW - controlled study
KW - dose response
KW - electrophysiology
KW - hippocampus
KW - mouse
KW - nerve cell
KW - nerve cell excitability
KW - neuroblastoma cell
KW - nonhuman
KW - potassium current
KW - priority journal
KW - pyramidal nerve cell
KW - rat
KW - steady state
KW - voltage clamp
KW - action potential
KW - animal
KW - comparative study
KW - cytology
KW - drug effects
KW - hippocampal CA1 region
KW - physiology
KW - tumor cell line
KW - Action Potentials
KW - Animals
KW - CA1 Region, Hippocampal
KW - Cell Differentiation
KW - Cell Line, Tumor
KW - Dose-Response Relationship, Drug
KW - Mice
KW - Neurons
KW - Potassium Channel Blockers
KW - Potassium Channels
KW - Rats
U2 - 10.1016/j.ejphar.2010.02.021
DO - 10.1016/j.ejphar.2010.02.021
M3 - Article
VL - 634
SP - 16
EP - 25
JO - European Journal Of Pharmacology
JF - European Journal Of Pharmacology
SN - 0014-2999
IS - 1-3
ER -