Modulation of Calcium and Potassium Currents by Lamotrigine

Grunze, Heinz; Wegerer, Jörg von; Greene, Robert; Walden, J.

doi:10.1159/000026528

Cited by 68 publications

(33 citation statements)

References 30 publications

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“…It thus seems unlikely that LTG-mediated inhibition of I A is due to its direct suppression of Ca 2+ current and the resultant decrease in intracellular Ca 2+ concentrations. This study seems to be inconsistent with previous reports showing that LTG might increase the amplitude of I A (6)(7)(8). The reason for this discrepancy is currently unknown.…”

Section: Discussioncontrasting

confidence: 99%

Inhibitory Effect of Lamotrigine on A‐type Potassium Current in Hippocampal Neuron–Derived H19‐7 Cells

Huang

Liu

et al. 2004

Epilepsia

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Summary: Purpose:We investigated the effects of lamotrigine (LTG) on the rapidly inactivating A-type K + current (I A ) in embryonal hippocampal neurons.Methods: The whole-cell configuration of the patch-clamp technique was applied to investigate the ion currents in cultured hippocampal neuron-derived H19-7 cells in the presence of LTG. Effects of various related compounds on I A in H19-7 cells were compared.Results: LTG (30 µM-3 mM) caused a reversible reduction in the amplitude of I A . The median inhibitory concentration (IC 50 ) value required for the inhibition of I A by LTG was 160 µM. 4-Aminopyridine (1 mM), quinidine (30 µM), and capsaicin (30 µM) were effective in suppressing the amplitude of I A , whereas tetraethylammonium chloride (1 mM) and gabapentin (100 µM) had no effect on it. The time course for the inactivation of I A was changed to the biexponential process during cell exposure to LTG (100 µM). LTG (300 µM) could shift the steady-state inactivation of I A to a more negative membrane potential by approximately −10 mV, although it had no effect on the slope of the inactivation curve. Moreover, LTG (100 µM) produced a significant prolongation in the recovery of I A inactivation. Therefore in addition to the inhibition of voltage-dependent Na + channels, LTG could interact with the A-type K + channels to suppress the amplitude of I A . The blockade of I A by LTG does not simply reduce current magnitude, but alters current kinetics, suggesting a state-dependent blockade. LTG might have a higher affinity to the inactivated state than to the resting state of the I A channel.Conclusions: This study suggests that in hippocampal neurons, during exposure to LTG, the LTG-mediated inhibition of these K + channels could be one of the ionic mechanisms underlying the increased neuronal excitability.

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Section: Discussioncontrasting

confidence: 99%

Inhibitory Effect of Lamotrigine on A‐type Potassium Current in Hippocampal Neuron–Derived H19‐7 Cells

Huang

Liu

et al. 2004

Epilepsia

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“…The most effective analgesics in our model were lamotrigine and flupirtine, both of which affect Na v and potassium channels [6,9]. Thus, it is plausible that rather than a subtype-selective effect on a particular isoform of Na v channels, the in vivo efficacy is a reflection of the combined pharmacological profile of a given compound on Na v , K v , and perhaps TRP channels relevant for signalling in pain pathways.…”

Section: Discussionmentioning

confidence: 91%

Analgesic treatment of ciguatoxin-induced cold allodynia

Zimmermann¹,

Deuis²,

Inserra³

et al. 2013

Pain

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Ciguatera, the most common form of nonbacterial ichthyosarcotoxism, is caused by consumption of fish that have bioaccumulated the polyether sodium channel activator ciguatoxin. The neurological symptoms of ciguatera include distressing, often persistent sensory disturbances such as paraesthesias and the pathognomonic symptom of cold allodynia. We show that intracutaneous administration of ciguatoxin in humans elicits a pronounced axon-reflex flare and replicates cold allodynia. To identify compounds able to inhibit ciguatoxin-induced Nav responses, we developed a novel in vitro ciguatoxin assay using the human neuroblastoma cell line SH-SY5Y. Pharmacological characterisation of this assay demonstrated a major contribution of Nav1.2 and Nav1.3, but not Nav1.7, to ciguatoxin-induced Ca2+ responses. Clinically available Nav inhibitors, as well as the Kv7 agonist flupirtine, inhibited tetrodotoxin-sensitive ciguatoxin-evoked responses. To establish their in vivo efficacy, we used a novel animal model of ciguatoxin-induced cold allodynia. However, differences in the efficacy of these compounds to reverse ciguatoxin-induced cold allodynia did not correlate with their potency to inhibit ciguatoxin-induced responses in SH-SY5Y cells or at heterologously expressed Nav1.3, Nav1.6, Nav1.7, or Nav1.8, indicating cold allodynia might be more complex than simple activation of Nav channels. These findings highlight the need for suitable animal models to guide the empiric choice of analgesics, and suggest that lamotrigine and flupirtine could be potentially useful for the treatment of ciguatera.

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“…Grunze et al (1998) and Zona et al (2002) reported that lamotrigine (100-500 μM) could increase a transient potassium current in hippocampus and cortex, respectively, although effects were small and required high drug concentrations. In a recent study, lamotrigine, again at relatively high concentrations (100-300 μM), was shown to inhibit the A-type potassium current in a hippocampal cell line, H19-7 (Huang et al 2004).…”

Section: Calcium Channel Inhibitionmentioning

confidence: 99%

The potential role of lamotrigine in schizophrenia

2005

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The efficacy of lamotrigine is most likely explained within the framework of a glutamate neuron dysregulation hypothesis, and may arise primarily through the drugs ability to influence glutamate transmission and neural activity in the cortex. The drug is likely to act through inhibition of voltage-gated sodium channels, though other molecular interactions cannot be ruled out. Lamotrigine may add to or synergise with some atypical antipsychotic drugs acting on glutamate transmission; alternatively, they may act independently on glutamate and dopamine systems to bring about a combined therapeutic effect. We propose new strategies for the treatment of schizophrenia using a combination of anti-dopaminergic and anti-glutamatergic drugs.

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Modulation of Calcium and Potassium Currents by Lamotrigine

Cited by 68 publications

References 30 publications

Inhibitory Effect of Lamotrigine on A‐type Potassium Current in Hippocampal Neuron–Derived H19‐7 Cells

Inhibitory Effect of Lamotrigine on A‐type Potassium Current in Hippocampal Neuron–Derived H19‐7 Cells

Analgesic treatment of ciguatoxin-induced cold allodynia

The potential role of lamotrigine in schizophrenia

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