An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels

doi:10.1016/0920-1211(92)90065-2

Epilepsy Research

Volume 13, Issue 2, November 1992, Pages 107-112

https://doi.org/10.1016/0920-1211(92)90065-2 Get rights and content

Abstract

Lamotrigine (LTG), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, is a novel antiepileptic drug structurally unrelated to the major anticonvulsants in current use. Previous studies of LTG in rodents revealed efficacy in maximal electroshock test, pentylenetetrazol test and kindling models of seizures suggesting potential utility in the treatment of partial and generalized (tonic-clonic) seizures. In the present study, LTG was found to block sustained repetitive firing of sodium-dependent action potentials in mouse spinal cord cultured neurons and inhibit [³H]batrachotoxinin A 20-α-benzoate binding in rat brain synaptosomes suggesting a direct interaction with voltage-activated sodium channels.

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Glycogen synthase kinase 3beta (GSK-3β) is an enzyme with a variety of cellular functions in addition to the regulation of glycogen metabolism. In the central nervous system, different intracellular signaling pathways converge on GSK-3β through a cascade of phosphorylation events that ultimately control a broad range of neuronal functions in the development and adulthood. In mice, genetically removing or increasing GSK-3β cause distinct functional and structural neuronal phenotypes and consequently affect cognition. Precise control of GSK-3β activity is important for such processes as neuronal migration, development of neuronal morphology, synaptic plasticity, excitability, and gene expression. Altered GSK-3β activity contributes to aberrant plasticity within neuronal circuits leading to neurological, psychiatric disorders, and neurodegenerative diseases. Therapeutically targeting GSK-3β can restore the aberrant plasticity of neuronal networks at least in animal models of these diseases. Although the complete repertoire of GSK-3β neuronal substrates has not been defined, emerging evidence shows that different ion channels and their accessory proteins controlling excitability, neurotransmitter release, and synaptic transmission are regulated by GSK-3β, thereby supporting mechanisms of synaptic plasticity in cognition. Dysregulation of ion channel function by defective GSK-3β activity sustains abnormal excitability in the development of epilepsy and other GSK-3β-linked human diseases.
Transformation of lamotrigine by white-rot fungus Pleurotus ostreatus
2019, Environmental Pollution
Citation Excerpt :
This compound is the second-most frequently used antiepileptic drug in Israel (Berman et al., 2016) and it is popular worldwide. It acts as a voltage-dependent sodium channel blocker (Cheung et al., 1992; Leach et al., 1986; Perucca, 2005). LTG is excreted in the urine mainly in its glucuronide form, while approximately 10% is excreted as the parent compound (Garnett, 1997; Posner et al., 1989).
One of the most persistent pharmaceutical compounds commonly found in treated wastewater is lamotrigine (LTG). It has also been detected in soils and crops irrigated with treated wastewater. Here we focused on the ability of the white-rot edible mushroom Pleurotus ostreatus to remove and transform LTG in liquid cultures. At concentrations of environmental relevance (1 and 10 μg L⁻¹) LTG was almost completely removed from the culture medium within 20 days. To elucidate the mechanism of LTG removal and transformation, we applied a physiological-based approach using inhibitors and a competing agent. These experiments were conducted at a higher concentration for metabolites detection. Based on identification of sulfur-containing metabolites and LTG N2-oxide and the effect of specific inhibitors, cytochrome P450 oxidation is suggested as one of the reaction mechanisms leading to LTG transformation. The variety and number of transformation products (i.e., conjugates) found in the current study were larger than reported in mammals. Moreover, known conjugates with glucuronide, glutathione, or cysteine/glycine, were not found in our system. Since the majority of the identified transformation products were conjugates of LTG, this study highlights the persistence of LTG as an organic pollutant in ecosystems exposed to wastewater.
The anticonvulsant lamotrigine enhances I <inf>h</inf> in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy
2019, Neuropharmacology
Citation Excerpt :
The human layer 2/3 neurons studied here were typical in their morphology, as shown by the examples in Fig. 1 (upper row), and firing behaviour upon rectangular current injections (Fig. 1 A lower row). Moreover, they reacted to LTG with a progressive reduction of the amplitudes of action potentials and an increase in late interspike intervals as expected for a potent Na+ channel inhibitor (Cheung et al., 1992). In 2 neurons the action potential firing ceased at the same current amplitude that elicited repetitive action potentials under control conditions.
Alterations of the hyperpolarization activated nonselective cation current (I_h) are associated with epileptogenesis. Accordingly, the second-generation antiepileptic drug lamotrigine (LTG) enhances I_h in rodent hippocampus. We directly evaluated here whether LTG fails to enhance I_h in neocortical slices from patients with pharmacoresistant epilepsy. With somatic current clamp recordings we observed that LTG depolarized the membrane potential, decreased the input resistance and increased the “sag” in human layer 2/3 neocortical pyramidal neurons when confounding I_Kir was blocked. In subsequent voltage clamp recordings we confirmed a LTG induced increase of I_h that was qualitatively similar to the one we found in rat neocortical and hippocampal pyramidal neurons. This increase is sufficient to curtail single excitatory postsynaptic potentials (EPSPs) and reduces their temporal summation in human neocortical pyramidal neurons under physiological conditions, i.e. without blocking any other currents, as estimated by sharp microelectrode recordings.
Taken together LTG increases I_h and thereby alters neuronal excitability, even in neurons of pharmacoresistant patients. However, whether this increase fully countervails the deficits of I_h in epileptic patients, remains elusive.
Antidepressant and pro-motivational effects of repeated lamotrigine treatment in a rat model of depressive symptoms
2018, Heliyon
The antiepileptic lamotrigine is approved for maintenance treatment of bipolar disorder and augmentation therapy in treatment-resistant depression. Previous preclinical investigations showed lamotrigine antidepressant-like effects without addressing its possible activity on motivational aspects of anhedonia, a symptom clinically associated with poor treatment response and with blunted mesolimbic dopaminergic responsiveness to salient stimuli in preclinical models. Thus, in rats expressing a depressive-like phenotype we studied whether repeated lamotrigine administration restored behavioral responses to aversive and positive stimuli and the dopaminergic response to sucrose in the nucleus accumbens shell (NAcS), all disrupted by stress exposure.
Depressive-like phenotype was induced in non-food-deprived adult male Sprague-Dawley rats by exposure to a chronic protocol of alternating unavoidable tail-shocks or restraint periods. We examined whether lamotrigine administration (7.5 mg/kg twice a day, i.p.) for 14–21 days restored a) the competence to escape aversive stimuli; b) the motivation to operate in sucrose self-administration protocols; c) the dopaminergic response to sucrose consumption, evaluated measuring phosphorylation levels of cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS, by immunoblotting.
Lamotrigine administration restored the response to aversive stimuli and the motivation to operate for sucrose. Moreover, it reinstated NAcS DARPP-32 phosphorylation changes in response to sucrose consumption.
The pro-motivational effects of lamotrigine that we report may not completely transpose to clinical use, since anhedonia is a multidimensional construct and the motivational aspects, although relevant, are not the only components.
This study shows antidepressant-like and pro-motivational effects of repeated lamotrigine administration in a rat model of depressive symptoms.
D2 dopamine receptors modulate neuronal resonance in subthalamic nucleus and cortical high-voltage spindles through HCN channels
2016, Neuropharmacology
Citation Excerpt :
LTG, an HCN channel agonist (Poolos et al., 2002), injected locally into the STN with the D2 antagonist, could counteract the effect induced by the D2 antagonist. But LTG also can block the voltage-activated sodium channels (Cheung et al., 1992) which may be one of possible targets for inhibiting the HVSs activities. However, blocking sodium channel only is not enough to explain the antiepileptic effect of LTG (Coulter, 1997).
The high-voltage spindles (HVSs), one of the characteristic oscillations that include theta frequencies in the basal ganglia (BG)-cortical system, are involved in immobile behavior and show increasing power in Parkinson's disease (PD). Our previous results suggested that the D2 dopamine receptor might be involved in HVSs modulations in a rat model of PD. Membrane resonance is one of the cellular mechanisms of network oscillation; therefore, we investigated how dopamine modulates the theta frequency membrane resonance of neurons in the subthalamic nucleus (STN), a central pacemaker of BG, and whether such changes in STN neurons subsequently alter HVSs in the BG-cortical system. In particular, we tested whether dopamine modulates HVSs through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels-dependent membrane resonance in STN neurons. We found that an antagonist of D2 receptors, but not of D1 receptors, inhibited membrane resonance and HCN currents of STN neurons through a G-protein activity in acute brain slices. Our further in vivo experiments using local injection of a D2 receptor antagonist or an HCN blocker in STNs of free-moving rats showed an increase in HVSs power and correlation in the BG-cortical system. Local injection of lamotrigine, an HCN agonist, counteracted the effect induced by the D2 antagonist. Taken together, our results revealed a potential cellular mechanism underlying HVSs activity modulation in the BG-cortical system, i.e. tuning HCN activities in STN neurons through dopamine D2 receptors. Our findings might lead to a new direction in PD treatment by providing promising new drug targets for HVSs activity modulation.
Lamotrigine-induced obsessive-compulsive disorder in patients with bipolar disorder
2019, CNS Spectrums

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Research paperAn in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels

Abstract

J. Biol. Chem.

Brain Res.

Brain Res.

J. Biol. Chem.

Neurosci. Lett.

Neuropharmacology

Calcium- and sodium-dependent action potentials of mouse spinal cord and dorsal root ganglion neurons in cell culture

J. Neurophysiol.

Animal experimental methods in study of antiepileptic drugs

Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action

Epilepsia

Neurochemical and behavioral aspects of lamotrigine

Epilepsia

Research paper
An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels