The anticonvulsant lamotrigine enhances Ih in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy

Lehnhoff, Janna; Strauß, Ulf; Wierschke, Stephan; Grosser, Sabine; Pollali, Evangelia; Schneider, Ulf C.; Holtkamp, Martin; Dehnicke, Christoph; Deisz, Rudolf A.

doi:10.1016/j.neuropharm.2018.10.004

Cited by 13 publications

(7 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, with continued maintenance of RIB (10 μM), the subsequent addition of cilobradine (10 μM) or lamotrigine (10 μM) effectively inhibited or increased the Ih amplitude, respectively (Figure 7B). Cilobradine was recently reported to decrease Ih amplitude in pituitary cells [47], while lamotrigine could activate Ih in cortical neurons [49]. As such, distinct from its perturbing actions on different types of whole-cell K + currents described above, RIB's addition failed to perturb the magnitude, or gating kinetics of Ih identified in GH3 cells.…”

Section: Lack Of Rib Effect On the Perturbation Of Hyperpolarization-activated Cation Current (Ih) In Gh3 Cellsmentioning

confidence: 91%

Characterization of the Synergistic Inhibition of IK(erg) and IK(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

Liu

Chang

2020

IJMS

View full text Add to dashboard Cite

Ribociclib (RIB, LE011, Kisqali®), an orally administered inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex, is clinically effective for the treatment of several malignancies, including advanced breast cancer. However, information regarding the effects of RIB on membrane ion currents is limited. In this study, the addition of RIB to pituitary tumor (GH3) cells decreased the peak amplitude of erg-mediated K+ current (IK(erg)), which was accompanied by a slowed deactivation rate of the current. The IC50 value for RIB-perturbed inhibition of deactivating IK(erg) in these cells was 2.7 μM. In continued presence of μM RIB, neither the subsequent addition of 17β-estradiol (30 μM), phorbol 12-myristate 13-acetate (10 μM), or transforming growth factor-β (1 μM) counteracted the inhibition of deactivating IK(erg). Its presence affected the decrease in the degree of voltage-dependent hysteresis for IK(erg) elicitation by long-duration triangular ramp voltage commands. The presence of RIB differentially inhibited the peak or sustained component of delayed rectifier K+ current (IK(DR)) with an effective IC50 of 28.7 or 11.4 μM, respectively, while it concentration-dependently decreased the amplitude of M-type K+ current with IC50 of 13.3 μM. Upon 10-s long membrane depolarization, RIB elicited a decrease in the IK(DR) amplitude, which was concomitant with an accelerated inactivation time course. However, the inability of RIB (10 μM) to modify the magnitude of the hyperpolarization-activated cation current was disclosed. The mean current–voltage relationship of IK(erg) present in HL-1 atrial cardiomyocytes was inhibited in the presence of RIB (10 μM). Collectively, the hyperpolarization-activated cation current was observed. RIB-mediated perturbations in ionic currents presented herein are upstream of its suppressive action on cytosolic CDK-4/6 activities and partly participates in its modulatory effects on the functional activities of pituitary tumor cells (e.g., GH3 cells) or cardiac myocytes (e.g., HL-1 cells).

show abstract

Section: Lack Of Rib Effect On the Perturbation Of Hyperpolarization-activated Cation Current (Ih) In Gh3 Cellsmentioning

confidence: 91%

Characterization of the Synergistic Inhibition of IK(erg) and IK(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

Liu

Chang

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Experimental procedure on human tissue was as previously described (Lehnhoff et al, 2019). In brief, tissue samples were collected at the operating theatre and transferred to the laboratory within 30 to 40 min in cooled sucrose based aCSF enriched with carbogen (95% O2, 5% CO 2 ).…”

Section: Methodsmentioning

confidence: 99%

High-throughput microcircuit analysis of individual human brains through next-generation multineuron patch-clamp

Peng

Mittermaier

Planert

et al. 2019

eLife

View full text Add to dashboard Cite

Comparing neuronal microcircuits across different brain regions, species and individuals can reveal common and divergent principles of network computation. Simultaneous patch-clamp recordings from multiple neurons offer the highest temporal and subthreshold resolution to analyse local synaptic connectivity. However, its establishment is technically complex and the experimental performance is limited by high failure rates, long experimental times and small sample sizes. We introduce an in vitro multipatch setup with an automated pipette pressure and cleaning system facilitating recordings of up to 10 neurons simultaneously and sequential patching of additional neurons. We present hardware and software solutions that increase the usability, speed and data throughput of multipatch experiments which allowed probing of 150 synaptic connections between 17 neurons in one human cortical slice and screening of over 600 connections in tissue from a single patient. This method will facilitate the systematic analysis of microcircuits and allow unprecedented assessment of inter-individual variability.

show abstract

“…Through the whole-cell and cell-attached recordings, it has been shown in rat hippocampal slices that lamotrigine selectively reduces action potential firing from dendritic depolarization, whereas it minimally affects firing at the soma, suggesting that lamotrigine targets dendrites specifically (Poolos et al, 2002 ). In addition, there is the evidence from human cortical pyramidal neurons that lamotrigine reduces input resistance and enhances Ih current in layers 2/3 in patients with drug-resistant epilepsy (Lehnhoff et al, 2019 ). Based on the electrophysiological studies on Xenopus oocytes, mouse spinal cord slices targeting either parvalbumin-positive or calretinin-positive inhibitory neurons, it was revealed that there is a hyperpolarizing shift in the V1/2 of Ih current measured from HCN4-expressing PV+ inhibitory neurons in the spinal dorsal horn but not calretinin-positive inhibitory neurons (Tae et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Kessi

Peng

Duan

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

BackgroundHyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.ObjectivesThis systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.MethodsThe review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.ResultsWe identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.ConclusionWe recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.

show abstract

The anticonvulsant lamotrigine enhances Ih in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy

Cited by 13 publications

References 88 publications

Characterization of the Synergistic Inhibition of IK(erg) and IK(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

Characterization of the Synergistic Inhibition of IK(erg) and IK(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

High-throughput microcircuit analysis of individual human brains through next-generation multineuron patch-clamp

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Contact Info

Product

Resources

About