Diphenytoin, riluzole and lidocaine: Three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity

Diao, Lihong; Hellier, Jennifer L.; Uskert-Newsom, Jessica; Williams, Philip A.; Staley, Kevin J.; Yee, Audrey S.

doi:10.1016/j.neuropharm.2013.04.057

Cited by 16 publications

(11 citation statements)

References 75 publications

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“…It has been reported that riluzole, lidocaine, phenytoin bound to distinct sites of the sodium channels [ 49 , 50 , 51 , 52 ]. For example, riluzole interacts with amino acids residues TYR 1787, LEU 1843 and GLN 1799 located in the transmembrane segment S6 of domain IV of the α-subunit [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin

Zhao

Jin

et al. 2016

Marine Drugs

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Voltage-gated sodium channels (VGSCs) are responsible for the generation of the action potential. Among nine classified VGSC subtypes (Nav1.1–Nav1.9), Nav1.7 is primarily expressed in the sensory neurons, contributing to the nociception transmission. Therefore Nav1.7 becomes a promising target for analgesic drug development. In this study, we compared the influence of an array of VGSC agonists including veratridine, BmK NT1, brevetoxin-2, deltamethrin and antillatoxin (ATX) on membrane depolarization which was detected by Fluorescence Imaging Plate Reader (FLIPR) membrane potential (FMP) blue dye. In HEK-293 cells heterologously expressing hNav1.7 α-subunit, ATX produced a robust membrane depolarization with an EC50 value of 7.8 ± 2.9 nM whereas veratridine, BmK NT1, and deltamethrin produced marginal response. Brevetoxin-2 was without effect on membrane potential change. The ATX response was completely inhibited by tetrodotoxin suggesting that the ATX response was solely derived from hNav1.7 activation, which was consistent with the results where ATX produced a negligible response in null HEK-293 cells. Six VGSC antagonists including lidocaine, lamotrigine, phenytoin, carbamazepine, riluzole, and 2-amino-6-trifluoromethylthiobenzothiazole all concentration-dependently inhibited ATX response with IC50 values comparable to that reported from patch-clamp experiments. Considered together, we demonstrate that ATX is a unique efficacious hNav1.7 activator which offers a useful probe to develop a rapid throughput screening assay to identify hNav1.7 antagonists.

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Section: Discussionmentioning

confidence: 99%

Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin

Zhao

Jin

et al. 2016

Marine Drugs

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“…The stereotypical spontaneous activity patterns in unperturbed networks can be manipulated by changing the balance between inhibition and excitation in the network (Chen and Dzakpasu 2010), applying electrical stimulation (Durand 2009;Wagenaar et al 2005), neuromodulators (Hammond et al 2013;Hasselmo 1995;Whalley et al 2005), pharmacological synaptic blockers (Li et al 2007;Niedringhaus et al 2013;Verstraelen et al 2014), or intrinsic membrane current blockers (Diao et al 2013;van Drongelen et al 2006). Such experimental manipulations provide powerful venues to unravel the diverse mechanisms and critical factors involved in the generation of physiological and pathological network behavior.…”

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confidence: 99%

Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents

Suresh

Radojicic

Pesce

et al. 2016

Journal of Neurophysiology

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AK, Marks JD, van Drongelen W. Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents. J Neurophysiol 115: 3073-3089, 2016. First published March 16, 2016 doi:10.1152/jn.00995.2015.-The goal of this work was to define the contributions of intrinsic and synaptic mechanisms toward spontaneous network-wide bursting activity, observed in dissociated rat hippocampal cell cultures. This network behavior is typically characterized by short-duration bursts, separated by order of magnitude longer interburst intervals. We hypothesize that while shorttimescale synaptic processes modulate spectro-temporal intraburst properties and network-wide burst propagation, much longer timescales of intrinsic membrane properties such as persistent sodium (Na p ) currents govern burst onset during interburst intervals. To test this, we used synaptic receptor antagonists picrotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (CPP) to selectively block GABA A , AMPA, and NMDA receptors and riluzole to selectively block Na p channels. We systematically compared intracellular activity (recorded with patch clamp) and network activity (recorded with multielectrode arrays) in eight different synaptic connectivity conditions: GABA A ϩ NMDA ϩ AMPA, NMDA ϩ AMPA, GABA A ϩ AMPA, GABA A ϩ NMDA, AMPA, NMDA, GABA A , and all receptors blocked. Furthermore, we used mixed-effects modeling to quantify the aforementioned independent and interactive synaptic receptor contributions toward spectro-temporal burst properties including intraburst spike rate, burst activity index, burst duration, power in the local field potential, network connectivity, and transmission delays. We found that blocking intrinsic Na p currents completely abolished bursting activity, demonstrating their critical role in burst onset within the network. On the other hand, blocking different combinations of synaptic receptors revealed that spectro-temporal burst properties are uniquely associated with synaptic functionality and that excitatory connectivity is necessary for the presence of network-wide bursting. In addition to confirming the critical contribution of direct excitatory effects, mixed-effects modeling also revealed distinct combined (nonlinear) contributions of excitatory and inhibitory synaptic activity to network bursting properties. epilepsy; multielectrode arrays; network bursting; pharmacology; synaptic mechanisms SPONTANEOUS NETWORK-WIDE SYNCHRONIZED bursting activity appears to play an important role in several aspects of the nervous system including development (Gu and Spitzer 1995;Meister et al. 1991;Shatz 1990;Yuste et al. 1992) and integration in the sensory system (Engel et al. 1992) but also in the initiation of pathological activity such as epileptic seizures (Gutnick et al. 1982;Miles and Wong 1983). Therefore, clarifying how the underlying synaptic and intrinsic neuronal properties modulate and cause this network behavior is likely to provide valuable under...

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“…Here we provided further support for the antiepileptic activity of eugenol by showing that direct application of eugenol (0.5 mM) can prevent or inhibit the PTZ-induced epileptiform activity under in vitro condition. Inhibition of Na + current is an essential mechanism of many antiepileptic drugs (Diao et al, 2013;Ren et al, 2014). Here, the regular action potentials that were recorded after application of eugenol (0.5 mM) on PTZ exposed neurons showed elevated threshold and reduced amplitude and maximum depolarization slope.…”

Section: Discussionmentioning

confidence: 83%

“…Cho et al also reported the inhibitory action of eugenol (0.3 mM) on Na + currents in rat dorsal root ganglion neurons of rat (Cho et al, 2008). The neuroprotective/anticonvulsant agent riluzole employs several mechanisms of actions, but it primarily targets persistent Na + current, which essentially contribute to the neuronal excitability and epileptogenesis (Diao et al, 2013;Ren et al, 2014). Riluzole showed almost comparable effect to that of low concentration eugenol in reducing the frequency, amplitude and slope of rising phase of action potentials and increasing the threshold of action potentials initiation.…”

Section: Discussionmentioning

confidence: 99%

Dual effects of eugenol on the neuronal excitability: An in vitro study

2017

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Besides its well-known actions on sensory afferents, eugenol also affects general excitability of the nervous system, but the mechanisms involved in the recent effect, especially through modulation of ion channels, have received much less attention. In this study, we studied the effects of eugenol on the excitability of central neurons of land snail Caucasotachea atrolabiata and tried to elucidate the underlying ionic mechanisms. The lower concentration of eugenol (0.5mM) reversibly reduced the frequency of spontaneous action potentials that was associated with elevation of threshold, reduction of maximum slope of rising phase and prolongation of actin potentials. These effects were mimicked by riluzole, suggesting that they might be mediated by inhibition of Na channels. Eugenol also prolonged the single-spike afterhyperpolarization and post stimulus inhibitory period, but these effects seemed to be consequent to action potential prolongation that indirectly augment Ca inward currents and Ca-activated K currents. This concentration of eugenol was also able to prevent or abolish pentylenetetrazole-induced epileptiform activity. On the other hand, a higher concentration of eugenol (2mM) reversibly increased the frequency of action potentials and then induced epileptiform activity in majority of treated neurons. Several criteria suggest that the inhibition of K channels by higher concentration of eugenol and indirect augmentation of Ca currents are central to the hyperexcitability and epileptiform activity induced by eugenol. Our findings indicate that while low concentration of eugenol could have antiepileptic properties, at higher concentration it induces epileptiform activity. It seems that does dependent inhibition of the ionic currents underlying rising and falling phases of action potential is relevant to the eugenol suppressant and excitatory actions, respectively.

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Diphenytoin, riluzole and lidocaine: Three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity

Cited by 16 publications

References 75 publications

Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin

Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin

Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents

Dual effects of eugenol on the neuronal excitability: An in vitro study

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