Valproic acid potently inhibits interictal-like epileptiform activity in prefrontal cortex pyramidal neurons

Szulczyk, Bartłomiej; Pasierski, Michał; Nurowska, Ewa

doi:10.1016/j.neulet.2019.134350

Cited by 8 publications

(9 citation statements)

References 28 publications

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“…Calcium-induced activation of TREK-2-like channels may be physiologically important in pathophysiological transient cellular hypercalcemia. It may reveal a novel calcium-dependent mechanism that prevents the neuron from becoming deleteriously overactive, e.g., it could prevent epileptiform activity [ 71 , 72 ] or activity in other pathological conditions…”

Section: Discussionmentioning

confidence: 99%

Activity of TREK-2-like Channels in the Pyramidal Neurons of Rat Medial Prefrontal Cortex Depends on Cytoplasmic Calcium

Dworakowska

Gawlak

Nurowska

2021

Biology

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TREK-2-like channels in the pyramidal neurons of rat prefrontal cortex are characterized by a wide range of spontaneous activity—from very low to very high—independent of the membrane potential and the stimuli that are known to activate TREK-2 channels, such as temperature or membrane stretching. The aim of this study was to discover what factors are involved in high levels of TREK-2-like channel activity in these cells. Our research focused on the PI(4,5)P2-dependent mechanism of channel activity. Single-channel patch clamp recordings were performed on freshly dissociated pyramidal neurons of rat prefrontal cortexes in both the cell-attached and inside-out configurations. To evaluate the role of endogenous stimulants, the activity of the channels was recorded in the presence of a PI(4,5)P2 analogue (PI(4,5)P2DiC8) and Ca2+. Our research revealed that calcium ions are an important factor affecting TREK-2-like channel activity and kinetics. The observation that calcium participates in the activation of TREK-2-like channels is a new finding. We showed that PI(4,5)P2-dependent TREK-2 activity occurs when the conditions for PI(4,5)P2/Ca2+ nanocluster formation are met. We present a possible model explaining the mechanism of calcium action.

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Section: Discussionmentioning

confidence: 99%

Activity of TREK-2-like Channels in the Pyramidal Neurons of Rat Medial Prefrontal Cortex Depends on Cytoplasmic Calcium

Dworakowska

Gawlak

Nurowska

2021

Biology

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“…Decapitation was the only procedure performed on animals in this study. Slices (300 µM) of the prefrontal cortex were prepared exactly the same way as shown in our previous publication [16]. After cutting, slices were incubated in a physiological artificial cerebrospinal fluid (ACSF) of the following composition (in mM): NaCl (130), KCl (2.5), glucose (10), NaHCO 3 (25), NaH 2 PO 4 (1.25), MgCl 2 (1), and CaCl 2 (2), pH = 7.4, bubbled with carbogen.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous publication showed that a common anti-epileptic drug—valproate, a sodium channel blocker and a GABA receptor agonist, inhibits interictal activity in the prefrontal cortex [ 16 ]. In the current report, we aimed to assess the effect of guanfacine on interictal activity in the rat’s prefrontal cortex in vitro.…”

Section: Introductionmentioning

confidence: 99%

Guanfacine inhibits interictal epileptiform events and sodium currents in prefrontal cortex pyramidal neurons

2023

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Background Guanfacine (an alpha-2A receptor agonist) is a commonly used drug with recognized efficacy in the treatment of attention deficit hyperactivity disorder (ADHD). This study aimed to assess the effects of guanfacine on short-lasting (interictal) epileptiform discharges in cortical neurons. Moreover, we assessed the effects of guanfacine on voltage-gated sodium currents. Methods We conducted patch-clamp recordings in prefrontal cortex pyramidal neurons obtained from young rats. Interictal epileptiform events were evoked in cortical slices in a zero magnesium proepileptic extracellular solution with an elevated concentration of potassium ions. Results Interictal epileptiform discharges were spontaneous depolarisations, which triggered action potentials. Guanfacine (10 and 100 µM) inhibited the frequency of epileptiform discharges. The effect of guanfacine on interictal events persisted in the presence of alpha-2 adrenergic receptor antagonist idazoxan. The tested drug inhibited neuronal excitability. Tonic NMDA currents were not influenced by guanfacine. Recordings from dispersed neurons showed that the tested drug (10 and 100 µM) inhibited persistent and fast inactivating voltage-gated sodium currents. Conclusions This study shows that guanfacine inhibits interictal discharges in cortical neurons independently of alpha-2A adrenergic receptors. This effect may be mediated by voltage-gated sodium currents. Inhibition of interictal activity by guanfacine may be of clinical importance because interictal events often occur in patients with ADHD and may contribute to symptoms of this disease. Graphical abstract

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“…The main action of VPA on the nervous system is related to the levels of gammaaminobutyric acid (GABA), and its antiepileptic properties are largely based on the increased levels of this neurotransmitter after its administration [17,18]. It is this agonist effect on the GABAergic system that underpins its potential anxiolytic properties, which have already been observed in several experiments with rodents, showing a reduction in behaviors associated with anxiety after VPA administration [19,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

“…In three experiments, we explored the result of pairing a neutral stimulus (a distinctive context) with the effects of Sodium Valproate (or Valproic Acid, VPA), one of the most widely used and effective anticonvulsants for the treatment of epilepsy [16]. The main action of VPA on the nervous system is related to the levels of gamma-aminobutyric acid (GABA), and its antiepileptic properties are largely based on the increased levels of this neurotransmitter after its administration [17,18]. It is this agonist effect on the GABAergic system that underpins its potential anxiolytic properties, which have already been observed in several experiments with rodents, showing a reduction in behaviors associated with anxiety after VPA administration [19,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

Unconditioned and Conditioned Anxiolytic Effects of Sodium Valproate on Flavor Neophobia and Fear Conditioning

Cintado

González-Tirado

Cárcel

et al. 2022

Preprint

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In three experiments with rats, we analyzed the potential anxiolytic effects of sodium valproate, an anticonvulsant drug that has shown additional pharmacodynamic effects in animal models, including anxiolytic action. Since previous results have revealed that injecting valproate before allowing animals to consume a novel flavor solution resulted in an attenuation of neophobia, we predicted a similar effect when the novel flavor is presented on a drug-free trial in the presence of a context previously associated with the drug. In line with this hypothesis, in our first experiment we observed a reduction in neophobia to a novel flavor for those animals tested in the presence of the context associated with Sodium Valproate. However, a control group that received the drug before being allowed access to the novel flavor showed a significant reduction in consumption. Experiment 2 revealed that the unconditioned effects of the drug include a deleterious effect on the animals' locomotor activity that probably interferes with drinking behavior. Finally, in a third experiment, we directly tested the potential anxiolytic properties of sodium valproate by injecting the drug before implementing a fear conditioning procedure. These findings are explained in terms of the unconditioned anxiolytic action of the drug and the formation of an association between the context and the effects of the drug that evokes a conditioned response reminiscent of such anxiolytic effect.

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Valproic acid potently inhibits interictal-like epileptiform activity in prefrontal cortex pyramidal neurons

Cited by 8 publications

References 28 publications

Activity of TREK-2-like Channels in the Pyramidal Neurons of Rat Medial Prefrontal Cortex Depends on Cytoplasmic Calcium

Activity of TREK-2-like Channels in the Pyramidal Neurons of Rat Medial Prefrontal Cortex Depends on Cytoplasmic Calcium

Guanfacine inhibits interictal epileptiform events and sodium currents in prefrontal cortex pyramidal neurons

Unconditioned and Conditioned Anxiolytic Effects of Sodium Valproate on Flavor Neophobia and Fear Conditioning

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