Summary
The pharmacologic profile of retigabine RTG (international nonproprietary name); ezogabine, EZG (U.S. adopted name), is different from all currently approved antiepileptic drugs (AEDs). Its ...primary mechanism of action (MoA) as a positive allosteric modulator of KCNQ2–5 (Kv7.2–7.5) ion channels defines RTG/EZG as the first neuronal potassium (K+) channel opener for the treatment of epilepsy. KCNQ2–5 channels are predominantly expressed in neurons and are important determinants of cellular excitability, as indicated by the occurrence of human genetic mutations in KCNQ channels that underlie inheritable disorders including, in the case of KCNQ2/3, the syndrome of benign familial neonatal convulsions. In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2–5 channels, particularly heteromeric KCNQ2/3. Furthermore, mutagenesis and modeling studies have pinpointed the RTG/EZG binding site to a hydrophobic pocket near the channel gate, indicating how RTG/EZG can stabilize the open form of KCNQ2–5 channels; the absence of this site in KCNQ1 also provides a clear explanation for the inbuilt selectivity RTG/EZG has for potassium channels other than the KCNQ cardiac channel. KCNQ channels are active at the normal cell resting membrane potential (RMP) and contribute a continual hyperpolarizing influence that stabilizes cellular excitability. The MoA of RTG/EZG increases the number of KCNQ channels that are open at rest and also primes the cell to retort with a larger, more rapid, and more prolonged response to membrane depolarization or increased neuronal excitability. In this way, RTG/EZG amplifies this natural inhibitory force in the brain, acting like a brake to prevent the high levels of neuronal action potential burst firing (epileptiform activity) that may accompany sustained depolarizations associated with the initiation and propagation of seizures. This action to restore physiologic levels of neuronal activity is thought to underlie the efficacy of RTG/EZG as an anticonvulsant in a broad spectrum of preclinical seizure models and in placebo‐controlled trials in patients with partial epilepsy. In this article, we consider the pharmacologic characteristics of RTG/EZG at the receptor, cellular, and network levels as a means of understanding the novel and efficacious MoA of this new AED as defined in both preclinical and clinical research.
Why Is There No Cure for Tinnitus? McFerran, Don J; Stockdale, David; Holme, Ralph ...
Frontiers in neuroscience,
08/2019, Letnik:
13
Journal Article
Recenzirano
Odprti dostop
Tinnitus is unusual for such a common symptom in that there are few treatment options and those that are available are aimed at reducing the impact rather than specifically addressing the tinnitus ...percept. In particular, there is no drug recommended specifically for the management of tinnitus. Whilst some of the currently available interventions are effective at improving quality of life and reducing tinnitus-associated psychological distress, most show little if any effect on the primary symptom of subjective tinnitus loudness. Studies of the delivery of tinnitus services have demonstrated considerable end-user dissatisfaction and a marked disconnect between the aims of healthcare providers and those of tinnitus patients: patients want their tinnitus loudness reduced and would prefer a pharmacological solution over other modalities. Several studies have shown that tinnitus confers a significant financial burden on healthcare systems and an even greater economic impact on society as a whole. Market research has demonstrated a strong commercial opportunity for an effective pharmacological treatment for tinnitus, but the amount of tinnitus research and financial investment is small compared to other chronic health conditions. There is no single reason for this situation, but rather a series of impediments: tinnitus prevalence is unclear with published figures varying from 5.1 to 42.7%; there is a lack of a clear tinnitus definition and there are multiple subtypes of tinnitus, potentially requiring different treatments; there is a dearth of biomarkers and objective measures for tinnitus; treatment research is associated with a very large placebo effect; the pathophysiology of tinnitus is unclear; animal models are available but research in animals frequently fails to correlate with human studies; there is no clear definition of what constitutes meaningful change or "cure"; the pharmaceutical industry cannot see a clear pathway to distribute their products as many tinnitus clinicians are non-prescribing audiologists. To try and clarify this situation, highlight important areas for research and prevent wasteful duplication of effort, the British Tinnitus Association (BTA) has developed a Map of Tinnitus. This is a repository of evidence-based tinnitus knowledge, designed to be free to access, intuitive, easy to use, adaptable and expandable.
Small-molecule modulators of diverse voltage-gated K
(Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their ...mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the channel's tetrameric assembly. Furthermore, we show that the unique extracellular turret regions of Kv3.1 and Kv3.2 essentially govern the selective positive modulation by AUT5. High-resolution apo and bound structures of Kv3.1 demonstrate how AUT5 binding promotes turret rearrangements and interactions with the voltage-sensing domain to favor the open conformation.
The combination of brain stimulation techniques like transcranial magnetic stimulation (TMS) with CNS active drugs in humans now offers a unique opportunity to explore the physiologic effects of ...these substances in vivo in the human brain. Motor threshold, motor evoked potential size, motor evoked potential intensity curves, cortical silent period, short-interval intracortical inhibition, intracortical facilitation, short-interval intracortical facilitation, long-interval intracortical inhibition and short latency afferent inhibition represent the repertoire for investigating drug effects on motor cortical excitability by TMS. Here we present an updated overview on the pharmacophysiologic mechanisms with special emphasis on methodologic pitfalls and possible future developments or requirements.
Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded
in mice lacking the gene (
...) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in
animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K
currents that activate at positive potentials ("high-threshold" K
currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in
mice, while K
currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 ((4-({5-(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile, a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K
current and increased the low-threshold K
currents in neurons from
animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and,
, restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS.
mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses
, suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.
Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C terminus of Kv3.3 contains a proline-rich domain conserved in ...proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filament network resistant to cytochalasin D that inhibits fast barbed end actin assembly. These Kv3.3-associated actin structures are required to prevent very rapid N-type channel inactivation during short depolarizations of the plasma membrane. The effects of Kv3.3 on the actin cytoskeleton are mediated by the binding of the cytoplasmic C terminus of Kv3.3 to Hax-1, an anti-apoptotic protein that regulates actin nucleation through Arp2/3. A human Kv3.3 mutation within a conserved proline-rich domain produces channels that bind Hax-1 but are impaired in recruiting Arp2/3 to the plasma membrane, resulting in growth cones with deficient actin veils in stem cell-derived neurons.
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•Kv3.3 ion channels coordinate assembly of Arp2/3-dependent cortical actin networks•These actin networks slow the rate of Kv3.3 channel closing during depolarization•Network assembly is coordinated by Hax-1, a Rac- and cortactin-binding protein•Cerebellar ataxia is correlated with a channel mutation that blocks network assembly
Kv3.3 channels coordinate assembly of cortical Arp2/3-dependent actin networks that in turn interact with channels to slow their rate of closing during sustained depolarization, suggesting a basis for how known channel mutations result in abnormal neuronal growth during development and cause cerebellar ataxia in human patients.
Noise exposure has been shown to produce long-lasting increases in spontaneous activity in central auditory structures in animal models, and similar pathologies are thought to contribute to clinical ...phenomena such as hyperacusis or tinnitus in humans. Here we demonstrate that multi-unit spontaneous neuronal activity in the inferior colliculus (IC) of mice is significantly elevated four weeks following noise exposure at recording sites with frequency tuning within or near the noise exposure band, and this selective central auditory pathology can be normalised through administration of a novel compound that modulates activity of Kv3 voltage-gated ion channels. The compound had no statistically significant effect on IC spontaneous activity without noise exposure, nor on thresholds or frequency tuning of tone-evoked responses either with or without noise exposure. Administration of the compound produced some reduction in the magnitude of evoked responses to a broadband noise, but unlike effects on spontaneous rates, these effects on evoked responses were not specific to recording sites with frequency tuning within the noise exposure band. Thus, the results suggest that modulators of Kv3 channels can selectively counteract increases in spontaneous activity in the auditory midbrain associated with noise exposure.
•Spontaneous activity in mouse inferior colliculus is elevated after noise exposure.•AUT00063, a novel Kv3 channel modulator, normalises this midbrain pathology.•No effect of AUT00063 on IC spontaneous activity without noise exposure.•No effect of AUT00063 on IC tone-evoked response thresholds or frequency tuning.
Exposure to loud sound increases burst-firing of dorsal cochlear nucleus (DCN) fusiform cells in the auditory brainstem, which has been suggested to be an electrophysiological correlate of tinnitus. ...The altered activity of DCN fusiform cells may be due to down-regulation of high voltage-activated (Kv3-like) K+ currents. Whole cell current-clamp recordings were obtained from DCN fusiform cells in brain slices from P15-P18 CBA mice. We first studied whether acoustic over-exposure (performed at P15) or pharmacological inhibition of K+ currents with tetraethylamonium (TEA) affect fusiform cell action potential characteristics, firing frequency and spike-timing relative to evoking current stimuli. We then tested whether AUT1, a modulator of Kv3 K+ currents reverses the effects of sound exposure or TEA. Both loud sound exposure and TEA decreased the amplitude of action potential after-hyperpolarization, reduced the maximum firing frequency, and disrupted spike-timing. These treatments also increased post-synaptic voltage fluctuations at baseline. AUT1 applied in the presence of TEA or following acoustic over-exposure, did not affect the firing frequency, but enhanced action potential after-hyperpolarization, prevented the increased voltage fluctuations and restored spike-timing. Furthermore AUT1 prevented the occurrence of bursts. Our study shows that the effect on spike-timing is significantly correlated with the amplitude of the action potential after-hyperpolarization and the voltage fluctuations at baseline. In conclusion, modulation of putative Kv3 K+ currents may restore regular spike-timing of DCN fusiform cell firing following noise exposure, and could provide a means to restore deficits in temporal encoding observed during noise-induced tinnitus.
•Whole cell recordings were performed in dorsal cochlear nucleus fusiform cells.•Spike-timing is dependent on the action potential after-hyperpolarization.•Spike-timing is dependent on synaptic baseline voltage fluctuations.•Inhibition of K+ currents using TEA or acoustic over-exposure disrupt spike-timing.•AUT1, a Kv3.1/3.2 K+ current modulator, counteracts the disruptive effects on spike-timing.
Various psychiatric diseases are characterized by aberrant cognition and emotional regulation. This includes inappropriately attributing affective salience to innocuous cues, which can be ...investigated using translationally relevant preclinical models of fear discrimination. Activity in the underpinning corticolimbic circuitry is governed by parvalbumin-expressing GABAergic interneurons, which also regulate fear discrimination. Kv3 voltage-gated potassium channels are highly expressed in these neurons and are important for controlling their activity, suggesting that pharmacological Kv3 modulation may regulate fear discrimination. We determined the effect of the positive Kv3 modulator AUT00206 given systemically to female rats undergoing limited or extended auditory fear discrimination training, which we have previously shown results in more discrimination or generalization, respectively, based on freezing at retrieval. We also characterized darting and other active fear-related responses. We found that limited training resulted in more discrimination based on freezing, which was unaffected by AUT00206. In contrast, extended training resulted in more generalization based on freezing and the emergence of discrimination based on darting during training and, to a lesser extent, at retrieval. Importantly, AUT00206 given before extended training had dissociable effects on fear discrimination and expression at retrieval depending on the response examined. While AUT00206 mitigated generalization without affecting expression based on freezing, it reduced expression without affecting discrimination based on darting, although darting levels were low overall. These results indicate that pharmacological Kv3 modulation regulates fear discrimination and expression in a response-dependent manner. They also raise the possibility that targeting Kv3 channels may ameliorate perturbed cognition and emotional regulation in psychiatric disease.
•We examined the effects of the Kv3 channel modulator AUT00206 on fear discrimination.•AUT00206 enhanced fear discrimination based on freezing but not darting at retrieval.•AUT00206 reduced fear expression based on darting but not freezing at retrieval.•Kv3 modulators may ameliorate aberrant cognition and emotional regulation.
N-methyL-D-aspartate (NMDA) receptor antagonists, such as ketamine and phencyclidine, induce perceptual abnormalities, psychosis-like symptoms, and mood changes in healthy humans and patients with ...schizophrenia. The similarity between NMDA receptor antagonist-induced psychosis and schizophrenia has led to the widespread use of the drugs to provide models to aid the development of novel treatments for the disorder. This review investigates the predictive validity of NMDA receptor antagonist models based on a range of novel treatments that have now reached clinical trials. Furthermore, it considers the extent to which the different hypotheses that have been proposed to account for the psychotomimetic effects of NMDA receptor antagonist have been validated by the results of these trials. Finally, the review discusses some of the caveats associated with use of the models and some suggestions as to how a greater use of translational markers might ensure progress in understanding the relationship between the models and schizophrenia.
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