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Neuro–Endocrine–Immune Dysfunction in the Chronic Pain Patient
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Local inhibitory pathways are interesting in that, over time, an inhibitory pathway can become excitatory and create a positive feedback loop. At baseline, there is a normal Cl− gradient with Cl− concentrations higher outside of the neuron than inside the neuron. This is established by the action of an active Cl− transporter pushing Cl− out of the cell. Typically, GABAA and glycine receptors are inhibitory secondary to their function as a Cl− ionophore and allow the influx of Cl− into the cell according to its gradient—diminishing the chance of a successful action potential. There are two receptor sites on GABA receptors. The active site binds GABA, muscimol, gaboxadol, and bicuculine, while drugs such as benzodiazepines, alcohol, and barbiturates bind to different allosteric binding sites. After nerve injury, the Cl− transporter activity becomes diminished. As a result, the Cl− concentration becomes reversed with higher concentrations of Cl− inside of the neuron. Now, these ionophore receptors result in membrane depolarization—improving the likelihood of a successful action potential.
Benzodiazepine drugs in sleep disorders
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
As with the anxiety disorders (see Chapter 9) there is interest in using new GABAA receptor acting drugs in the treatment of sleep disorders. The partial agonist, pagoclone has been evaluated in a small trial and shown to have a profile as predicted from its pharmacology—it improved some aspects of sleep but to a lesser extent than that produced by the full agonist zopiclone (Wilson et al, 1997). Other GABAA receptor modulating drugs, such as the direct GABAAagonist, THIP (also called gaboxadol), are in clinical trials for insomnia.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
Mol. Pharmacol., 52, 1150, 1997. Gulinello, M., Gong, Q.H., and Smith, S.S., Progesterone withdrawal increases the anxiolytic actions of gaboxadol: role of alpha4betadelta GABA(A) receptors, Neu-roreport, 14, 43, 2003.Mihic, S.J., Ye, Q., Wick, M.J., Koltchine, V.V., Krasowski, M.D., Finn, S.E., Mascia, M.O., Valenzuela, C.F., Hanson, K.K., Greenblatt, E.P., Harris, R.A., and Harrison, N.L., Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine
Emerging therapeutic targets for narcolepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Marieke Vringer, Birgitte Rahbek Kornum
Gaboxadol is a GABAA agonist selective for the extrasynaptically located alpha4-delta subunit containing GABAA receptor subtype. When activated, alpha4-delta GABAA receptors produce a tonic inhibitory conductance, which is thought to result in a more stable inhibitory pattern, as compared to phasic synaptic inhibition [103]. Gaboxadol can increase slow wave sleep in a dose-related manner in adult and elderly healthy subjects, and in primary insomnia patients [104–106], but a phase III study did not succeed in replicating the sleep-promoting effects and the drug never made it to an FDA or EMA approval [107]. A patent-family for the use of gaboxadol in narcolepsy exists (e.g., WO/2019/055369), but its clinical efficacy in NT1 or NT2 has never been demonstrated.
Sleep restores place learning to the adenylyl cyclase mutant rutabaga
Published in Journal of Neurogenetics, 2020
Stephane Dissel, Ellen Morgan, Vincent Duong, Dorothy Chan, Bruno van Swinderen, Paul Shaw, Troy Zars
As with social enrichment, the mushroom body is not necessary for heat-box learning (Putz & Heisenberg, 2002). During heat-box learning, one side of a chamber is randomly assigned to be the punished side such that the entire chamber will heat up when the fly crosses into that half of the chamber. When the fly is on the unpunished side, the entire chamber is cool. During training, the chamber will be heated up to 41 °C when an individual fly crosses an invisible midline and cooled when it moves back across the midline (Figure 4(A)). As seen in Figure 4(B), CS flies display normal performance in the heat-box and Gab-induced sleep does not improve performance further. Performance is impaired in rut2080 mutants as expected. However, two days of Gaboxadol induced sleep restores performance in the heat box to wild-type levels. In contrast to rut2080, the performance index remains low in dnc1 mutants and is not improved by Gab (Figure 4(B)). Gab did not alter thermal preference in any genotype studies (Figure 4(C)). Thus, Gab induced sleep restores place learning to rut2080 mutants.
Novel and emerging therapeutics for genetic epilepsies
Published in Expert Review of Neurotherapeutics, 2021
Ana Pejčić, Slobodan M. Janković, Miralem Đešević, Refet Gojak, Snežana Lukić, Nenad Marković, Miloš Milosavljević
Gaboxadol (OV101) is a highly selective orthosteric agonist that activates δ-subunit–containing extra synaptic GABAA receptors, which is investigated for use in Angelman syndrome [84]. Angelman syndrome is caused primarily by the loss of function of the UBE3A gene, which subsequently leads to reduced activation of extra synaptic GABAA receptors and attenuation of tonic inhibition [84]. Results of gaboxadol phase II multicenter, double-blind, placebo-controlled, parallel-group trial (NCT02996305) in adolescent and adult patients with diagnosis of the Angelman syndrome confirmed by molecular testing were recently published [84]. The Full Analysis Set/Safety Set consisted of 87 individuals randomized into three groups: 29 who received gaboxadol once daily (placebo in the morning and 15 mg gaboxadol in the evening), 29 who received gaboxadol twice daily (gaboxadol 10 mg in the morning and 15 mg in the evening), and 29 who received only placebo (in the morning and evening) [84]. Gaboxadol was found to be generally well-tolerated with a favorable safety profile after 12 weeks of treatment [84]. Most adverse events were mild and moderate, and none was life-threatening [84]. While the study was not designed to be sufficiently powered for efficacy outcomes, a pre-specified supportive Mixed Model Repeated Measures analysis of Clinical Global Impression–Improvement overall showed an improvement in the once-daily gaboxadol group vs. placebo (LS mean difference, −0.78; SE 0.218; p = 0.0006), while the twice-daily gaboxadol group showed no difference from placebo (LS mean, −0.21; SE, 0.216; p = 0.3446) [84]. Comparison of the combined gaboxadol group vs. placebo for the endpoints in the Seizure Activity e-Diary did not show a significant difference [84]. A phase III study of gaboxadol in pediatric patients (2–12 years) with Angelman syndrome has been completed, but full results have not been published yet [85]. However, the manufacturer announced in December 2020 that the trial did not meet its primary goal of showing a difference between the treatment group and the placebo group in changing score on the clinical global impression-improvement-Angelman syndrome scale [86].