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1.
Drugs ; 84(5): 607-611, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38546956

RESUMO

Dimdazenil (Junoenil®) is a small-molecule, oral, partial positive allosteric modulator of the gamma-aminobutyric acid (GABA)A receptor that is being developed by Zhejiang Jingxin Pharmaceutical in collaboration with Evotec for the treatment of insomnia. Dimdazenil is designed to overcome issues associated with full GABAA receptor agonists, such as tolerance, withdrawal symptoms and associated adverse effects. On 29 November 2023, dimdazenil oral capsules received approval in China for the short-term treatment of insomnia. This article summarizes the milestones in the development of dimdazenil leading to this first approval for insomnia.


Assuntos
Aprovação de Drogas , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , China , Moduladores GABAérgicos/farmacologia , Moduladores GABAérgicos/uso terapêutico , Moduladores GABAérgicos/efeitos adversos , Moduladores GABAérgicos/administração & dosagem , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Administração Oral , Flumazenil/farmacologia , Flumazenil/uso terapêutico
2.
Neuropsychopharmacol Rep ; 44(2): 464-467, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38500267

RESUMO

Burning mouth syndrome (BMS) is characterized by burning sensations in the oral region without corresponding abnormalities and is often accompanied by uncomfortable sensations. Herein, we present cases of BMS in which the remaining uncomfortable sensations improved with perospirone augmentation with clonazepam. Case 1: A 61-year-old man complained of a burning pain in his tongue, a sensation of dryness and discomfort as if his tongue was sticking to a palatal plate. With the diagnosis of BMS, psychopharmacotherapy was initiated with amitriptyline. At the dose of amitriptyline 50 mg, the pain lessened but uncomfortable sensations persisted. Further attempts to alleviate symptoms by combining aripiprazole with amitriptyline, aripiprazole with mirtazapine, or aripiprazole with clonazepam were limited; however, nearly all symptoms were relieved by a combination of perospirone 8.0 mg with clonazepam 1.5 mg. Case 2: A 51-year-old woman complained of a burning sensation along with oral dryness and crumb-like feeling on her tongue. She was diagnosed with BMS and began treatment with amitriptyline. Her burning sensation improved at the dose of 25 mg, but uncomfortable sensations persisted. Augmentation of amitriptyline with aripiprazole, aripiprazole either with valproate, mirtazapine, or clonazepam failed to produce a significant improvement. However, a regimen of perospirone 6.0 mg and clonazepam 1.5 mg relieved the crumb-like sensation and pain and culminated in a stabilized condition. The reported cases suggested that multiple approaches targeting the dopaminergic circuit in basal ganglia involving the serotoninergic and GABA systems, through the administration of perospirone with clonazepam is an effective adjunctive treatment for the remaining uncomfortable sensations in patients with BMS.


Assuntos
Síndrome da Ardência Bucal , Clonazepam , Quimioterapia Combinada , Isoindóis , Humanos , Clonazepam/uso terapêutico , Clonazepam/administração & dosagem , Pessoa de Meia-Idade , Síndrome da Ardência Bucal/tratamento farmacológico , Masculino , Feminino , Isoindóis/uso terapêutico , Isoindóis/administração & dosagem , Tiazóis/uso terapêutico , Tiazóis/administração & dosagem , Moduladores GABAérgicos/uso terapêutico , Moduladores GABAérgicos/administração & dosagem
3.
CNS Drugs ; 37(8): 679-693, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37542704

RESUMO

Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain.


Assuntos
Transtorno Disfórico Pré-Menstrual , Síndrome Pré-Menstrual , Feminino , Humanos , Transtorno Disfórico Pré-Menstrual/tratamento farmacológico , Transtorno Disfórico Pré-Menstrual/psicologia , Pregnanolona/uso terapêutico , Qualidade de Vida , Ciclo Menstrual/fisiologia , Fase Luteal/fisiologia , Moduladores GABAérgicos , Ácido gama-Aminobutírico , Síndrome Pré-Menstrual/tratamento farmacológico , Síndrome Pré-Menstrual/psicologia
4.
Biomed Pharmacother ; 161: 114498, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36906973

RESUMO

In a screening of a small library of extracts from plants of the Amazonian and Cerrado biomes, a hexane extract of Connarus tuberosus roots was found to significantly potentiate the GABA induced fluorescence in a fluorescence (FLIPR) assay in CHO cells stably expressing the α1ß2γ2 subtype of human GABAA receptors. With the aid of HPLC-based activity profiling the activity was linked to the neolignan connarin. In CHO cells the activity of connarin was not abolished by increasing concentrations of flumazenil, while the effect of diazepam was increased by increasing concentrations of connarin. The effect of connarin was abolished by pregnenolone sulfate (PREGS) in a concentration-dependent manner, and the effect of allopregnanolone was further increased by increasing concentrations of connarin. In a two-microelectrode voltage clamp assay with Xenopus laevis oocytes transiently expressing GABAA receptors composed of human α1ß2γ2S and α1ß2 subunits connarin potentiated the GABA-induced currents, with EC50 values of 1.2 ± 0.3 µM (α1ß2γ2S) and 1.3 ± 0.4 µM (α1ß2), and with a maximum enhancement of currents Emax of 1959 ± 70% (α1ß2γ2S) and 185 ± 48% (α1ß2). The activation induced by connarin was abolished by increasing concentrations of PREGS.


Assuntos
Connaraceae , Neuroesteroides , Animais , Cricetinae , Humanos , Receptores de GABA-A/metabolismo , Neuroesteroides/metabolismo , Moduladores GABAérgicos/farmacologia , Cricetulus , Sítios de Ligação , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/metabolismo , Oócitos
5.
J Cogn Neurosci ; 35(6): 976-989, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36976900

RESUMO

Animals need to cope with abundant sensory information, and one strategy is to selectively direct attention to only the most relevant part of the environment. Although the cortical networks of selective attention have been studied extensively, its underlying neurotransmitter systems, especially the role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), remain less well understood. Increased GABAA receptor activity because of administration of benzodiazepines such as lorazepam is known to slow reactions in cognitive tasks. However, there is limited knowledge about GABAergic involvement in selective attention. Particularly, it is unknown whether increased GABAA receptor activity slows the build-up of selectivity or generally widens attentional focus. To address this question, participants (n = 29) received 1 mg lorazepam and placebo (within-subjects, double-blind) and performed an extended version of the flanker task. The spatial distribution of selective attention was studied by systematically manipulating number and position of incongruent flankers; the temporal build-up was characterized using delta plots. An online task version was presented to an independent, unmedicated sample (n = 25) to verify task effects. Under placebo and in the unmedicated sample, only the number of incongruent flankers, but not their position, influenced RTs. Incongruent flankers impaired RTs more strongly under lorazepam than placebo, especially when adjacent to the target. Delta plot analyses of RT showed that this effect persisted even when participants reacted slowly, indicating that lorazepam-induced impairments in selective attention do not result from simply slowed down build-up of selectivity. Instead, our data indicate that increased GABAA receptor activity widens the attentional focus.


Assuntos
Atenção , Moduladores GABAérgicos , Receptores de GABA-A , Método Duplo-Cego , Lorazepam/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Humanos , Atenção/efeitos dos fármacos , Atenção/fisiologia , Moduladores GABAérgicos/farmacologia
6.
Molecules ; 27(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36363979

RESUMO

Scientific evidence suggests that quercetin (QUR) has anxiolytic-like effects in experimental animals. However, the mechanism of action responsible for its anxiolytic-like effects is yet to be discovered. The goal of this research is to assess QUR's anxiolytic effects in mouse models to explicate the possible mechanism of action. After acute intraperitoneal (i.p.) treatment with QUR at a dose of 50 mg/kg (i.p.), behavioral models of open-field, hole board, swing box, and light-dark tests were performed. QUR was combined with a GABAergic agonist (diazepam) and/or antagonist (flumazenil) group. Furthermore, in silico analysis was also conducted to observe the interaction of QUR and GABA (α5), GABA (ß1), and GABA (ß2) receptors. In the experimental animal model, QUR had an anxiolytic-like effect. QUR, when combined with diazepam (2 mg/kg, i.p.), drastically potentiated an anxiolytic effect of diazepam. QUR is a more highly competitive ligand for the benzodiazepine recognition site that can displace flumazenil (2.5 mg/kg, i.p.). In all the test models, QUR acted similar to diazepam, with enhanced effects of the standard anxiolytic drug, which were reversed by pre-treatment with flumazenil. QUR showed the best interaction with the GABA (α5) receptor compared to the GABA (ß1) and GABA (ß2) receptors. In conclusion, QUR may exert an anxiolytic-like effect on mice, probably through the GABA-receptor-interacting pathway.


Assuntos
Ansiolíticos , Camundongos , Animais , Ansiolíticos/farmacologia , Flumazenil/farmacologia , Quercetina/farmacologia , Moduladores GABAérgicos/farmacologia , Receptores de GABA/metabolismo , Receptores de GABA-A/metabolismo , Aprendizagem em Labirinto , Diazepam/farmacologia , Ácido gama-Aminobutírico/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal
7.
Basic Clin Pharmacol Toxicol ; 131(6): 514-524, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36180380

RESUMO

Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague-Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6-GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.


Assuntos
Diazepam , Receptores de GABA-A , Animais , Ratos , Masculino , Diazepam/farmacologia , Ratos Sprague-Dawley , Receptores de GABA-A/química , Benzodiazepinas/farmacologia , Ligantes , Ácido gama-Aminobutírico , Ataxia , Moduladores GABAérgicos
8.
Nat Commun ; 13(1): 4582, 2022 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933426

RESUMO

γ-Aminobutyric acid type A (GABAA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABAA) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABAA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at ß/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABAA receptor allosteric modulators acting through a common site can have diverging activities.


Assuntos
Benzodiazepinas , Receptores de GABA-A , Sítios de Ligação/fisiologia , Moduladores GABAérgicos/farmacologia , Receptores de GABA-A/metabolismo , Zolpidem , Ácido gama-Aminobutírico
9.
Mol Biol Rep ; 49(9): 9041-9049, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35690686

RESUMO

BACKGROUND: Newly identified multifunctional peptidergic modulators of stress responses: neuromedin U (NMU) and neuropeptide S (NPS) are involved in the wide spectrum of brain functions. However, there are no reports dealing with potential molecular relationships between the action of diverse anxiolytic or antidepressant drugs and NMU and NPS signaling in the brain. The present work was therefore focused on local expression of the aforementioned stress-related neuropeptides in the rat brain after long-term treatment with escitalopram and clonazepam. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 3 groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 5 mg/kg daily), and clonazepam (at single dose 0.5 mg/kg). All individuals were sacrificed under anaesthesia and the whole brain excised. Total mRNA was isolated from homogenized samples of amygdala, hippocampus, hypothalamus, thalamus, cerebellum and brainstem. Real time-PCR method was used for estimation of related NPS, NPS receptor (NPSR), NMU, NMU and receptor 2 (NMUR2) mRNA expression. The whole brains were also sliced for general immunohistochemical assessment of the neuropeptides expression. RESULTS: Chronic administration of clonazepam resulted in an increase of NMU mRNA expression and formation of NMU-expressing fibers in the amygdala, while escitalopram produced a significant decrease in NPSR mRNA level in hypothalamus. Long-term escitalopram administration affects the local expression of examined neuropeptides mRNA in a varied manner depending on the brain structure. CONCLUSIONS: Pharmacological effects of escitalopram may be connected with local at least partially NPSR-related alterations in the NPS/NMU/NMUR2 gene expression at the level selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed.


Assuntos
Ansiedade , Encéfalo , Clonazepam , Escitalopram , Moduladores GABAérgicos , Neuropeptídeos , Receptores de Neuropeptídeos , Receptores de Neurotransmissores , Animais , Ansiedade/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Clonazepam/farmacologia , Clonazepam/uso terapêutico , Escitalopram/farmacologia , Escitalopram/uso terapêutico , Moduladores GABAérgicos/farmacologia , Moduladores GABAérgicos/uso terapêutico , Masculino , Neuropeptídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeos/metabolismo , Receptores de Neurotransmissores/metabolismo
10.
J Nat Prod ; 85(5): 1201-1210, 2022 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-35475609

RESUMO

An EtOAc extract of Casearia corymbosa leaves led to an allosteric potentiation of the GABA signal in a fluorometric imaging plate reader (FLIPR) assay on Chinese hamster ovary (CHO) cells stably expressing GABAA receptors with an α1ß2γ2 subunit composition. The activity was tracked by HPLC-based activity profiling, and four known (2, 3, 4, and 8) and five new clerodane-type diterpenoids (1, 5-7, and 9) were isolated. Compounds 1-8 were obtained from the active time window. The absolute configuration of all compounds was established by ECD. Compounds 3, 7, and 8 exhibited EC50 values of 0.5, 4.6, and 1.4 µM, respectively. To explore possible binding sites at the receptor, the most abundant diterpenoid 8 was tested in combination with diazepam, etazolate, and allopregnanolone. An additive potentiation of the GABA signal was observed with these compounds, while the effect of 8 was not inhibited by flumazenil, a negative allosteric modulator at the benzodiazepine binding site. Finally, the activity was validated in voltage clamp studies on Xenopus laevis oocytes transiently expressing GABAA receptors of the α1ß2γ2S and α1ß2 subtypes. Compound 8 potentiated GABA-induced currents with both receptor subunit compositions [EC50 (α1ß2γ2S) = 43.6 µM; Emax = 809% and EC50 (α1ß2) = 57.6 µM; Emax = 534%]. The positive modulation of GABA-induced currents was not inhibited by flumazenil, thereby confirming an allosteric modulation independent of the benzodiazepine binding site.


Assuntos
Casearia , Diterpenos Clerodânicos , Animais , Benzodiazepinas/farmacologia , Células CHO , Cricetinae , Cricetulus , Diterpenos Clerodânicos/farmacologia , Flumazenil/metabolismo , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Oócitos/metabolismo , Receptores de GABA-A , Xenopus laevis/metabolismo , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
11.
Molecules ; 27(6)2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35335130

RESUMO

Natural products can act as potential GABA modulators, avoiding the undesirable effects of traditional pharmacology used for the inhibition of the central nervous system such as benzodiazepines (BZD). Phenolics, especially flavonoids and phlorotannins, have been considered as modulators of the BZD-site of GABAA receptors (GABAARs), with sedative, anxiolytic or anticonvulsant effects. However, the wide chemical structural variability of flavonoids shows their potential action at more than one additional binding site on GABAARs, which may act either negatively, positively, by neutralizing GABAARs, or directly as allosteric agonists. Therefore, the aim of the present review is to compile and discuss an update of the role of phenolics, namely as pharmacological targets involving dysfunctions of the GABA system, analyzing both their different compounds and their mechanism as GABAergic modulators. We focus this review on articles written in English since the year 2010 until the present. Of course, although more research would be necessary to fully establish the type specificity of phenolics and their pharmacological activity, the evidence supports their potential as GABAAR modulators, thereby favoring their inclusion in the development of new therapeutic targets based on natural products. Specifically, the data compiled in this review allows for the directing of future research towards ortho-dihydroxy diterpene galdosol, the flavonoids isoliquiritigenin (chalcone), rhusflavone and agathisflavone (biflavonoids), as well as the phlorotannins, dieckol and triphlorethol A. Clinically, flavonoids are the most interesting phenolics due to their potential as anticonvulsant and anxiolytic drugs, and phlorotannins are also of interest as sedative agents.


Assuntos
Moduladores GABAérgicos , Receptores de GABA-A , Benzodiazepinas/metabolismo , Sítios de Ligação , Moduladores GABAérgicos/farmacologia , Ligantes , Receptores de GABA-A/metabolismo
12.
Biol Psychiatry ; 91(3): 283-293, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34561029

RESUMO

BACKGROUND: Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABAA (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects. METHODS: We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states. RESULTS: We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABAA receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6-12 Hz) through δ-containing GABAA receptors, a mechanism distinct from other GABAA positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress-induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress. CONCLUSIONS: Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Pregnanolona , Animais , Antidepressivos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Feminino , Moduladores GABAérgicos , Camundongos , Pregnanolona/farmacologia , Ratos , Receptores de GABA-A/metabolismo
13.
J Neurosci ; 41(45): 9350-9360, 2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34732523

RESUMO

Aging is associated with cognitive impairment, but there are large individual differences in these declines. One neural measure that is lower in older adults and predicts these individual differences is moment-to-moment brain signal variability. Testing the assumption that GABA should heighten neural variability, we examined whether reduced brain signal variability in older, poorer performing adults could be boosted by increasing GABA pharmacologically. Brain signal variability was estimated using fMRI in 20 young and 24 older healthy human adults during placebo and GABA agonist sessions. As expected, older adults exhibited lower signal variability at placebo, and, crucially, GABA agonism boosted older adults' variability to the levels of young adults. Furthermore, poorer performing older adults experienced a greater increase in variability on drug, suggesting that those with more to gain benefit the most from GABA system potentiation. GABA may thus serve as a core neurochemical target in future work on aging- and cognition-related human brain dynamics.SIGNIFICANCE STATEMENT Prior research indicates that moment-to-moment brain signal variability is lower in older, poorer performing adults. We found that this reduced brain signal variability could be boosted through GABA agonism in older adults to the levels of young adults and that this boost was largest in the poorer performing older adults. These results provide the first evidence that brain signal variability can be restored by increasing GABAergic activity and suggest the promise of developing interventions targeting inhibitory systems to help slow cognitive declines in healthy aging.


Assuntos
Envelhecimento/fisiologia , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Lorazepam/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto Jovem
14.
Neurotherapeutics ; 18(3): 1564-1581, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34386906

RESUMO

Neonatal seizures are a common neurologic emergency for which therapies have not significantly changed in decades. Improvements in diagnosis and pathophysiologic understanding of the distinct features of acute symptomatic seizures and neonatal-onset epilepsies present exceptional opportunities for development of precision therapies with potential to improve outcomes. Herein, we discuss the pathophysiology of neonatal seizures and review the evidence for currently available treatment. We present emerging therapies in clinical and preclinical development for the treatment of acute symptomatic neonatal seizures. Lastly, we discuss the role of precision therapies for genetic neonatal-onset epilepsies and address barriers and goals for developing new therapies for clinical care.


Assuntos
Anticonvulsivantes/uso terapêutico , Eletroencefalografia/métodos , Moduladores GABAérgicos/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Animais , Anticonvulsivantes/farmacologia , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Eletroencefalografia/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Humanos , Recém-Nascido , Canais de Potássio/agonistas , Canais de Potássio/fisiologia , Convulsões/diagnóstico
15.
Nat Neurosci ; 24(10): 1392-1401, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34400844

RESUMO

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO's synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.


Assuntos
Cerebelo/crescimento & desenvolvimento , Glândulas Endócrinas/fisiologia , Placenta/fisiologia , Pregnanolona/deficiência , Pregnanolona/fisiologia , Comportamento Social , Aldeído Redutase/genética , Animais , Transtorno do Espectro Autista/etiologia , Cerebelo/fisiologia , Feminino , Agonistas GABAérgicos/farmacologia , Moduladores GABAérgicos , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Muscimol/farmacologia , Gravidez , Receptores de GABA-A/fisiologia , Caracteres Sexuais , Trofoblastos/metabolismo , Substância Branca/patologia
16.
Biochem Pharmacol ; 192: 114711, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324871

RESUMO

Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (NaV1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABAA receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of NaV1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA.


Assuntos
Clonazepam/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Neurônios GABAérgicos/imunologia , Transtornos Mentais/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Transmissão Sináptica/imunologia , Animais , Clonazepam/farmacologia , Feminino , Moduladores GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Agonistas de Receptores de GABA-A/uso terapêutico , Neurônios GABAérgicos/química , Neurônios GABAérgicos/efeitos dos fármacos , Masculino , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Canal de Sódio Disparado por Voltagem NAV1.1/biossíntese , Canal de Sódio Disparado por Voltagem NAV1.1/imunologia , Poli I-C/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Receptores de GABA-A/imunologia , Transmissão Sináptica/efeitos dos fármacos
17.
Toxicol Appl Pharmacol ; 426: 115643, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265354

RESUMO

The chemical threat agent tetramethylenedisulfotetramine (TETS) is a γ-aminobutyric acid type A receptor (GABA AR) antagonist that causes life threatening seizures. Currently, there is no specific antidote for TETS intoxication. TETS-induced seizures are typically treated with benzodiazepines, which function as nonselective positive allosteric modulators (PAMs) of synaptic GABAARs. The major target of TETS was recently identified as the GABAAR α2ß3γ2 subtype in electrophysiological studies using recombinantly expressed receptor combinations. Here, we tested whether these in vitro findings translate in vivo by comparing the efficacy of GABAAR subunit-selective PAMs in reducing TETS-induced seizure behavior in larval zebrafish. We tested PAMs targeting α1, α2, α2/3/5, α6, ß2/3, ß1/2/3, and δ subunits and compared their efficacy to the benzodiazepine midazolam (MDZ). The data demonstrate that α2- and α6-selective PAMs (SL-651,498 and SB-205384, respectively) were effective at mitigating TETS-induced seizure-like behavior. Combinations of SB-205384 and MDZ or SL-651,498 and 2-261 (ß2/3-selective) mitigated TETS-induced seizure-like behavior at concentrations that did not elicit sedating effects in a photomotor behavioral assay, whereas MDZ alone caused sedation at the concentration required to stop seizure behavior. Isobologram analyses suggested that SB-205384 and MDZ interacted in an antagonistic fashion, while the effects of SL-651,498 and 2-261 were additive. These results further elucidate the molecular mechanism by which TETS induces seizures and provide mechanistic insight regarding specific countermeasures against this chemical convulsant.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Convulsivantes , Moduladores GABAérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Subunidades Proteicas/fisiologia , Receptores de GABA-A/fisiologia , Convulsões/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Larva , Locomoção/efeitos dos fármacos , Midazolam/farmacologia , Subunidades Proteicas/genética , Receptores de GABA-A/genética , Convulsões/fisiopatologia , Peixe-Zebra
18.
Phytomedicine ; 90: 153646, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34280827

RESUMO

BACKGROUND: Gamma-aminobutyric acid A (GABAA) receptors have been implicated in anxiety and epileptic disorders. HYPOTHESIS/PURPOSE: This study aimed to investigate the effects of stigmasterol, a plant sterol (phytosterol) isolated from Artemisia indica Linn on neurological disorders. METHODS: Stigmasterol was evaluated on various recombinant GABAA receptor subtypes expressed in Xenopus laevis oocytes and its anxiolytic and anticonvulsant potential was assessed using the elevated plus maze (EPM), light-dark box (LDB) test, and pentylenetetrazole- (PTZ-) induced seizure paradigms. Furthermore, computational modeling of α2ß2γ2L, α4ß3δ, and α4ß3 subtypes was performed to gain insights into the GABAergic mechanism of stigmasterol. For the first time, a model of GABAδ subtype was generated. Stigmasterol was targeted to all the binding sites (neurotransmitters, positive and negative modulator binding sites) of GABAA α2ß2γ2L, α4ß3, and α4ß3δ complexes by in silico docking. RESULTS: Stigmasterol enhanced GABA-induced currents at ternary α2ß2γ2L, α4ß3δ, and binary α4ß3 GABAAR subtypes. The potentiation of GABA-induced currents at extrasynaptic α4ß3δ was significantly higher compared to the binary α4ß3 subtype, indicating that the δ subunit is important for efficacy. Stigmasterol was found to be a potent positive modulator of the extrasynaptic α4ß3δ subtype, which was also confirmed by computational analysis. The computational analysis reveals that stigmasterol preferentially binds at the transmembrane region shared by positive modulators or a binding site constituted by the M2-M3 region of α4 and M1-M2 of ß3 at α4ß3δ complex. In in vivo studies, Stigmasterol (0.5-3.0 mg/kg, i.p.) exerted significant anxiolytic and anticonvulsant effects in an identical manner of allopregnanolone, indicating the involvement of a GABAergic mechanism. CONCLUSION: To our knowledge, this is the first study reporting the positive modulation of GABAA receptors, anxiolytic and anticonvulsant potential of stigmasterol. Thus, stigmasterol is considered to be a candidate steroidal drug for the treatment of neurological disorders due to its positive modulation of GABA receptors.


Assuntos
Ansiolíticos , Anticonvulsivantes/farmacologia , Moduladores GABAérgicos/farmacologia , Estigmasterol , Animais , Ansiolíticos/farmacologia , Oócitos , Receptores de GABA-A , Convulsões/tratamento farmacológico , Estigmasterol/farmacologia , Xenopus laevis
19.
Toxicol Appl Pharmacol ; 426: 115616, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102243

RESUMO

Oxytetracycline (OTC) is one of the broad-spectrum antibiotics widely used for the treatment of fish-farm infection. Considering that behavior is directly related to reproduction, individual fitness, and survival, it is important to evaluate the impact of antibiotics on the behavioral repertoire in fish. Zebrafish (Danio rerio) presents a well-described behavioral repertoire to reliably demonstrate complex responses to chemical compound exposure. This work aims to identify the role of OTC in comprehensive behavioral parameters and whole-body cortisol levels in adult zebrafish. Here we report that OTC exposure (10, 20, and 100 mg/L) induces an anxiogenic-like phenotype in the novel tank test. OTC exposure also changes the behavior of social interaction with a shoal of unknown zebrafish - characterized as a stimulus group. Zebrafish exposed to OTC (10 mg/L) remains a longer period in the stimulus zone when compared to the control group. Clonazepam (0.006 mg/L) was able to reverse anxiogenic-like behavior and the changes in social behavior induced by OTC. We also demonstrated that cortisol levels were significantly decreased after exposure to OTC (10, 20, and 100 mg/L), which were not reversed by clonazepam. These findings highlight the growing utility of zebrafish as a model to understand the impact of antibiotics on behavior and their underlying mechanisms.


Assuntos
Antibacterianos/efeitos adversos , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Oxitetraciclina/efeitos adversos , Peixe-Zebra , Animais , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Aquicultura , Clonazepam/uso terapêutico , Feminino , Moduladores GABAérgicos/uso terapêutico , Hidrocortisona/metabolismo , Masculino
20.
JAMA Psychiatry ; 78(9): 951-959, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34190962

RESUMO

Importance: Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. Objective: To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD. Design, Setting, and Participants: This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019. Interventions: Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks. Main Outcomes and Measures: Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments. Results: Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo. Conclusions and Relevance: In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD. Trial Registration: ClinicalTrials.gov Identifier: NCT02978326.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Moduladores GABAérgicos/farmacologia , Pregnanos/farmacologia , Pirazóis/farmacologia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Período Pós-Parto , Gravidez , Terceiro Trimestre da Gravidez , Pregnanos/administração & dosagem , Pregnanos/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Adulto Jovem
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