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1.
Methods Mol Biol ; 2798: 195-203, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38587744

RESUMO

Gamma-aminobutyric acid (GABA) is an amino acid that has a role as a signaling molecule. In plants, its involvement in stress responses is widely investigated. A newly developed method of quantification of GABA is described in this chapter. The assay kit consisting of three bacterial enzymes enables easy but accurate measurement of GABA (~200 mg/mL) based on the serial enzymatic reaction leading to dye formation. The method was successfully applied to measure the GABA content in several plant tissues.


Assuntos
Aminoácidos , Ácido gama-Aminobutírico , Bioensaio , Ensaios Enzimáticos
2.
Proc Natl Acad Sci U S A ; 121(15): e2318041121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38568976

RESUMO

Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters regulate the stabilization of postsynaptic transmitter receptors. Whether postsynaptic receptors regulate stabilization of presynaptic transmitters has received less attention. Here, we show that blockade of endogenous postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction destabilizes the cholinergic phenotype in motor neurons and stabilizes an earlier, developmentally transient glutamatergic phenotype. Further, expression of exogenous postsynaptic gamma-aminobutyric acid type A receptors (GABAA receptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABAA receptors are linked to presynaptic neurons through transsynaptic bridges. Knockdown of specific components of these transsynaptic bridges prevents stabilization of the cholinergic or GABAergic phenotypes. Bidirectional communication can enforce a match between transmitter and receptor and ensure the fidelity of synaptic transmission. Our findings suggest a potential role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.


Assuntos
Receptores Colinérgicos , Sinapses , Sinapses/metabolismo , Receptores Colinérgicos/metabolismo , Transmissão Sináptica/fisiologia , Neurônios Motores/metabolismo , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Neurotransmissores/metabolismo , Colinérgicos , Receptores Pré-Sinápticos
4.
Cell Death Dis ; 15(4): 249, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38582872

RESUMO

Acyl-CoA binding protein (ACBP) encoded by diazepam binding inhibitor (DBI) is an extracellular inhibitor of autophagy acting on the gamma-aminobutyric acid A receptor (GABAAR) γ2 subunit (GABAARγ2). Here, we show that lipoanabolic diets cause an upregulation of GABAARγ2 protein in liver hepatocytes but not in other major organs. ACBP/DBI inhibition by systemically injected antibodies has been demonstrated to mediate anorexigenic and organ-protective, autophagy-dependent effects. Here, we set out to develop a new strategy for developing ACBP/DBI antagonists. For this, we built a molecular model of the interaction of ACBP/DBI with peptides derived from GABAARγ2. We then validated the interaction between recombinant and native ACBP/DBI protein and a GABAARγ2-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABAARγ2-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP/DBI protein in vitro. Moreover, the GABAARγ2-derived eicosapeptide (but not its F77I-mutated control) blocked appetite stimulation by recombinant ACBP/DBI in vivo, induced autophagy in the liver, and protected mice against the hepatotoxin concanavalin A. We conclude that peptidomimetics disrupting the interaction between ACBP/DBI and GABAARγ2 might be used as ACBP/DBI antagonists. This strategy might lead to the future development of clinically relevant small molecules of the ACBP/DBI system.


Assuntos
Inibidor da Ligação a Diazepam , Ácido gama-Aminobutírico , Animais , Camundongos , Inibidor da Ligação a Diazepam/farmacologia
5.
Int. microbiol ; 27(2): 505-512, Abr. 2024. graf, tab
Artigo em Inglês | IBECS | ID: ibc-ADZ-161

RESUMO

As a consequence of alcoholic fermentation (AF) in wine, several compounds are released by yeasts, and some of them are linked to the general quality and mouthfeel perceptions in wine. However, others, such as succinic acid, act as inhibitors, mainly of malolactic fermentation. Succinic acid is produced by non-Saccharomyces and Saccharomyces yeasts during the initial stages of AF, and the presence of some amino acids such as γ-aminobutyric acid (GABA) and glutamic acid can increase the concentration of succinic acid. However, the influence of these amino acids on succinic acid production has been studied very little to date. In this work, we studied the production of succinic acid by different strains of non-Saccharomyces and Saccharomyces yeasts during AF in synthetic must, and the influence of the addition of GABA or glutamic acid or a combination of both. The results showed that succinic acid can be produced by non-Saccharomyces yeasts with values in the range of 0.2–0.4 g/L. Moreover, the addition of GABA or glutamic acid can increase the concentration of succinic acid produced by some strains to almost 100 mg/L more than the control, while other strains produce less. Consequently, higher succinic acid production by non-Saccharomyces yeast in coinoculated fermentations with S. cerevisiae strains could represent a risk of inhibiting Oenococcus oeni and therefore the MLF.(AU)


Assuntos
Humanos , Ácido Succínico , Ácido Glutâmico , Aminoácidos , Saccharomyces cerevisiae , Vinho/análise , Vinho/microbiologia , Ácido gama-Aminobutírico , Microbiologia , Leveduras , Fermentação
6.
Int J Mol Sci ; 25(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38473763

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in reduced dopamine levels in the striatum and eventual onset of motor symptoms. Linalool (3,7-dimethyl-1,6-octadien-3-ol) is a monoterpene in aromatic plants exhibiting antioxidant, antidepressant, and anti-anxiety properties. The objective of this study is to evaluate the neuroprotective impacts of linalool on dopaminergic SH-SY5Y cells, primary mesencephalic and cortical neurons treated with 1-methyl-4-phenylpyridinium ion (MPP+), as well as in PD-like mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell viability, α-tubulin staining, western blotting, immunohistochemistry and behavioral experiments were performed. In MPP+-treated SH-SY5Y cells, linalool increased cell viability, reduced neurite retraction, enhanced antioxidant defense by downregulation of apoptosis signaling (B-cell lymphoma 2 (Bcl-2), cleaved caspase-3 and poly ADP-ribose polymerase (PARP)) and phagocyte NADPH oxidase (gp91phox), as well as upregulation of neurotrophic signaling (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) and nuclear factor-erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. In MPP+-treated primary mesencephalic neurons, linalool enhanced the expressions of tyrosine hydroxylase (TH), Sirtuin 1 (SirT1), and parkin. In MPP+-treated primary cortical neurons, linalool upregulated protein expression of SirT1, γ-Aminobutyric acid type A-α1 (GABAA-α1), and γ-Aminobutyric acid type B (GABAB). In PD-like mice, linalool attenuated the loss of dopamine neurons in SNpc. Linalool improved the motor and nonmotor behavioral deficits and muscle strength of PD-like mice. These findings suggest that linalool potentially protects dopaminergic neurons and improves the impairment symptoms of PD.


Assuntos
Monoterpenos Acíclicos , Neuroblastoma , Fármacos Neuroprotetores , Doença de Parkinson , Humanos , Camundongos , Animais , Doença de Parkinson/metabolismo , Neurônios Dopaminérgicos/metabolismo , Antioxidantes/metabolismo , Odorantes , Sirtuína 1/metabolismo , Fármacos Neuroprotetores/farmacologia , Neuroblastoma/metabolismo , 1-Metil-4-fenilpiridínio , Força Muscular , Modelos Teóricos , Ácido gama-Aminobutírico/metabolismo
7.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473838

RESUMO

The occurrence, inhibitory modulation, and trophic effects of GABA have been identified in the peripheral sympathetic nervous system. We have demonstrated that GABA and acetylcholine (ACh) may colocalize in the same axonal varicosities or be segregated into separate ones in the rat superior cervical ganglia (SCG). Neurotransmitter segregation varies with age and the presence of neurotrophic factors. Here, we explored age-dependent changes in the occurrence and segregation of GABA and ACh in rats ranging from 2 weeks old (wo) to 12 months old or older. Using immunohistochemistry, we characterized the expression of L-glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular acetylcholine transporter (VAChT) in the rat SCG at 2, 4, 8, 12 wo and 12 months old or older. Our findings revealed that GAD67 was greater at 2 wo compared with the other ages, whereas VAChT levels were greater at 4 wo than at 12 wo and 12 months old or older. The segregation of these neurotransmitters was more pronounced at 2 and 4 wo. We observed a caudo-rostral gradient of segregation degree at 8 and 12 wo. Data point out that the occurrence and segregation of GABA and ACh exhibit developmental adaptative changes throughout the lifetime of rats. We hypothesize that during the early postnatal period, the increase in GABA and GABA-ACh segregation promotes the release of GABA alone which might play a role in trophic actions.


Assuntos
Acetilcolina , Gânglio Cervical Superior , Ratos , Animais , Acetilcolina/metabolismo , Axônios/metabolismo , Ácido gama-Aminobutírico/metabolismo
8.
Handb Clin Neurol ; 200: 151-172, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38494275

RESUMO

Seizures are a common feature of autoimmune encephalitis and are especially prevalent in patients with the commonest autoantibodies, against LGI1, CASPR2 and the NMDA, GABAB, and GABAA receptors. In this chapter, we discuss the classification, clinical, investigation, and treatment aspects of patients with these, and other autoantibody-mediated and -associated, illnesses. We highlight distinctive and common seizure semiologies which, often alongside other features we outline, can help the clinical diagnosis of an autoantibody-associated syndrome. Next, we classify these syndromes by either focusing on whether they represent underlying causative autoantibodies or T-cell-mediated syndromes and on the distinction between acute symptomatic seizures and a more enduring tendency to autoimmune-associated epilepsy, a practical and valuable distinction for both patients and clinicians which relates to the pathogenesis. We emphasize the more effective immunotherapy response in patients with causative autoantibodies, and discuss the emerging evidence for various first-, second-, and third-line immunotherapies. Finally, we highlight available clinical rating scales which can guide autoantibody testing and immunotherapy in patients with seizures of unknown etiology. Throughout, we relate the clinical and therapeutic observations to the immunobiology and neuroscience which drive these seizures.


Assuntos
Encefalite , Epilepsia , Humanos , Convulsões/diagnóstico , Convulsões/etiologia , Convulsões/terapia , Epilepsia/diagnóstico , Encefalite/complicações , Encefalite/diagnóstico , Encefalite/terapia , Autoanticorpos , Ácido gama-Aminobutírico
9.
Cereb Cortex ; 34(3)2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38430105

RESUMO

Human brain development is ongoing throughout childhood, with for example, myelination of nerve fibers and refinement of synaptic connections continuing until early adulthood. 1H-Magnetic Resonance Spectroscopy (1H-MRS) can be used to quantify the concentrations of endogenous metabolites (e.g. glutamate and γ -aminobutyric acid (GABA)) in the human brain in vivo and so can provide valuable, tractable insight into the biochemical processes that support postnatal neurodevelopment. This can feasibly provide new insight into and aid the management of neurodevelopmental disorders by providing chemical markers of atypical development. This study aims to characterize the normative developmental trajectory of various brain metabolites, as measured by 1H-MRS from a midline posterior parietal voxel. We find significant non-linear trajectories for GABA+ (GABA plus macromolecules), Glx (glutamate + glutamine), total choline (tCho) and total creatine (tCr) concentrations. Glx and GABA+ concentrations steeply decrease across childhood, with more stable trajectories across early adulthood. tCr and tCho concentrations increase from childhood to early adulthood. Total N-acetyl aspartate (tNAA) and Myo-Inositol (mI) concentrations are relatively stable across development. Trajectories likely reflect fundamental neurodevelopmental processes (including local circuit refinement) which occur from childhood to early adulthood and can be associated with cognitive development; we find GABA+ concentrations significantly positively correlate with recognition memory scores.


Assuntos
Ácido Glutâmico , Glutamina , Criança , Humanos , Adolescente , Adulto Jovem , Glutamina/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Ácido Glutâmico/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Colina/metabolismo , Creatina/metabolismo , Inositol/metabolismo , Ácido gama-Aminobutírico/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Ácido Aspártico/metabolismo
10.
Adv Ther ; 41(4): 1351-1371, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38443647

RESUMO

Stiripentol (Diacomit®) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet syndrome (DS), a severe form of childhood epilepsy, in conjunction with clobazam and, in some regions valproic acid. Since the discovery of STP, several mechanisms of action (MoA) have been described that may explain its specific effect on seizures associated with DS. STP is mainly considered as a potentiator of gamma-aminobutyric acid (GABA) neurotransmission: (i) via uptake blockade, (ii) inhibition of degradation, but also (iii) as a positive allosteric modulator of GABAA receptors, especially those containing α3 and δ subunits. Blockade of voltage-gated sodium and T-type calcium channels, which is classically associated with anticonvulsant and neuroprotective properties, has also been demonstrated for STP. Finally, several studies indicate that STP could regulate glucose energy metabolism and inhibit lactate dehydrogenase. STP is also an inhibitor of several cytochrome P450 enzymes involved in the metabolism of other ASMs, contributing to boost their anticonvulsant efficacy as add-on therapy. These different MoAs involved in treatment of DS and recent data suggest a potential for STP to treat other neurological or non-neurological diseases.


Assuntos
Dioxolanos , Epilepsias Mioclônicas , Humanos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Dioxolanos/farmacologia , Dioxolanos/uso terapêutico , Convulsões/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Ácido gama-Aminobutírico
11.
J Med Food ; 27(3): 231-241, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38502788

RESUMO

Various neurotransmitters are involved in regulating stress systems. In this study, we investigated the effects of gamma-aminobutyric acid-rich rice bran extract (GRBe) in mice stressed by forced swimming and tail suspension tests. Four weeks of oral administration of GRBe (500-2000 mg/kg) reduced the levels of dopamine and corticosterone in the blood and brain while increasing serotonin levels. GRBe was involved not only in stress but also in regulating sleep and obesity-related genes. Modern society experiences diverse and tense lives because of urbanization and informatization, which cause excessive stress due to complicated interpersonal relationships, heavy work burden, and fatigue from the organized society. High levels of stress cause psychological instability and disrupt the balance in the autonomic nervous system, which maintains the body's equilibrium, resulting in cardiovascular and cerebrovascular diseases, hormonal imbalances, and sleep disorders. Therefore, our results suggest that GRBe is a useful substance that can relieve tension by ultimately influencing a depressive-like state by lowering the levels of neuronal substances, hormones, and cytokines involved in stress and sleep disorders.


Assuntos
Produtos Biológicos , Oryza , Transtornos do Sono-Vigília , Camundongos , Animais , Depressão/tratamento farmacológico , Natação , Ácido gama-Aminobutírico , Modelos Animais de Doenças , Estresse Psicológico/tratamento farmacológico
12.
Syst Rev ; 13(1): 92, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509623

RESUMO

BACKGROUND: Antidepressants, noninvasive brain stimulation (NIBS), and their combination are commonly used in routine clinical practice. Nevertheless, there is a continuous dispute regarding whether the effectiveness of NIBS in combination with antidepressants exceeds that of antidepressants alone. This meta-analysis aimed to evaluate the existing evidence and draw a definitive conclusion on this issue. METHODS: We conducted a comprehensive search of five databases: Embase, PubMed, Web of Science, SinoMed, and the Cochrane Database of Randomized Controlled Trials. The search was conducted until October 6, 2023. The primary outcomes were the pre- and post-intervention depression and anxiety scores. Secondary outcomes included dropout rates, response rates, and certain levels of neurotransmitters [ 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma-aminobutyric acid (GABA)] at the end of the intervention. Subgroup, meta-regression, and sensitivity analyses were performed to explore the sources of heterogeneity. The data were analysed using R 4.2.2. RESULTS: We included 18 RCTs [1357 participants; 11 studies used repetitive transcranial magnetic stimulation (rTMS) and 7 studies used transcranial direct current stimulation (tDCS)]. The follow-up duration varied from two weeks to three months. Overall, whether in combination with rTMS or tDCS, antidepressants proved more effective in alleviating depressive symptoms compared to when used as monotherapy. However, this advantage was not evident during the follow-up period. (p > 0.05). And the combination's efficacy in improving anxiety was found to be lacking. Post-treatment serum levels of 5-HT, DA, and GABA were higher in the rTMS group were higher than antidepressant medication group (p < 0.05). Furthermore, subgroup analysis results indicated that only the rTMS + antidepressant medication treatment significantly improved remission and remission rates. The meta-regression results showed that the type of antidepressant and the sex of the participants had a significant association with the depression score. CONCLUSION: Combination treatment with NIBS was significantly more effective in improving depression symptoms than medication alone. rTMS combined with antidepressants appears to be more effective in improving response and remission rates. However, efficacy may be influenced by the type of medicine used in combination, and long-term efficacy data is lacking. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023388259.


Assuntos
Estimulação Transcraniana por Corrente Contínua , Humanos , Depressão/tratamento farmacológico , Serotonina , Ensaios Clínicos Controlados Aleatórios como Assunto , Antidepressivos/uso terapêutico , Estimulação Magnética Transcraniana/métodos , Ácido gama-Aminobutírico , Encéfalo/fisiologia
13.
J Integr Neurosci ; 23(3): 51, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38538228

RESUMO

BACKGROUND: The flavonoid chrysin produces rapid and long-lasting anxiolytic- and antidepressant-like effects in rats. However, it is not known whether low and high doses of chrysin produce differential anti-immobility effects through the Gamma-Aminobutyric Acid sub-type A (GABAA) receptor. The goal of this work was therefore to compare low and high doses of chrysin for their effects on depression-like behavior in a longitudinal study. Moreover, chrysin was compared with the serotonergic fluoxetine and Gamma-Aminobutyric Acid (GABA)ergic allopregnanolone, and its involvement with the GABAA receptor after chronic treatment was also investigated. METHODS: Male Wistar rats were assigned to five groups (n = 8 each): vehicle, 1 mg/kg chrysin, 5 mg/kg chrysin, 1 mg/kg fluoxetine, and 1 mg/kg allopregnanolone. In the first experiment, treatments were injected daily and the effects on locomotor activity and the forced swim test were evaluated at 0, 1, 14, and 28 days of treatment, and 48 h after the final treatment. In the second experiment, similar groups were treated for 28 days with injection of 1 mg/kg picrotoxin to investigate the role of the GABAA receptor. Depending on the experimental design, one- and two-way analysis of variance (ANOVA) tests were used for statistical analysis, with p < 0.05 set as the criteria for significance. RESULTS: In both experiments, the treatments did not alter locomotor activity. However, low and high doses of chrysin, allopregnanolone, and fluoxetine gradually produced antidepressant-like effects in the forced swim test, and maintained this effect for 48 h post-treatment, except with low dose chrysin. Picrotoxin blocked the antidepressant-like effects produced by low dose chrysin, but did not affect those produced by high dose chrysin, allopregnanolone, or fluoxetine. CONCLUSIONS: The differential antidepressant-like effects caused by low and high doses of chrysin are time-dependent. Low dose chrysin produces a rapid antidepressant-like effect, whereas high dose chrysin produces a delayed but sustained the effect, even 48 h after withdrawal. The effect with high dose chrysin was similar to that observed with allopregnanolone and fluoxetine. The mechanism for the antidepressant-like effect of low chrysin appears to be GABAergic, whereas the effect of high dose chrysin may involve other neurotransmission and neuromodulation systems related to the serotonergic system.


Assuntos
Fluoxetina , Receptores de GABA-A , Ratos , Masculino , Animais , Fluoxetina/farmacologia , Pregnanolona , Ratos Wistar , Receptores de GABA , Picrotoxina , Estudos Longitudinais , Antidepressivos/farmacologia , Flavonoides/farmacologia , Ácido gama-Aminobutírico
14.
Biomed Pharmacother ; 173: 116392, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38479183

RESUMO

Gamma-aminobutyric acid (GABA) neuronal system-related transcription factors (TFs) play a critical role in GABA production, and GABA modulates diabetic neuropathic pain (DNP). The present study investigated the therapeutic effects of intrathecal delivery of two TFs achaete-scute homolog 1 (Ascl1) and LIM homeobox protein 6 (Lhx6) in a mouse model of DNP and elucidated their underlying mechanisms. GABA-related specific TFs, including Ascl1, Lhx6, distal-less homeobox 1, distal-less homeobox 5, the Nkx2.1 homeobox gene, and the Nkx2.2 homeobox gene, were investigated under normal and diabetic conditions. Among these, the expression of Ascl1 and Lhx6 was significantly downregulated in mice with diabetes. Therefore, a single intrathecal injection of combined lenti-Ascl1/Lhx6 was performed. Intrathecal delivery of lenti-Ascl1/Lhx6 significantly relieved mechanical allodynia and heat hyperalgesia in mice with DNP. Ascl1/Lhx6 delivery also reduced microglial activation, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-1ß, increased the levels of anti-inflammatory cytokines including IL-4, IL-10, and IL-13, and reduced the activation of p38, c-Jun N-terminal kinase, and NF-κB in the spinal cord of mice with DNP, thereby reducing DNP. The results of this study suggest that intrathecal Ascl1/Lhx6 delivery attenuates DNP via upregulating spinal GABA neuronal function and inducing anti-inflammatory effects.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Neuralgia , Ratos , Camundongos , Animais , Ratos Sprague-Dawley , Doenças Neuroinflamatórias , Microglia/metabolismo , Medula Espinal/metabolismo , Citocinas/metabolismo , Neuropatias Diabéticas/metabolismo , Hiperalgesia/metabolismo , Anti-Inflamatórios/uso terapêutico , Ácido gama-Aminobutírico/metabolismo , Diabetes Mellitus/tratamento farmacológico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
15.
Int J Mol Sci ; 25(6)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38542102

RESUMO

The preBötzinger complex (preBötC) and the Bötzinger complex (BötC) are interconnected neural circuits that are involved in the regulation of breathing in mammals. Fast inhibitory neurotransmission is known to play an important role in the interaction of these two regions. Moreover, the corelease of glycine and GABA has been described in the respiratory network, but the contribution of the individual neurotransmitter in different pathways remains elusive. In sagittal brainstem slices of neonatal mice, we employed a laser point illumination system to activate glycinergic neurons expressing channelrhodopsin-2 (ChR2). This approach allowed us to discern the contribution of glycine and GABA to postsynaptic currents of individual whole-cell clamped neurons in the preBötC and BötC through the application of glycine and GABA receptor-specific antagonists. In more than 90% of the recordings, both transmitters contributed to the evoked IPSCs, with the glycinergic component being larger than the GABAergic component. The GABAergic component appeared to be most prominent when stimulation and recording were both performed within the preBötC. Taken together, our data suggest that GABA-glycine cotransmission is the default mode in the respiratory network of neonatal mice with regional differences that may be important in tuning the network activity.


Assuntos
Glicina , Ácido gama-Aminobutírico , Camundongos , Animais , Glicina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Transmissão Sináptica/fisiologia , Neurônios/metabolismo , Antagonistas GABAérgicos/farmacologia , Mamíferos/metabolismo
16.
Int J Mol Sci ; 25(6)2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38542362

RESUMO

Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABAA receptors (GABAARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC50 of 31.5 ± 1.7 and 40.6 ± 8.2 µM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABAARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.


Assuntos
Alcaloides , Gelsemium , Animais , Gelsemium/química , Alcaloides/química , Extratos Vegetais/química , Alcaloides Indólicos/química , Ácido gama-Aminobutírico , Mamíferos/metabolismo
17.
Neuropharmacology ; 249: 109897, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38462041

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopment disorder that affects approximately 5% of the population. The disorder is characterized by impulsivity, hyperactivity, and deficits in attention and cognition, although symptoms vary across patients due to the heterogenous and polygenic nature of the disorder. Stimulant medications are the standard of care treatment for ADHD patients, and their effectiveness has led to the dopaminergic hypothesis of ADHD in which deficits in dopaminergic signaling, especially in cortical brain regions, mechanistically underly ADHD pathophysiology. Despite their effectiveness in many individuals, almost one-third of patients do not respond to stimulant treatments and the long-term negative side effects of these medications remain unclear. Emerging clinical evidence is beginning to highlight an important role of dysregulated excitatory/inhibitory (E/I) balance in ADHD. These deficits in E/I balance are related to functional abnormalities in glutamate and Gamma-Aminobutyric Acid (GABA) signaling in the brain, with increasing emphasis placed on GABAergic interneurons driving specific aspects of ADHD pathophysiology. Recent genome-wide association studies (GWAS) have also highlighted how genes associated with GABA function are mutated in human populations with ADHD, resulting in the generation of several new genetic mouse models of ADHD. This review will discuss how GABAergic dysfunction underlies ADHD pathophysiology, and how specific receptors/proteins related to GABAergic interneuron dysfunction may be pharmacologically targeted to treat ADHD in subpopulations with specific comorbidities and symptom domains. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Animais , Camundongos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudo de Associação Genômica Ampla , Encéfalo , Dopamina , Ácido gama-Aminobutírico/genética
18.
Science ; 383(6688): 1252-1259, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38484078

RESUMO

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. In this study, we show that generalized fear in mice results from a transmitter switch from glutamate to γ-aminobutyric acid (GABA) in serotonergic neurons of the lateral wings of the dorsal raphe. Similar change in transmitter identity was found in the postmortem brains of individuals with posttraumatic stress disorder (PTSD). Overriding the transmitter switch in mice prevented the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors mediated the switch, and prompt antidepressant treatment blocked the cotransmitter switch and generalized fear. Our results provide important insight into the mechanisms involved in fear generalization.


Assuntos
Encéfalo , Medo , Generalização da Resposta , Ácido Glutâmico , Transtornos de Estresse Pós-Traumáticos , Estresse Psicológico , Ácido gama-Aminobutírico , Animais , Camundongos , Encéfalo/metabolismo , Medo/fisiologia , Ácido gama-Aminobutírico/metabolismo , Neurônios/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estresse Psicológico/metabolismo , Ácido Glutâmico/metabolismo , Corticosterona/metabolismo , Receptores de Glucocorticoides/metabolismo , Humanos
19.
Aging (Albany NY) ; 16(5): 4282-4298, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38441529

RESUMO

White matter hyperintensities (WMH) and gamma-aminobutyric acid (GABA) are associated with executive function. Multiple studies suggested cortical alterations mediate WMH-related cognitive decline. The aim of this study was to investigate the crucial role of cortical GABA in the WMH patients. In the 87 WMH patients (46 mild and 41 moderate to severe) examined in this study, GABA levels in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) assessed by the Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence, WMH volume and executive function were compared between the two groups. Partial correlation and mediation analyses were carried out to examine the GABA levels in mediating the association between WMH volume and executive function. Patients with moderate to severe WMH had lower GABA+/Cr in the ACC (p = 0.034) and worse executive function (p = 0.004) than mild WMH patients. In all WMH cases, the GABA+/Cr levels in the ACC mediated the negative correlation between WMH and executive function (ab: effect = -0.020, BootSE = 0.010, 95% CI: -0.042 to -0.004). This finding suggested GABA+/Cr levels in the ACC might serve as a protective factor or potential target for preventing the occurrence and progression of executive function decline in WMH people.


Assuntos
Disfunção Cognitiva , Substância Branca , Humanos , Função Executiva , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Disfunção Cognitiva/psicologia , Ácido gama-Aminobutírico
20.
Neurochem Int ; 175: 105720, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38458538

RESUMO

The anteroventral bed nucleus of stria terminalis (avBNST) is a key brain region which involves negative emotional states, such as anxiety. The most neurons in the avBNST are GABAergic, and it sends GABAergic projections to the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN), respectively. The VTA and DRN contain dopaminergic and serotonergic cell groups in the midbrain which regulate anxiety-like behaviors. However, it is unclear the role of GABAergic projections from the avBNST to the VTA and the DRN in the regulation of anxiety-like behaviors, particularly in Parkinson's disease (PD)-related anxiety. In the present study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, and decreased level of dopamine (DA) in the basolateral amygdala (BLA). Chemogenetic activation of avBNSTGABA-VTA or avBNSTGABA-DRN pathway induced anxiety-like behaviors and decreased DA or 5-HT release in the BLA in sham and 6-OHDA rats, while inhibition of avBNSTGABA-VTA or avBNSTGABA-DRN pathway produced anxiolytic-like effects and increased level of DA or 5-HT in the BLA. These findings suggest that avBNST inhibitory projections directly regulate dopaminergic neurons in the VTA and serotonergic neurons in the DRN, and the avBNSTGABA-VTA and avBNSTGABA-DRN pathways respectively exert impacts on PD-related anxiety-like behaviors.


Assuntos
Ansiolíticos , Doença de Parkinson , Núcleos Septais , Ratos , Animais , Núcleo Dorsal da Rafe/metabolismo , Área Tegmentar Ventral/metabolismo , Serotonina/metabolismo , Núcleos Septais/metabolismo , Oxidopamina/toxicidade , Ansiedade , Doença de Parkinson/metabolismo , Dopamina/metabolismo , Ansiolíticos/farmacologia , Neurônios Dopaminérgicos/metabolismo , Ácido gama-Aminobutírico/metabolismo
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