Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.452
Filtrar
1.
J Pharmacol Toxicol Methods ; 112: 107127, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34619314

RESUMO

Drug-induced convulsion is a severe adverse event; however, no useful biomarkers for it have been discovered. We propose a new method for predicting drug-induced convulsions in monkeys based on heart rate variability (HRV) and a machine learning technique. Because autonomic nervous activities are altered around the time of a convulsion and such alterations affect HRV, they may be predicted by monitoring HRV. In the proposed method, anomalous changes in multiple HRV parameters are monitored by means of a convulsion prediction model, and convulsion alarms are issued when abnormal changes in HRV are detected. The convulsion prediction model is constructed based on multivariate statistical process control (MSPC), a well-known anomaly detection algorithm in machine learning. In this study, HRV data were collected from four cynomolgus monkeys administered with multiple doses of pentylenetetrazol (PTZ) and picrotoxin (PTX), which are GABA receptor antagonists, as convulsant agents. In addition, low doses of pilocarpine (PILO) were administered as a negative control. Twelve HRV parameters in three hours after drug administration were monitored by means of the prediction model. The number and duration of convulsion alarms from HRV increased at medium and high doses of PTZ and PTX (1/3 or 1/4 of convulsion dose). On the other hand, the frequency of convulsion alarms did not increase with PILO. Although vomiting was observed in all drugs, convulsion alarms were not associated with the vomiting. Thus, convulsion alarms can be used as a biomarker for convulsions induced by GABA receptor antagonists.


Assuntos
Aprendizado de Máquina , Convulsões , Animais , Antagonistas GABAérgicos , Frequência Cardíaca , Macaca fascicularis , Convulsões/induzido quimicamente
2.
Sci Rep ; 11(1): 16133, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373508

RESUMO

The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.


Assuntos
Endocanabinoides/fisiologia , Região Hipotalâmica Lateral/fisiologia , Angústia Psicológica , Núcleos Septais/fisiologia , Animais , Antagonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas GABAérgicos/administração & dosagem , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Modelos Neurológicos , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Piridazinas/administração & dosagem , Ratos , Ratos Wistar , Núcleos Septais/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Taquicardia/fisiopatologia
3.
J Med Chem ; 64(10): 7033-7043, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33949869

RESUMO

In a program to identify pain treatments with low addiction potential, we isolated five steroids, conosteroids A-E (1-5), from the hypobranchial gland of the mollusk Conus geographus. Compounds 1-5 were active in a mouse dorsal root ganglion (DRG) assay that suggested that they might be analgesic. A synthetic analogue 6 was used for a detailed pharmacological study. Compound 6 significantly increased the pain threshold in mice in the hot-plate test at 2 and 50 mg/kg. Compound 6 at 500 nM antagonizes type-A γ-aminobutyric acid receptors (GABAARs). In a patch-clamp experiment, out of the six subunit combinations tested, 6 exhibited subtype selectivity, most strongly antagonizing α1ß1γ2 and α4ß3γ2 receptors (IC50 1.5 and 1.0 µM, respectively). Although the structures of 1-6 differ from those of known neuroactive steroids, they are cell-type-selective modulators of GABAARs, expanding the known chemical space of neuroactive steroids.


Assuntos
Analgésicos/química , Caramujo Conus/química , Antagonistas GABAérgicos/química , Neuroesteroides/química , Receptores de GABA/química , Potenciais de Ação/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Caramujo Conus/metabolismo , Modelos Animais de Doenças , Antagonistas GABAérgicos/isolamento & purificação , Antagonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/uso terapêutico , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Neuroesteroides/isolamento & purificação , Neuroesteroides/farmacologia , Neuroesteroides/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/patologia , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Receptores de GABA/metabolismo
4.
Anim Reprod Sci ; 229: 106764, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33991835

RESUMO

This study was conducted to evaluate the luteinizing hormone (LH) secretion pattern after gamma-aminobutyric acid (GABAA) antagonist to determine the effects of the GABAergic system on LH secretion during reproductive maturation in pre-pubertal Nellore heifers. Nellore heifers (n = 10) were administered a picrotoxin injection of 0.18 mg/kg, i.v. Blood samples were collected every 15 min for 3 h at different developmental stages (8, 10, 14 and 17 mo of age). Plasma concentrations of LH were quantified using an RIA (sensitivity of 0.04 ng/mL and CV of 15 %). There was an interaction between treatment and age (P = 0.034). Picrotoxin-treated heifers had lesser (P ≤  0.05) LH mean concentrations during a 3 h period at 10 and 17 mo of age compared to control heifers (P ≤  0.05). Comparing the period before and after Picrotoxin injection in the same animals, there was a 33 % decrease in LH concentration at 8 mo of age (P = 0.0165). These results indicate the GABAergic system has a stimulatory function in inducing LH secretion in pre-pubertal Nellore heifers. These findings corroborate previous results that GABA increases GnRH/LH secretion in other species during the pre-pubertal period.


Assuntos
Bovinos/fisiologia , Antagonistas GABAérgicos/farmacologia , Hormônio Luteinizante/sangue , Picrotoxina/farmacologia , Receptores de GABA/metabolismo , Maturidade Sexual/fisiologia , Animais , Bovinos/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de GABA/genética
5.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808762

RESUMO

Epilepsy is characterized by recurrent seizures due to abnormal hyperexcitation of neurons. Recent studies have suggested that the imbalance of excitation and inhibition (E/I) in the central nervous system is closely implicated in the etiology of epilepsy. In the brain, GABA is a major inhibitory neurotransmitter and plays a pivotal role in maintaining E/I balance. As such, altered GABAergic inhibition can lead to severe E/I imbalance, consequently resulting in excessive and hypersynchronous neuronal activity as in epilepsy. Phospholipase C (PLC) is a key enzyme in the intracellular signaling pathway and regulates various neuronal functions including neuronal development, synaptic transmission, and plasticity in the brain. Accumulating evidence suggests that neuronal PLC is critically involved in multiple aspects of GABAergic functions. Therefore, a better understanding of mechanisms by which neuronal PLC regulates GABAergic inhibition is necessary for revealing an unrecognized linkage between PLC and epilepsy and developing more effective treatments for epilepsy. Here we review the function of PLC in GABAergic inhibition in the brain and discuss a pathophysiological relationship between PLC and epilepsy.


Assuntos
Epilepsia/etiologia , Epilepsia/metabolismo , Receptores de GABA/metabolismo , Fosfolipases Tipo C/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Biomarcadores , Suscetibilidade a Doenças , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Antagonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/uso terapêutico , Humanos , Isoenzimas , Transdução de Sinais/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica
6.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810317

RESUMO

The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK's mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABAA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.


Assuntos
Analgésicos/farmacologia , Cromonas/farmacologia , Antagonistas GABAérgicos/farmacologia , Analgésicos/química , Animais , Sítios de Ligação , Cromonas/química , Antagonistas GABAérgicos/química , Camundongos , Simulação de Acoplamento Molecular , Nociceptividade , Ligação Proteica , Receptores de GABA/química , Receptores de GABA/metabolismo
7.
Br J Anaesth ; 126(6): 1141-1156, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33641936

RESUMO

BACKGROUND: Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood. METHODS: Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy. RESULTS: Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits. CONCLUSIONS: Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia.


Assuntos
Anestésicos Intravenosos/toxicidade , Comportamento Animal/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Córtex Motor/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Propofol/toxicidade , Animais , Animais Recém-Nascidos , Sinalização do Cálcio/efeitos dos fármacos , Teste de Labirinto em Cruz Elevado , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Camundongos Transgênicos , Córtex Motor/metabolismo , Córtex Motor/fisiopatologia , Inibição Neural/efeitos dos fármacos , Síndromes Neurotóxicas/fisiopatologia , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/psicologia , Teste de Campo Aberto/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Comportamento Social
8.
PLoS One ; 16(3): e0240074, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33711021

RESUMO

Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4ß2 nAChRs, MLA and DhßE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4ß2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/efeitos dos fármacos , Mecamilamina/farmacologia , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Bicuculina/farmacologia , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Mecamilamina/uso terapêutico , Antagonistas Nicotínicos/uso terapêutico , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Receptores Nicotínicos/química , Convulsões/prevenção & controle , Convulsões/veterinária , Transmissão Sináptica/efeitos dos fármacos
9.
J Neurosci ; 41(16): 3610-3621, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33687961

RESUMO

Local interneurons of the olfactory bulb (OB) are densely innervated by long-range GABAergic neurons from the basal forebrain (BF), suggesting that this top-down inhibition regulates early processing in the olfactory system. However, how GABAergic inputs modulate the OB output neurons, the mitral/tufted cells, is unknown. Here, in male and female mice acute brain slices, we show that optogenetic activation of BF GABAergic inputs produced distinct local circuit effects that can influence the activity of mitral/tufted cells in the spatiotemporal domains. Activation of the GABAergic axons produced a fast disinhibition of mitral/tufted cells consistent with a rapid and synchronous release of GABA onto local interneurons in the glomerular and inframitral circuits of the OB, which also reduced the spike precision of mitral/tufted cells in response to simulated stimuli. In addition, BF GABAergic inhibition modulated local oscillations in a layer-specific manner. The intensity of locally evoked θ oscillations was decreased on activation of top-down inhibition in the glomerular circuit, while evoked γ oscillations were reduced by inhibition of granule cells. Furthermore, BF GABAergic input reduced dendrodendritic inhibition in mitral/tufted cells. Together, these results suggest that long-range GABAergic neurons from the BF are well suited to influence temporal and spatial aspects of processing by OB circuits.SIGNIFICANCE STATEMENT Disruption of GABAergic inhibition from the basal forebrain (BF) to the olfactory bulb (OB) impairs the discrimination of similar odors, yet how this centrifugal inhibition influences neuronal circuits in the OB remains unclear. Here, we show that the BF GABAergic neurons exclusively target local inhibitory neurons in the OB, having a functional disinhibitory effect on the output neurons, the mitral cells. Phasic inhibition by BF GABAergic neurons reduces spike precision of mitral cells and lowers the intensity of oscillatory activity in the OB, while directly modulating the extent of dendrodendritic inhibition. These circuit-level effects of this centrifugal inhibition can influence the temporal and spatial dynamics of odor coding in the OB.


Assuntos
Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Bulbo Olfatório/citologia , Bulbo Olfatório/efeitos dos fármacos , Animais , Dendritos/fisiologia , Potenciais Evocados/fisiologia , Feminino , Neurônios GABAérgicos/ultraestrutura , Ritmo Gama/fisiologia , Interneurônios/fisiologia , Interneurônios/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibição Neural , Optogenética , Técnicas de Patch-Clamp , Área Pré-Óptica/fisiologia , Prosencéfalo/citologia , Prosencéfalo/fisiologia , Ritmo Teta
10.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619110

RESUMO

The organization of sensory maps in the cerebral cortex depends on experience, which drives homeostatic and long-term synaptic plasticity of cortico-cortical circuits. In the mouse primary somatosensory cortex (S1) afferents from the higher-order, posterior medial thalamic nucleus (POm) gate synaptic plasticity in layer (L) 2/3 pyramidal neurons via disinhibition and the production of dendritic plateau potentials. Here we address whether these thalamocortically mediated responses play a role in whisker map plasticity in S1. We find that trimming all but two whiskers causes a partial fusion of the representations of the two spared whiskers, concomitantly with an increase in the occurrence of POm-driven N-methyl-D-aspartate receptor-dependent plateau potentials. Blocking the plateau potentials restores the archetypical organization of the sensory map. Our results reveal a mechanism for experience-dependent cortical map plasticity in which higher-order thalamocortically mediated plateau potentials facilitate the fusion of normally segregated cortical representations.


Assuntos
Potenciais de Ação/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Rede Nervosa/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Vibrissas/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Mapeamento Encefálico/métodos , Maleato de Dizocilpina/farmacologia , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/anatomia & histologia , Plasticidade Neuronal/efeitos dos fármacos , Imagem Óptica , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Córtex Somatossensorial/anatomia & histologia , Tálamo/anatomia & histologia , Vibrissas/lesões
11.
Cell Calcium ; 94: 102359, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33550209

RESUMO

Dopamine is a neuromodulator and neurotransmitter responsible for a number of physiological processes. Dysfunctions of the dopamine metabolism and signalling are associated with neurological and psychiatric diseases. Here we report that in primary co-culture of neurons and astrocytes dopamine-induces calcium signal in astrocytes and suppress spontaneous synchronous calcium oscillations (SSCO) in neurons. Effect of dopamine on SSCO in neurons was dependent on calcium signal in astrocytes and could be modified by inhibition of dopamine-induced calcium signal or by stimulation of astrocytic calcium rise with ATP. Ability of dopamine to suppress SSCO in neurons was independent on D1- or D2- like receptors but dependent on GABA and alpha-adrenoreceptors. Inhibitor of monoaminoxidase bifemelane blocked effect of dopamine on astrocytes but also inhibited the effect dopamine on SSCO in neurons. These findings suggest that dopamine-induced calcium signal may stimulate release of neuromodulators such as GABA and adrenaline and thus suppress spontaneous calcium oscillations in neurons.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio , Dopamina/metabolismo , Neurônios/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Canais de Cloreto/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas GABAérgicos/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de GABA/metabolismo
12.
Biochem Pharmacol ; 186: 114457, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33556341

RESUMO

Astrocytes are the major glial cells in the central nervous system, but unlike neurons, they do not produce action potentials. For many years, astrocytes were considered supporting cells in the central nervous system (CNS). Technological advances over the last two decades are changing the face of glial research. Accumulating data from recent investigations show that astrocytes display transient calcium spikes and regulate synaptic transmission by releasing transmitters called gliotransmitters. Many new powerful technologies are used to interfere with astrocytic activity, in order to obtain a better understanding of the roles of astrocytes in the brain. Among these technologies, chemogenetics has recently been used frequently. In this review, we will summarize new functions of astrocytes in the brain that have been revealed using this cutting-edge technique. Moreover, we will discuss the possibilities and challenges of manipulating astrocytic activity using this technology.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Desenho de Fármacos , Animais , Sinalização do Cálcio/fisiologia , Antagonistas GABAérgicos/metabolismo , Antagonistas GABAérgicos/farmacologia , Humanos , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
13.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401784

RESUMO

Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.


Assuntos
Neurônios GABAérgicos/metabolismo , Neurônios Aferentes/metabolismo , Dor/metabolismo , Receptores de GABA/metabolismo , Corno Dorsal da Medula Espinal/fisiologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Astrócitos/metabolismo , Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Fibras Nervosas/metabolismo , Fibras Nervosas/fisiologia , Dor/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos
14.
Sleep ; 44(1)2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-32808987

RESUMO

STUDY OBJECTIVES: The substantia nigra pars reticulata (SNR) is a major output nucleus of the basal ganglia. Animal studies have shown that lesions of the SNR cause hyposomnia and motor hyperactivity, indicating that the SNR may play a role in the control of sleep and motor activity. METHODS: Eight 8- to 10-week-old adult male Sprague-Dawley rats were used. After 3 days of baseline polysomnographic recording, dialysates were collected from the lateral SNR across natural sleep-wake states. Muscimol and bicuculline were microinfused into the lateral SNR. RESULTS: We found that GABA release in the lateral SNR is negatively correlated with slow wave sleep (SWS; R = -0.266, p < 0.01, n = 240) and positively correlated with waking (R = 0.265, p < 0.01, n = 240) in rats. Microinfusion of muscimol into the lateral SNR decreased sleep time and sleep quality, as well as eliciting motor hyperactivity in wake and increased periodic leg movement in SWS, while bicuculline infused into the lateral SNR increased sleep and decreased motor activity in SWS in rats. Muscimol infusion skewed the distribution of inter-movement intervals, with most between 10 and 20 s, while a flat distribution of intervals between 10 and 90 s was seen in baseline conditions. CONCLUSIONS: Activation of the lateral SNR is important for inducing sleep and inhibiting motor activity prior to and during sleep, and thus to the maintenance of sleep. Abnormal function of the lateral SNR may cause hyposomnia and motor hyperactivity in quiet wake and in sleep.


Assuntos
Parte Reticular da Substância Negra , Substância Negra , Animais , Antagonistas GABAérgicos , Masculino , Atividade Motora , Ratos , Ratos Sprague-Dawley , Sono , Ácido gama-Aminobutírico
15.
J Surg Res ; 259: 431-441, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33069391

RESUMO

BACKGROUND: Ivermectin (IVM) was first used as an antiparasitic agent; however, the role of this drug evolved into a broad spectrum. Many mechanisms have been proposed, including interaction with the GABAergic system. Considering the presence of GABA receptor in the skin tissue and its role in ischemia-reperfusion I/R injury, we aimed to evaluate the effect of IVM through GABA receptors on random-pattern skin flap survival. METHODS: Sixty Wistar male rats were used. Multiple doses of IVM (0.01, 0.05, 0.2, and 0.5 mg/kg) were injected intraperitoneally before the surgery. Baclofen (selective GABAB agonist) and bicuculline (selective GABAA antagonist) were administered in combination with IVM to assess the role of the GABAergic system. Histopathological evaluations, immunohistochemical staining, quantitative assessment of IL-1ß and TNFα, and the expression of GABAA α1 subunit and GABAB R1 receptors were evaluated in the skin tissue. RESULTS: IVM 0.05 mg/kg could significantly increase flap survival compared with the control group (P < 0.001). Subeffective dose of baclofen (0.1 mg/kg) had synergistic effect with the subeffective dose of IVM (0.01 mg/kg) (P < 0.001), whereas bicuculline 1 mg/kg reversed the effect of IVM (0.05 mg/kg) (P < 0.001). IVM 0.05 mg/kg could also decrease the IL-1ß and TNFα levels and increase the expression of GABAA α1 subunit and GABAB R1 receptors in the flap tissue compared with the control group. CONCLUSIONS: IVM could improve skin flap survival, probably mediated by the GABAergic pathway. Both GABAA and GABAB receptors are involved in this process. This finding may repurpose the use of old drug, "Ivermectin."


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Ivermectina/administração & dosagem , Retalhos Cirúrgicos/transplante , Ácido gama-Aminobutírico/metabolismo , Animais , Baclofeno/administração & dosagem , Bicuculina/administração & dosagem , Reposicionamento de Medicamentos , Antagonistas GABAérgicos/administração & dosagem , Antagonistas de Receptores de GABA-A/administração & dosagem , Humanos , Masculino , Modelos Animais , Ratos , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Retalhos Cirúrgicos/efeitos adversos
16.
Exp Neurol ; 336: 113527, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33188818

RESUMO

The hippocampus is vulnerable to traumatic brain injury (TBI), and hippocampal damage is associated with cognitive deficits that are often the hallmark of TBI. Recent studies have found that TBI induces enhanced neurogenesis in the dentate gyrus (DG) of the hippocampus, and this cellular response is related to innate cognitive recovery. However, cellular mechanisms of the role of DG neurogenesis in post-TBI recovery remain unclear. This study investigated changes in long-term potentiation (LTP) within the DG in relation to TBI-induced neurogenesis. Adult male rats received a moderate TBI or sham injury and were sacrificed for brain slice recordings at 30 or 60 days post-injury. Recordings were taken from the medial perforant path input to DG granule cells in the presence or absence of the GABAergic antagonist picrotoxin, reflecting activity of either all DG granule cells or predominately newborn granule cells, respectively. Measurements of LTP observed in the total granule cell population (with picrotoxin) showed a prolonged impairment which worsened between 30 and 60 days post-TBI. Under conditions which predominantly reflected the LTP elicited in newly born granule cells (no picrotoxin), a strikingly different pattern of post-TBI changes was observed, with a time-dependent cycle of functional impairment and recovery. At 30 days after injury this cell population showed little or no LTP, but by 60 days the capacity for LTP of the newly born granule cells was no different from that of sham controls. The time-frame of LTP improvements in the newborn cell population, comparable to that of behavioral recovery reported previously, suggests the unique functional properties of newborn granule cells enable them to contribute to restorative change following brain injury.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Hipocampo/patologia , Plasticidade Neuronal , Sinapses/patologia , Animais , Atrofia , Comportamento Animal , Lesões Encefálicas Traumáticas/psicologia , Grânulos Citoplasmáticos/patologia , Fenômenos Eletrofisiológicos , Antagonistas GABAérgicos/farmacologia , Potenciação de Longa Duração , Masculino , Picrotoxina/farmacologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica
17.
J Neurophysiol ; 125(2): 408-425, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33236936

RESUMO

Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex brain-region-specific networks. The previously reported forms include bursts of electrical activity and oscillations in intracellular Ca2+ concentration. Here, we use ratiometric Na+ imaging to demonstrate spontaneous fluctuations in the intracellular Na+ concentration of CA1 pyramidal neurons and astrocytes in tissue slices obtained from the hippocampus of mice at postnatal days 2-4 (P2-4). These occur at very low frequency (∼2/h), can last minutes with amplitudes up to several millimolar, and mostly disappear after the first postnatal week. To further investigate their mechanisms, we model a network consisting of pyramidal neurons and interneurons. Experimentally observed Na+ fluctuations are mimicked when GABAergic inhibition in the simulated network is made depolarizing. Both our experiments and computational model show that blocking voltage-gated Na+ channels or GABAergic signaling significantly diminish the neuronal Na+ fluctuations. On the other hand, blocking a variety of other ion channels, receptors, or transporters including glutamatergic pathways does not have significant effects. Our model also shows that the amplitude and duration of Na+ fluctuations decrease as we increase the strength of glial K+ uptake. Furthermore, neurons with smaller somatic volumes exhibit fluctuations with higher frequency and amplitude. As opposed to this, larger extracellular to intracellular volume ratio observed in neonatal brain exerts a dampening effect. Finally, our model predicts that these periods of spontaneous Na+ influx leave neonatal neuronal networks more vulnerable to seizure-like states when compared with mature brain.NEW & NOTEWORTHY Spontaneous activity in the neonate forebrain plays a key role in cell maturation and brain development. We report spontaneous, ultraslow, asynchronous fluctuations in the intracellular Na+ concentration of neurons and astrocytes. We show that this activity is not correlated with the previously reported synchronous neuronal population bursting or Ca2+ oscillations, both of which occur at much faster timescales. Furthermore, extracellular K+ concentration remains nearly constant. The spontaneous Na+ fluctuations disappear after the first postnatal week.


Assuntos
Potenciais de Ação , Prosencéfalo/fisiologia , Canais de Sódio/metabolismo , Sódio/metabolismo , Animais , Feminino , Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Neurológicos , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Bloqueadores dos Canais de Sódio/farmacologia
18.
J Neurophysiol ; 125(2): 321-330, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296606

RESUMO

Mammalian neurons undergo rapid excitotoxic cell death when deprived of oxygen; however, the common goldfish (Carassius auratus) has the unique ability of surviving in oxygen-free waters, under anoxia. This organism utilizes γ-amino butyric acid (GABA) signaling to suppress excitatory glutamatergic activity during anoxic periods. Although GABAA receptor antagonists are not deleterious to the cellular survival, coinhibition of GABAA and GABAB receptors is detrimental by abolishing anoxia-induced neuroprotective mechanisms. Here we show that blocking the anoxic GABAergic neurotransmission induces seizure-like activity (SLA) analogous to a paroxysmal depolarization shift (PDS), with hyperpolarization of action potential (AP) threshold and elevation of threshold currents. The observed PDS was attributed to an increase in excitatory postsynaptic currents (EPSCs) that are normally attenuated with decreasing oxygen levels. Furthermore, for the first time, we show that in addition to PDS, some neurons undergo depolarization block and do not generate AP despite a suprathreshold membrane potential. In conclusion, our results indicate that with severe hypoxia and absence of GABA receptor activity, telencephalic neurons of C. auratus manifest a paroxysmal depolarization shift, a key feature of epileptic discharge.NEW & NOTEWORTHY This work shows that the combination of anoxia and inhibition of GABA receptors induces seizure-like activities in goldfish telencephalic pyramidal and stellate neurons. Importantly, to prevent seizure-like activity, an intact GABA-mediated inhibitory pathway is required.


Assuntos
Potenciais de Ação , Antagonistas GABAérgicos/farmacologia , Hipóxia/fisiopatologia , Neurônios/fisiologia , Animais , Proteínas de Peixes/metabolismo , Carpa Dourada , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxigênio/metabolismo , Receptores de GABA/metabolismo
19.
J Agric Food Chem ; 68(50): 15005-15014, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33269911

RESUMO

To control the development of resistance to conventional insecticides acting as γ-aminobutyric acid (GABA) receptor antagonists (e.g., fipronil), new GABAergic 5,5-disubstituted 4,5-dihydropyrazolo[1,5-a]quinazolines were designed via a scaffold-hopping strategy and synthesized with a facile method. Among the 50 target compounds obtained, compounds 5a, 5b, 7a, and 7g showed excellent insecticidal activities against a susceptible strain of Plutella xylostella (LC50 values ranging from 1.03 to 1.44 µg/mL), which were superior to that of fipronil (LC50 = 3.02 µg/mL). Remarkably, the insecticidal activity of compound 5a was 64-fold better than that of fipronil against the field population of fipronil-resistant P. xylostella. Electrophysiological studies against the housefly GABA receptor heterologously expressed in Xenopus oocytes indicated that compound 5a could act as a potent GABA receptor antagonist, and IC50 was calculated to be 32.5 nM. Molecular docking showed that the binding poses of compound 5a with the housefly GABA receptor can be different compared to fipronil, which explains the effectiveness of compound 5a against fipronil-resistant insects. These findings have suggested compound 5a as a lead compound for a novel GABA receptor antagonist controlling field-resistant insects and provided a basis for further design, structural modification, and development of 4,5-dihydropyrazolo[1,5-a]quinazoline motifs as new insecticidal GABA receptor antagonists.


Assuntos
Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/farmacologia , Moscas Domésticas/efeitos dos fármacos , Proteínas de Insetos/antagonistas & inibidores , Inseticidas/síntese química , Inseticidas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Animais , Desenho de Fármacos , Moscas Domésticas/química , Moscas Domésticas/genética , Moscas Domésticas/metabolismo , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Simulação de Acoplamento Molecular , Receptores de GABA/química , Receptores de GABA/metabolismo
20.
Molecules ; 25(23)2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33255851

RESUMO

Herein, we describe novel pentafluorosulfanyl (SF5) group-containing meta-diamide insecticides. For the facile preparation of the SF5-based compounds 4a-d, practical synthetic methods were applied. Among newly synthesized compounds, 3-benzamido-N-(2,6-dimethyl-4-(pentafluoro-λ6-sulfanyl)phenyl)-2-fluorobenzamide 4d showed (i) a high insecticidal activity, (ii) an excellent selectivity to insects, and (iii) good levels of water solubility and log P values. In this study, we demonstrated that the pentafluorosulfanyl moiety could serve as an attractive functionality for the discovery of a new scope of crop-protecting agents.


Assuntos
Técnicas de Química Sintética , Diamida/síntese química , Diamida/farmacologia , Inseticidas/síntese química , Inseticidas/farmacologia , Metais/química , Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/farmacologia , Estrutura Molecular , Receptores de GABA/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...