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1.
J Chem Ecol ; 46(2): 176-185, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32062821

RESUMO

Females of the Queensland fruit fly (QFF), Bactrocera tryoni, are amongst the most damaging pests of horticulture in Australia and neighboring countries. Females can lay eggs into more than a hundred species of fruits and vegetables, resulting in large crop losses. Sexually mature males can be managed sustainably with traps baited with long-lasting synthetic lures, and sexually immature males and females can be attracted and killed by short-lived protein baits applied directly on surfaces, with a low success rate (< 20%). No long-lasting attractants for virgin or mated females exist. With the aim of developing a female attractant for surveillance, we collected and analyzed the odors of four ripe host fruits: orange, cherry guava, banana and feijoa. Virgin and mated female QFF were tested with gas-chromatography coupled with electro-antennographic detection to identify electrophysiologically (EAD)-active compounds. We detected 41 EAD-active compounds, with seven found common for more than one fruit. Overall, mated females responded more often and with higher intensity than virgin females. In particular, five compounds present either in cherry guava or feijoa triggered a significantly higher EAD response from mated females than from virgins. Twenty-six EAD-active compounds were selected and tested individually in a Y-tube olfactometer to measure attraction of both virgin and mated females. Behavioral responses differed significantly amongst the compounds, but not strongly between virgin and mated females. We did not find any correlation between electrophysiological and behavioral responses. Further field testing with behaviorally-active compounds is needed for the development of a new QFF female lure.


Assuntos
Odorantes/análise , Tephritidae/fisiologia , Compostos Orgânicos Voláteis/análise , Animais , Antenas de Artrópodes/fisiologia , Comportamento Animal/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Frutas/química , Frutas/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Psidium/química , Psidium/metabolismo , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/farmacologia
2.
J Chem Ecol ; 45(10): 858-868, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31637564

RESUMO

Vine weevil, Otiorhynchus sulcatus F. (Coleoptera: Curculionidae), is an economically important pest species in many soft-fruit and ornamental crops. Economic losses arise from damage to the roots, caused by larvae, and to the leaves, caused by adults. As adults are nocturnal and larvae feed below ground, infestations can be missed initially, with controls applied too late. In the absence of a vine weevil sex or aggregation pheromone, the development of an effective semiochemical lure for better management of this pest is likely to focus on host-plant volatiles. Here, we investigate the electrophysiological and behavioral responses of adult vine weevils to volatile organic compounds (VOCs) originating from their preferred host plant Euonymus fortunei, and synthetic VOCs associated with this host when presented individually or as blends. Consistent electroantennographic responses were observed to a range of generalist VOCs. Behavioral responses of weevils to VOCs, when presented individually, were influenced by concentration. Vine weevil adults showed directional movement toward a mixture of seven plant volatiles, methyl salicylate, 1-octen-3-ol, (E)-2-hexenol, (Z)-3-hexenol, 1-hexanol, (E)-2-pentenol, and linalool, even though no, or negative, responses were recorded to each of these compounds presented individually. Similarly, vine weevils showed directional movement toward a 1:1 ratio mixture of (Z)-2-pentenol and methyl eugenol. Results presented here point to the importance of blends of generalist compounds and their concentrations in the optimization of a lure.


Assuntos
Euonymus/química , Compostos Orgânicos Voláteis/química , Gorgulhos/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Euonymus/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Larva/efeitos dos fármacos , Larva/fisiologia , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/farmacologia
3.
Molecules ; 24(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561643

RESUMO

Kynurenic acid (KYNA), a metabolite of tryptophan, as an excitatory amino acid receptor antagonist is an effective neuroprotective agent in case of excitotoxicity, which is the hallmark of brain ischemia and several neurodegenerative processes. Therefore, kynurenine pathway, KYNA itself, and its derivatives came into the focus of research. During the past fifteen years, our research group has developed several neuroactive KYNA derivatives, some of which proved to be neuroprotective in preclinical studies. In this study, the synthesis of these KYNA derivatives and their evaluation with divergent molecular characteristics are presented together with their most typical effects on the monosynaptic transmission in CA1 region of the hippocampus of the rat. Their effects on the basic neuronal activity (on the field excitatory postsynaptic potentials: fEPSP) were studied in in vitro hippocampal slices in 1 and 200 µM concentrations. KYNA and its derivative 4 in both 1 and 200 µM concentrations proved to be inhibitory, while derivative 8 only in 200 µM decreased the amplitudes of fEPSPs. Derivative 5 facilitated the fEPSPs in 200 µM concentration. This is the first comparative study which evaluates the structural and functional differences of formerly and newly developed KYNA analogs. Considerations on possible relations between molecular structures and their physiological effects are presented.


Assuntos
Ácido Cinurênico/química , Ácido Cinurênico/farmacologia , Desenho de Drogas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ácido Cinurênico/análogos & derivados , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Relação Estrutura-Atividade
4.
J Chem Ecol ; 45(10): 849-857, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31512099

RESUMO

Odorant binding proteins (OBPs) play a key role in chemoreception in insects. In an earlier study, we identified CmedOBP14 from the rice leaf folder, Cnaphalocrocis medinalis, with potential physiological functions in olfaction. Here, we performed a competitive binding assay under different pH conditions as well as knockdown via RNA interference to determine the specific role of CmedOBP14 in C. medinalis. CmedOBP14 displayed broad binding affinities to many host-related compounds, with higher affinities at pH 7.4 compared with pH 5.0. After treatment with CmedOBP14-dsRNA, the transcript level of OBP14 was significantly decreased at 72 h compared with controls, and the electroantennogram response evoked by nerolidol, L-limonene and beta-ionone was reduced. Furthermore, behavioral assays revealed consistent patterns among these compounds, especially for nerolidol, with adults could no longer able to differentiate 0.1% nerolidol from controls. RNAi experiments suggest that at least in part, CmedOBP14 mediates the ability to smell nerolidol and beta-ionone.


Assuntos
Proteínas de Insetos/metabolismo , Mariposas/metabolismo , Receptores Odorantes/metabolismo , Animais , Antenas de Artrópodes/metabolismo , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/genética , Norisoprenoides/farmacologia , Interferência de RNA , RNA de Cadeia Dupla/metabolismo , Receptores Odorantes/antagonistas & inibidores , Receptores Odorantes/genética , Sesquiterpenos/farmacologia
5.
Eur J Pharmacol ; 858: 172514, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31265841

RESUMO

Recently, we reported the role of coixol (6-methoxy-2(3H)-benzoxazolone), an alkaloid from Scoparia dulcis, in glucose-dependent insulin secretion; however, its insulin secretory mechanism(s) remained unknown. Here, we explored the insulinotropic mechanism(s) of coixol in vitro and in vivo. Mice islets were batch incubated, perifused with coixol in the presence of agonists/antagonists, and insulin secretion was measured by ELISA. Intracellular cAMP levels were measured using enzyme immunoassay. K+- and Ca2+-currents were recorded in MIN6 cells using whole-cell patch-clamp technique. The in vivo glucose tolerance and the insulinogenic index were evaluated in diabetic rats treated with coixol at 25 and 50 mg/kg, respectively. Coixol, unlike sulfonylurea, enhanced insulin secretion in batch incubated and perifused islets at high glucose, with no effect at basal glucose concentrations. Coixol showed no pronounced effect on the inward rectifying K+- and Ca2+-currents in whole-cell patch recordings. Moreover, coixol-induced insulin secretion was further amplified in the depolarized islets. Coixol showed an additive effect with forskolin (10 µM)-induced cAMP level, and in insulin secretion; however, no additive effect was observed with isobutylmethylxanthine (IBMX, 100 µM)-induced cAMP level, nor in insulin secretion. The PKA inhibitor H-89 (50 µM), and Epac2 inhibitor MAY0132 (50 µM) significantly inhibited the coixol-induced insulin secretion (P < 0.01). Furthermore, insulin secretory kinetics revealed that coixol potentiates insulin secretion in both early and late phases of insulin secretion. In diabetic animals, coixol showed significant improvement in glucose tolerance and on fasting blood glucose levels. These data suggest that coixol amplifies glucose-stimulated insulin secretion by cAMP-mediated signaling pathways.


Assuntos
Benzoxazóis/farmacologia , AMP Cíclico/metabolismo , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia/metabolismo , Canais de Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Potássio/metabolismo , Ratos
6.
Prog Biophys Mol Biol ; 144: 128-138, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182191

RESUMO

Cardiac two-pore-domain potassium (K2P) channels have been proposed as novel antiarrhythmic targets. K2P13.1 (THIK-1) channels are expressed in the human heart, and atrial K2P13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K2P13.1 currents. Second, we assessed atrial K2P13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K2P13.1-based antiarrhythmic concepts. K2P13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K2P13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K2P13.1 channel pharmacology in Xenopus oocytes. Propafenone (-26%; 100 µM), mexiletine (-75%; 1.5 mM), propranolol (-38%; 200 µM), and lidocaine (-59%; 100 µM) significantly inhibited K2P13.1 currents. By contrast, K2P13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K2P13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K2P13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K2P13.1 channels in a porcine model resemble human findings and support a general role for K2P13.1 in AF pathophysiology. K2P13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Miocárdio/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Animais , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mexiletina/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/genética , Suínos
7.
Eur J Pharmacol ; 858: 172496, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31242440

RESUMO

A natural monoterpene alkaloid incarvillateine isolated from the plant Incarvillea sinensis is known to relieve inflammatory and neuropathic pain. However, the molecular target for the action of incarvillateine remains elusive. Here, we report that incarvillateine exacerbates epileptic seizures by inhibiting subtypes of γ-Aminobutyric acid type A (GABAA) receptors. Two-electrode voltage clamp recordings of α1ß3γ2, α2ß3γ2, α3ß3γ2 and α5ß3γ2 subtypes expressed in Xenopus oocytes revealed that incarvillateine inhibited the GABAA currents with IC50 of 25.1 µM, 43.1 µM, 105.1 µM and 93.7 µM, respectively. Whole-cell patch clamp recordings of hippocampal slices confirmed that incarvillateine inhibited spontaneous inhibitory postsynaptic currents (IPSCs), and miniature IPSCs and tonic currents. Moreover, inhibition of GABAA currents and spontaneous IPSCs by incarvillateine persisted even in the presence of blockers of adenosine receptors. In addition, incarvillateine enhanced epileptic discharges induced by Mg2+-free artificial cerebrospinal fluid (ACSF) in hippocampal slices. Furthermore, intracerebral ventricular injections of incarvillateine increased the severity of seizures induced by kainic acid in a dose-dependent manner. Taken together, our data demonstrate that incarvillateine aggravates seizures by inhibition of GABAA currents and GABAergic synaptic transmissions.


Assuntos
Alcaloides/efeitos adversos , Produtos Biológicos/efeitos adversos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/efeitos adversos , Monoterpenos/efeitos adversos , Receptores de GABA-A/metabolismo , Segurança , Convulsões/fisiopatologia , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos , Neurotransmissores/metabolismo , Ratos , Convulsões/induzido quimicamente , Convulsões/metabolismo , Transmissão Sináptica/efeitos dos fármacos
8.
Eur J Pharmacol ; 858: 172474, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31238068

RESUMO

The Kv7 family of voltage-dependent non-inactivating potassium channels is composed of five members, of which four are expressed in the CNS. Kv7.2, 7.3 and 7.5 are responsible for the M-current, which plays a critical role in the regulation of neuronal excitability. Stimulation of M1 muscarinic acetylcholine receptor, M1 receptor, increases neuronal excitability by suppressing the M-current generated by the Kv7 channel family. The M-current modulation via M1 receptor is well-described in in vitro assays using cell lines and in native rodent tissue. However, this mechanism was not yet reported in human induced pluripotent stem cells (hiPSC) derived neurons. In the present study, we investigated the effects of both agonists and antagonists of Kv7.2/7.3 channel and M1 receptor in hiPSC derived neurons and in primary rat cortical neuronal cells. The role of M1 receptors in the modulation of neuronal excitability could be demonstrated in both rat primary and hiPSC neurons. The M1 receptors agonist, xanomeline, increased neuronal excitability in both rat cortical and the hiPSC neuronal cells. Furthermore, M1 receptor agonist-induced neuronal excitability in vitro was reduced by an agonist of Kv7.2/7.3 in both neuronal cells. These results show that hiPSC derived neurons recreate the modulation of the M-current by the muscarinic receptor in hiPSC neurons similarly to rat native neurons. Thus, hiPSC neurons could be a useful human-based cell assay for characterization of drugs that affect neuronal excitability and/or induce seizure activity by modulation of M1 receptors or inhibition of Kv7 channels.


Assuntos
Fenômenos Eletrofisiológicos , Células-Tronco Pluripotentes Induzidas/citologia , Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ3/metabolismo , Neurônios/citologia , Receptor Muscarínico M1/metabolismo , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Canal de Potássio KCNQ2/agonistas , Canal de Potássio KCNQ2/antagonistas & inibidores , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ3/agonistas , Canal de Potássio KCNQ3/antagonistas & inibidores , Canal de Potássio KCNQ3/genética , Antagonistas Muscarínicos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/antagonistas & inibidores
9.
Eur J Pharmacol ; 857: 172444, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185218

RESUMO

Studies demonstrated that the incidence of atrial fibrillation is significantly increased in patients with diabetes mellitus. Increase of late sodium current (INaL) has been associated with atrial arrhythmias. However, the role of INaL in the setting of atrial fibrillation in diabetes mellitus remained unknown. In this study, we investigated the alteration of INaL in the atria of diabetic mice and the therapeutic effect of its inhibitor (GS967) on the susceptibility of atrial fibrillation. The whole-cell patch-clamp technique was used to detect single cell electrical activities. The results showed that the density of INaL in diabetic cardiomyocytes was larger than that of the control cells at the holding potential of -100 mV. The action potential duration at both 50% and 90% repolarization, APD50 and APD90, respectively, was markedly increased in diabetic mice than in controls. GS967 application inhibited INaL and shortened APD of diabetic mice. High-frequency electrical stimuli were used to induce atrial arrhythmias. We found that the occurrence rate of atrial fibrillation was significantly increased in diabetic mice, which was alleviated by the administration of GS967. In GS967-treated diabetic mice, the INaL current density was reduced and APD was shortened. In conclusion, the susceptibility to atrial fibrillation was increased in diabetic mice, which is associated with the increased late sodium current and the consequent prolongation of action potential. Inhibition of INaL by GS967 is beneficial against the occurrence of atrial fibrillation in diabetic mice.


Assuntos
Fibrilação Atrial/complicações , Fibrilação Atrial/fisiopatologia , Diabetes Mellitus Experimental/complicações , Fenômenos Eletrofisiológicos , Sódio/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Triazóis/farmacologia
10.
Insect Biochem Mol Biol ; 111: 103176, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31150760

RESUMO

The Oriental armyworm, Mythimna separata, has been described to emit geographic population-specific sex pheromones, with either Z11-16:Ald or Z11-16:Ac as the major component. Using a comprehensive set of electrophysiological, behavioral, and genetic analyses, we study the sex pheromone communication of M. separata in North China from pheromone receptors and antennal lobe to behavior. GC-EAD results show that Z11-16:Ald is the only compound eliciting electrophysiological responses in pheromone gland extracts. Further in vivo optical imaging studies reveal that Z11-16:Ald activates the cumulus of the MGC and show dose-dependent responses. The wind tunnel tests demonstrate that Z11-16:Ald alone is sufficient to induce the entire sequence of male sexual behaviors. Transcriptome and q-PCR results show that MsepOR3 is specifically and abundantly expressed in male antennae. By using the Xenopus oocytes and two-electrode voltage-clamp recording, we finally validate that the oocytes expressing MsepOR3/ORco gave dose dependent responses to Z11-16:Ald. We suggest single Z11-16:Ald could be used for monitoring the population of M. separata in North China.


Assuntos
Mariposas/efeitos dos fármacos , Atrativos Sexuais/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Antenas de Artrópodes/fisiologia , China , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Masculino , Mariposas/genética , Oócitos , Técnicas de Patch-Clamp , Xenopus
11.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035589

RESUMO

BACKGROUND: Astaxanthin (ATX) is a lipophilic compound found in many marine organisms. Studies have shown that ATX has many strong biological properties, including antioxidant, antiviral, anticancer, cardiovascular, anti-inflammatory, neuro-protective and anti-diabetic activities. However, no research has elucidated the effect of ATX on ionic channels. ATX can be extracted from shrimp by-products. Our work aims to characterize ATX cell targets to lend value to marine by-products. METHODS: We used the Xenopus oocytes cell model to characterize the pharmacological target of ATX among endogenous Xenopus oocytes' ionic channels and to analyze the effects of all carotenoid-extract samples prepared from shrimp by-products using a supercritical fluid extraction (SFE) method. RESULTS: ATX inhibits amiloride-sensitive sodium conductance, xINa, in a dose-dependent manner with an IC50 of 0.14 µg, a maximum inhibition of 75% and a Hill coefficient of 0.68. It does not affect the potential of half activation, but significantly changes the kinetics, according to the slope factor values. The marine extract prepared from shrimp waste at 10 µg inhibits xINa in the same way as ATX 0.1 µg does. When ATX was added to the entire extract at 10 µg, inhibition reached that induced with ATX 1 µg. CONCLUSIONS: ATX and the shrimp Extract inhibit amiloride-sensitive sodium channels in Xenopus oocytes and the TEVC method makes it possible to measure the ATX inhibitory effect in bioactive SFE-Extract samples.


Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Oócitos/fisiologia , Amilorida/farmacologia , Animais , Descoberta de Drogas/métodos , Canais de Sódio/metabolismo , Xenopus laevis
12.
Cell Mol Neurobiol ; 39(6): 809-822, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31037516

RESUMO

We established a model of Alzheimer's disease in vitro by exposing primary hippocampal neurons of neonatal Wistar rats to the ß-Amyloid peptide fragment 25-35, Aß25-35. We then observed the effects of genistein, a type of soybean isoflavone, on Aß25-35-incubated hippocampal neuron viability, and the electrophysiological properties of voltage-gated sodium channels (NaV) and potassium channels (KV) in the hippocampal neurons. Aß25-35 exposure reduced the viability of hippocampal neurons, decreased the peak amplitude of voltage-activated sodium channel currents (INa), and significantly reduced INa at different membrane potentials. Moreover, Aß25-35 shifted the activation curve toward depolarization, shifted the inactivation curve toward hyperpolarization, and increased the time constant of recovery from inactivation. Aß25-35 exposure significantly shifted the inactivation curve of transient outward K+ currents (IA) toward hyperpolarization and increased its time constant of recovery from inactivation. In addition, Aß25-35 significantly decreased the peak density of outward-delayed rectifier potassium channel currents (IDR) and significantly reduced IDR value at different membrane potentials. We found that genistein partially reversed the decrease in hippocampal neuron viability, and the alterations in electrophysiological properties of NaV and KV induced by Aß25-35. Our results suggest that genistein could inhibit Aß25-35-induced neuronal damage with changes in the electrophysiological properties of NaV and KV.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Genisteína/farmacologia , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/toxicidade , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/patologia , Ativação do Canal Iônico/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos Wistar
13.
J Chem Ecol ; 45(5-6): 474-489, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31053976

RESUMO

Bark beetles kill apparently vigorous conifers during epidemics by means of pheromone-mediated aggregation. During non-endemic conditions the beetles are limited to use trees with poor defense, like wind-thrown. To find olfactory cues that help beetles to distinguish between trees with strong or weak defense, we collected volatiles from the bark surface of healthy felled or standing Picea abies trees. Furthermore, living trees were treated with methyl jasmonate in order to induce defense responses. Volatiles were analyzed by combined gas chromatography and electroantennographic detection (GC-EAD) on Ips typographus antennae. Compounds eliciting antennal responses were characterized by single sensillum recording for identification of specific olfactory sensory neurons (OSN). Release of monoterpene hydrocarbons decreased, while oxygenated compounds increased, from spring to early summer in felled trees. In both beetle sexes particular strong EAD activity was elicited by trace amounts of terpene alcohols and ketones. 4-Thujanol gave a very strong response and the absolute configuration of the tested natural product was assigned to be (+)-trans-(1R,4S,5S)-thujanol by stereoselective synthesis and enantioselective gas chromatography. One type of OSN responded to all ketones and five other OSN were characterized by the type of compounds that elicited responses. Three new OSN classes were found. Of the eight EAD-active compounds found in methyl jasmonate-treated bark, the known anti-attractant 1,8-cineole was the one most strongly induced. Our data support the hypothesis that highly active oxygenated host volatiles could serve as positive or negative cues for host selection in I. typographus and in other bark beetles.


Assuntos
Besouros/fisiologia , Monoterpenos/química , Estireno/química , Acetatos/farmacologia , Animais , Ciclopentanos/farmacologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Monoterpenos/síntese química , Monoterpenos/farmacologia , Oxilipinas/farmacologia , Picea/química , Picea/metabolismo , Casca de Planta/química , Casca de Planta/efeitos dos fármacos , Casca de Planta/metabolismo , Estereoisomerismo , Estireno/farmacologia
14.
Exp Brain Res ; 237(7): 1593-1614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079238

RESUMO

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ritmo Gama/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Antidepressivos/farmacologia , Depressão/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ritmo Gama/fisiologia , Humanos , Córtex Pré-Frontal/fisiopatologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia
15.
Eur J Pharmacol ; 856: 172414, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31129155

RESUMO

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton were purified from Croton tonkinensis. By using patch-clamp recording technique, we thoroughly examined the effect of a group of croton compounds, croton-01 (ent-18-acetoxy-7α-hydroxykaur-16-en-15-one), croton-02 (ent-7α,14ß-dihydroxykaur-16-en-15-one), and croton-03 (ent-1ß-acetoxy-7α,14ß-dihydroxykaur-16-en-15-one), on the membrane current in SM826 and BV2 microglial cells. Although neither voltage-gated Na+ nor Ca2+ currents were present in these cells, both delayed-rectifier K+ outward (IK(DR)) and inwardly rectifying K+ currents (IK(IR)) were readily detected. Croton-03 differentially caused inhibition of IK(DR) or IK(IR) in a concentration-dependent manner. According to a minimal scheme, the shortening of the time constant in either the IK(DR)-related block or IK(IR) caused by different concentrations of croton-03 was quantitatively estimated with a dissociation constant of 6.45 and 29.5 µM, respectively. In SM826 cells differentiated with ß-amyloid, inhibitory action on these K+ currents remained unaltered. In ultraviolet C-irradiated cells, the magnitude of IK(IR) was still decreased by addition of croton-03. Therefore, our study suggests that these ent-kaurane diterpenoids ought to somehow act on the cellular mechanisms by which they influence the functional activities of microglial cells.


Assuntos
Croton/química , Canais de Potássio de Retificação Tardia/metabolismo , Diterpenos de Caurano/farmacologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Potássio/metabolismo , Linhagem Celular , Canais de Potássio de Retificação Tardia/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Cinética , Microglia/citologia , Microglia/metabolismo , Folhas de Planta/química , Fatores de Tempo
16.
Eur J Pharmacol ; 854: 380-386, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31034820

RESUMO

Levetiracetam was initially developed as a nootropic drug, although since 2002 it has been used as anticonvulsant for the treatment of partial and generalized epilepsy syndromes. The purpose of the research was to investigate anti-paroxysmal activity of levetiracetam (LEV) on the model of cobalt-induced chronic epilepsy caused by the application of cobalt to the sensorimotor area of the rat cortex to evaluate LEV impact on the different stages of epileptogenesis. LEV effects were studied at the initial stage of the epileptogenesis (2nd day after the cobalt application) and at the stage of generalized paroxysmal activity (6th day after the cobalt application). The research showed that levetiracetam administration (dosages 50 mg/kg and 200 mg/kg) at the early stage of the epileptogenesis had no statistically significant effect on the development of paroxysmal activity in both primary and secondary epileptic areas: in the ipsi- and contralateral cortex, hypothalamus and hippocampus. LEV administration on 6th day (dosage 50 mg/kg) did not have statistical effect on the epileptogenesis, while at a dosage of 200 mg/kg on 6th day LEV significantly suppressed paroxysmal activity in the studied structures of rats with cobalt epilepsy. The strongest anti-paroxysmal effect was detected in hippocampus and was expressed as the normalization of bioelectrical activity and the appearance of a regular theta rhythm. Thus, LEV effects are mostly directed to the hippocampal area of epileptiform activity and, to a lesser extent, to the cortical area.


Assuntos
Anticonvulsivantes/farmacologia , Cobalto/efeitos adversos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Epilepsia/fisiopatologia , Levetiracetam/farmacologia , Animais , Doença Crônica , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar
17.
Eur J Pharmacol ; 853: 247-255, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30930251

RESUMO

The nonsteroidal anti-inflammatory drug (NSAID) niflumic acid, a fenamate in structure, has many molecular targets, one of them being specific subtypes of the main inhibitory ligand-gated anion channel, the GABAA receptor. Here, we report on the effects of other fenamates and other classes of NSAIDs on brain picrotoxinin-sensitive GABAA receptors, using an autoradiographic assay with [35S]TBPS as a ligand on mouse brain sections. We found that the other fenamates studied (flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid) affected the autoradiographic signal at low micromolar concentrations in a facilitatory-like allosteric fashion, i.e., without having affinity to the [35S]TBPS binding site. Unlike niflumic acid that shows clear preference for inhibiting cerebellar granule cell layer GABAA receptors, the other fenamates showed little brain regional selectivity, indicating that their actions are not receptor-subtype selective. Of the non-fenamate NSAIDs studied at 100 µM concentration, diclofenac induced the greatest inhibition of the binding, which is not surprising as it has close structural similarity with the potent fenamate meclofenamic acid. Using two-electrode voltage-clamp assays on Xenopus oocytes, the effect of niflumic acid was found to be dependent on the ß subunit variant and the presence of γ2 subunit in rat recombinant α1ß and α1ßγ2 GABAA receptors, with the ß1 allowing the niflumic acid inhibition and ß3 the stimulation of the receptor-mediated currents. In summary, the fenamate NSAIDs constitute an interesting class of compounds that could be used for development of potent GABAA receptor allosteric agonists with other targets to moderate inflammation, pain and associated anxiety/depression.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Fenamatos/farmacologia , Receptores de GABA-A/metabolismo , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenamatos/metabolismo , Masculino , Ratos
18.
Eur J Pharmacol ; 854: 92-100, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30954564

RESUMO

Cariprazine is a novel atypical antipsychotic drug that is widely used for the treatment of schizophrenia and bipolar mania/mixed disorder. We used the whole-cell patch-clamp technique to investigate the effects of cariprazine on hERG channels that are stably expressed in HEK cells. Cariprazine inhibited the hERG 1A and hERG 1A/3.1 tail currents at -50 mV in a concentration-dependent manner with IC50 values of 4.1 and 12.2 µM, respectively. The block of hERG 1A currents by cariprazine was voltage-dependent, and increased over a range of voltage for channel activation. Cariprazine shifted the steady-state inactivation curve of the hERG 1A currents in a hyperpolarizing direction and produced a use-dependent block. A fast application of cariprazine inhibited the hERG 1A currents elicited by a 5 s depolarizing pulse to +60 mV to fully inactivate the hERG 1A currents. During a repolarizing pulse wherein the hERG 1A current was deactivated slowly, cariprazine rapidly and reversibly blocked the open state of the hERG 1A current. However, cariprazine did not affect hERG 1A and hERG 1A/3.1 channel trafficking to the cell membrane. Our results indicated that cariprazine concentration-dependently inhibited hERG 1A and hERG 1A/3.1 currents by preferentially interacting with the open states of the hERG 1A channel, but not by the disruption of hERG 1A and hERG 1A/3.1 channel protein trafficking. Our study examined cariprazine's mechanism of action provides a biophysical profile that is necessary to assess the potential therapeutic effects of this drug.


Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Piperazinas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína
19.
Eur J Pharmacol ; 854: 320-327, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31009638

RESUMO

Alpha 2 (α2-) adrenoceptor agonists, such as clonidine or dexmedetomidine, have been found to inhibit hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels, not only by reducing intracellular cyclic AMP levels but also by directly blocking HCN channels. In this study, we examined the inhibitory effect of guanabenz, a centrally acting α2-adrenoceptor agonist with high specificity for α2A-subtype, on HCN channels in mesencephalic trigeminal nucleus (MTN) neurons which robustly express HCN channels and have been suggested to coexpress α2A-adrenoceptors. By performing whole-cell patch-clamp recording on MTN neurons in brainstem slices, hyperpolarization-activated inward current (Ih) was examined during guanabenz treatment. Guanabenz inhibited Ih in a dose-dependent manner, which was likely to be ZD7288-sensitive HCN current as it did not affect barium-sensitive inward rectifying potassium current. Guanabenz not only inhibited Ih but also shifted the voltage-dependent activation curve to hyperpolarizing potentials. Interestingly, Ih inhibition by guanabenz was not reversed by α2-adrenoceptor antagonist atipamezole treatment or by intracellular cyclic AMP perfusion, suggesting that the inhibition may not result from α2A-adrenoceptor signalling pathway but from direct inhibition of HCN channels. Coherent to our electrophysiological results, single-cell RT-PCR revealed that most MTN neurons lack α2A-adrenoceptor mRNA. Our study demonstrates that guanabenz can directly inhibit HCN channels in addition to its primary role of activating α2A-adrenoceptors.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Guanabenzo/farmacologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Tegmento Mesencefálico/citologia , Animais , Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/genética
20.
Artif Cells Nanomed Biotechnol ; 47(1): 491-500, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30942090

RESUMO

Peripheral nerve injury has troubled clinical doctors for many years. To obtain better function recovery of peripheral nerve repair at the base of hollow nerve guidance conduit (NGC), many NGCs with fillers were developed in the application of tissue-engineered nerve graft. In this study, expanded 3D nanofibre sponge scaffolds with orientation and porosity were first fabricated by electrospinning and gas-foaming technique. Polylactic acid (PLA)/silk fibroin nanofibre sponge scaffolds were prepared as filler to construct 3D nanofibre sponges containing NGC (SNGC). SNGC could promote the proliferation of Schwann cells compared with the hollow NGC in vitro. The results of animal experiments confirm that SNGC can significantly promote peripheral nerve function recovery from histology and function evaluation. In conclusion, we design a new method to construct a 3D scaffold containing NGC with orientation and porosity. The application of this 3D scaffold material has good prospects in future peripheral nerve repair.


Assuntos
Materiais Biocompatíveis/farmacologia , Gases/química , Nanofibras/química , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia , Tecidos Suporte/química , Animais , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fibroínas/química , Camundongos , Músculos/efeitos dos fármacos , Músculos/fisiologia , Poliésteres/química , Porosidade , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/citologia
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