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1.
J Med Chem ; 63(8): 4133-4154, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32233403

RESUMO

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indicated a M2R preference. Flow cytometric and high-content imaging saturation and competition binding (M1R, M2R, and M4R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM2R cells). Results from dissociation and saturation binding experiments (M2R) in the presence of allosteric M2R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M2R in imaging and binding studies and suggest that they have a dualsteric mode of action.


Assuntos
Corantes Fluorescentes/metabolismo , Antagonistas Muscarínicos/metabolismo , Ftalimidas/metabolismo , Compostos de Amônio Quaternário/metabolismo , Receptor Muscarínico M2/antagonistas & inibidores , Receptor Muscarínico M2/metabolismo , Animais , Células CHO , Colinérgicos/química , Colinérgicos/metabolismo , Colinérgicos/farmacologia , Cricetulus , Corantes Fluorescentes/química , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Ftalimidas/química , Ftalimidas/farmacologia , Estrutura Secundária de Proteína , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia
2.
Nat Chem Biol ; 16(3): 240-249, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32080630

RESUMO

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including 'epileptic-like' seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.


Assuntos
Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Colinérgicos/farmacologia , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Técnicas de Introdução de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação
3.
Psychopharmacology (Berl) ; 237(1): 137-153, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31620809

RESUMO

RATIONALE: Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and, in patients with Parkinson's disease (PD), to impairments in gait and balance and the resulting risks for falls. Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. OBJECTIVES: Here, we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that a M1 PAM amplifies such transient signaling and thereby rescues attentional performance. RESULTS: Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period. The post-dSAT period served to assess the capacity for recovering performance following a disruptive event. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose). Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, but also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d') in lesioned rats and facilitated the adoption of a more liberal response bias (B˝D) in all female rats. CONCLUSIONS: These findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.


Assuntos
Atenção/efeitos dos fármacos , Colinérgicos/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Animais , Sinais (Psicologia) , Masculino , Ratos , Análise e Desempenho de Tarefas
4.
Int J Radiat Biol ; 96(2): 236-244, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31633438

RESUMO

Purpose: Pharmacological medications can reduce the radiation damage in the organism when applied in the stage before or after exposure to radiation. Cholinergic drugs are a category of pharmaceutical agents acting on the neurotransmitter acetylcholine, the primary neurotransmitter in the parasympathetic nervous system. In this investigation, some gamma radiation interaction parameters namely mass attenuation coefficients (µρ), effective atomic number (Zeff) and electron densities (Nel) of 12 cholinergic system drugs have been calculated in the energy range 1 KeV-100 GeV. In addition, gamma-ray energy absorption (EABF) and exposure (EBF) of buildup factors have been computed using the five-parameter geometric progression (G-P) fitting formula for investigated drugs in the energy range 0.015-15 MeV, and for penetration depths up to 40 mean free path (mfp).Materials and methods: In order to perform these calculations, data obtained from WinXCom computer program were used. The computed µρ values were then used to calculate the effective atomic numbers and electron density of the investigated drugs. To compute the buildup factors, the G-P fitting parameters were determined by the method of interpolation from the equivalent atomic number, 'Zeq'Results and Conclusions: It has been concluded that effective atomic number and electron density of malathion is bigger than the other drugs and the variations in values of Zeff and Nel for all drugs depend on chemical compositions and photon energy where the K-absorption edge of elements may affect the energy dependence of Zeff and Nel. It should also be noted that the buildup of photons is less in malathion and carbachol and is more in tabun and parathion compared with other drugs. Photon interaction parameters evaluated in the present study may be beneficial in radiation dosimetry and therapy.


Assuntos
Acetilcolina/farmacologia , Acetilcolina/efeitos da radiação , Colinérgicos/farmacologia , Colinérgicos/efeitos da radiação , Raios gama , Algoritmos , Carbacol/farmacologia , Carbacol/efeitos da radiação , Cloro/química , Elétrons , Malation/farmacologia , Malation/efeitos da radiação , Modelos Estatísticos , Organofosfatos/farmacologia , Organofosfatos/efeitos da radiação , Paration/farmacologia , Paration/efeitos da radiação , Fósforo/química , Fótons , Probabilidade , Doses de Radiação , Radiometria , Espalhamento de Radiação , Software
5.
Nat Commun ; 10(1): 5280, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754098

RESUMO

Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1-3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10-20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.


Assuntos
Atenção/efeitos dos fármacos , Colinérgicos/farmacologia , Interneurônios/fisiologia , Córtex Pré-Frontal/metabolismo , Acetilcolina/farmacologia , Animais , Atenção/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Colina O-Acetiltransferase/metabolismo , Feminino , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Camundongos da Linhagem 129 , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Ratos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo
6.
Invest Ophthalmol Vis Sci ; 60(14): 4759-4773, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31738824

RESUMO

Purpose: Reaggregates from E6 embryonic chicken retina exhibit areas corresponding to an inner plexiform layer (IPL), which presents an ideal in vitro model to test conditions and constraints of cholinergic and glutamatergic network formation, providing a basis for retinal tissue engineering. Here, we show that ipl formation is regulated by cholinergic starburst amacrine cells (SACs), a glial scaffold and by L-glutamate. Methods: Rosetted spheroids were cultured in absence or presence of 0.2 to 0.4 mM L-glutamate and analyzed by immuno- and enzyme histochemistry, proliferation, and apoptosis assays. Results: After 2 days in vitro (div), ipl formation was announced by acetylcholinesterase+ (AChE) and choline acetyltransferase+ (ChAT) cells. Individual vimentin+ or transitin+ Müller glial cell precursors (MCPs) in ipl centers coexpressed ChAT. Comparable to in vivo, pairwise arranged ChAT+ SACs formed two laminar subbands. Projections of calretinin+ amacrine cells (ACs) into ipl associated with MCP processes. In L-glutamate-, or NMDA-treated spheroids ipls were disrupted, including loss of SACs and MCs; coincubation with NMDA receptor inhibitor MK-801 prevented these effects. Also, many Pax6+ cells, comprising most ACs, were lost, while rho4D2+ rod photoreceptors were increased. Cell proliferation was slightly increased, while apoptosis remained unaffected. Conclusions: This demonstrated: (1) a far-advanced differentiation of an IPL in retinal spheroids, as never described before; (2) ipl sublamination was initiated by cholinergic precursor cells, which-functioning as "ipl founder cells"-(3) gave rise to neurons and glial cells; (4) these SACs and MCPs together organized ipl formation; and (5) this process was counteracted by NMDA-dependent glutamate actions.


Assuntos
Diferenciação Celular/fisiologia , Colinérgicos/farmacologia , Células Ependimogliais/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/embriologia , Transdução de Sinais/fisiologia , Esferoides Celulares/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Proliferação de Células/fisiologia , Células Cultivadas , Embrião de Galinha , Colina O-Acetiltransferase/metabolismo , Crioultramicrotomia , Ácido Glutâmico/farmacologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Neurônios Retinianos/citologia , Esferoides Celulares/metabolismo , Fixação de Tecidos , Vimentina/metabolismo
7.
Bol. latinoam. Caribe plantas med. aromát ; 18(6): 595-606, nov. 2019. ilus
Artigo em Espanhol | LILACS | ID: biblio-1102648

RESUMO

Petiveria alliacea (PA) have anxiolytic, antidepressant and cognitive effects. In the present paper the effect of PA water infusion and cholinergic drugs on cognitive behavior were studied. For that, 40 male NMRI mice were divided in 4 groups: Control (n=10), Drug Control (n=10), PA (n=10) and PA plus Drug (n=10). PA 1% was administered orally (7.59±1.39 ml/day); while scopolamine (2 mg/Kg), galantamine (1 mg/Kg) and nicotine (0.1 mg/Kg) were administered intraperitoneally. Behavioral tests included: anxiety maze (AM), open field (OF) and marble burying (MB). Habituation cognitive behavior was evaluated in 4 sessions, one week each session. PA had anxiolytic and antidepressant effect effect in AM, combined with nicotine potentiated an anxiogenic effect in AM, galantamine favored habituation in OF. Scopolamine potentiated the habituation in LA and decreased the obsessive-compulsive behavior in OF. In conclusion; PA had an anxiolytic effect and favored deshabituation, combined with nicotine induced an anxiogenic effect, galantamine favored habituation and scopolamine decreased obsessive-compulsive behavior and favored motor habituation indicated a possible anxiolytic effect.


La Petiveria alliacea (PA) está relacionada con efectos ansiolíticos, antidepresivos y cognitivos. El presente trabajo estudió el efecto de la infusión de PA y drogas colinérgicas sobre la habituación. 40 ratones NMRI machos fueron divididos en 4 grupos: Control (n=10), Control Drogas (n=10), PA (n=10) y PA plus Drogas (n=10). La PA (1%) fue administrada vía oral (7.59±1.39 ml/día); escopolamina (2 mg/Kg), galantamina (1 mg/Kg) y nicotina (0.1 mg/Kg) fueron administrados vía intraperitoneal. Los ensayos conductuales incluyeron: laberinto de ansiedad (LA), campo abierto (CA) y enterramiento aversivo (EA). La habituación fue evaluada en 4 sesiones con duración de una semana cada una. PA mostró un efecto ansiolítico en el LA, combinada con nicotina potenció un efecto ansiogénico en el LA. Galantamina favoreció la habituación en CA, y escopolamina potenció el fenómeno de habituación en LA y disminuyó la conducta obsesivo-compulsiva en CA. En conclusión, la PA mostró un efecto ansiolítico y antidepresivo que potencia la deshabituación, combinada con nicotina indujo un efecto ansiogénico, galantamina favoreció la habituación y escopolamina disminuyó la conducta obsesivo­ compulsiva y favoreció la habituación motora indicando un posible efecto ansiolítico.


Assuntos
Animais , Masculino , Camundongos , Colinérgicos/farmacologia , Phytolaccaceae/química , Habituação Psicofisiológica/efeitos dos fármacos , Escopolamina/farmacologia , Galantamina/farmacologia , Nicotina/farmacologia
8.
Arch Med Res ; 50(5): 295-303, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31600601

RESUMO

BACKGROUND: Melatonin is a neurohormone that is linked to the pathogenesis of schizophrenia. The aim of this study was to assess the potential of melatonin in attenuating MK-801 induced schizophrenia-like behavioral and brain neurotoxicity markers. METHODS: Swiss albino mice were assigned into three groups (n = 6). Animals were administered MK-801 (1 mg/kg/mL, i.p.). MK-801 treated animals were supplemented with melatonin (10 mg/kg/1 mL i.p.) 10 min prior to MK-801 injection. The relative degrees of modulation of induced behaviors by melatonin were assessed in the open field, elevated plus maze, grip strength and rota rod. The changes in neurotoxicity enzymes and neuronal activity (c-fos) were demonstrated in this study. RESULTS: MK-801 injection effected normal open-field behaviors, c-fos expression, motor coordination and muscular strength. Melatonin was able to reduce the histological changes in the prefrontal cortex of mice brain. CONCLUSION: Our data demonstrated that the treatment with melatonin attenuates the schizophrenic like symptoms in the mice having a protective effect on prefrontal cortex region of brain by mitigating the alteration of neurotoxicity markers. The protective effect of the treatment was shown to reduced elevation of AChE, c-fos expression and histopathological alterations.


Assuntos
Colinérgicos/uso terapêutico , Melatonina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Animais , Colinérgicos/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Melatonina/farmacologia , Camundongos , Esquizofrenia/patologia
9.
Invert Neurosci ; 19(4): 11, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31486912

RESUMO

Parasitic nematode infections are treated using anthelmintic drugs, some of which target nicotinic acetylcholine receptors (nAChRs) located in different parasite tissues. The limited arsenal of anthelmintic agents and the prevalence of drug resistance imply that future defense against parasitic infections will depend on the discovery of novel targets and therapeutics. Previous studies have suggested that Ascaris suum ACR-16 nAChRs are a suitable target for the development of antinematodal drugs. In this study, we characterized the pharmacology of the Ancylostoma caninum ACR-16 receptor using two-electrode voltage-clamp electrophysiology. This technique allowed us to study the effects of cholinergic agonists and antagonists on the nematode nAChRs expressed in Xenopus laevis oocytes. Aca-ACR-16 was not sensitive to many of the existing cholinomimetic anthelmintics (levamisole, oxantel, pyrantel, and tribendimidine). 3-Bromocytisine was the most potent agonist (> 130% of the control acetylcholine current) on the Aca-ACR-16 nAChR but, unlike Asu-ACR-16, oxantel did not activate the receptor. The mean time constants of desensitization for agonists on Aca-ACR-16 were longer than the rates observed in Asu-ACR-16. In contrast to Asu-ACR-16, the A. caninum receptor was completely inhibited by DHßE and moderately inhibited by α-BTX. In conclusion, we have successfully reconstituted a fully functional homomeric nAChR, ACR-16, from A. caninum, a model for human hookworm infections. The pharmacology of the receptor is distinct from levamisole-sensitive nematode receptors. The ACR-16 homologue also displayed some pharmacological differences from Asu-ACR-16. Hence, A. caninum ACR-16 may be a valid target site for the development of anthelmintics against hookworm infections.


Assuntos
Ancylostoma/metabolismo , Anti-Helmínticos/farmacologia , Proteínas de Helminto/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Ancilostomíase , Animais , Colinérgicos/farmacologia , Proteínas de Helminto/análise , Proteínas de Helminto/metabolismo , Receptores Nicotínicos/análise , Receptores Nicotínicos/metabolismo
10.
Anesth Analg ; 129(3): 745-752, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31425216

RESUMO

BACKGROUND: The ability of inotropic agents to alter airway reactivity and lung tissue mechanics has not been compared in a well-controlled experimental model. Therefore, we compared the potential to alter lung tissue viscoelasticity and bronchodilator effects of commonly used inotropic agents in an isolated perfused rat lung model. METHODS: After achieving steady state lung perfusion, sustained bronchoconstriction was induced by acetylcholine (ACh). Isolated rat lungs were then randomly allocated to 6 groups treated with either saline vehicle (n = 8) or incremental concentrations of inotropes (adrenaline, n = 8; dopamine, n = 7; dobutamine, n = 7; milrinone, n = 8; or levosimendan, n = 6) added to the whole-blood perfusate. Airway resistance (Raw), lung tissue damping (G), and elastance were measured under baseline conditions, during steady-state ACh-induced constriction and for each inotrope dose. RESULTS: No change in Raw was observed after addition of the saline vehicle. Raw was significantly lower after addition of dopamine (maximum difference [95% CI] of 29 [12-46]% relative to the saline control, P = .004), levosimendan (58 [39-77]%, P < .001), and adrenaline (37 [21-53]%, P < .001), whereas no significant differences were observed at any dose of milrinone (5 [-12 to 22]%) and dobutamine (4 [-13 to 21]%). Lung tissue damping (G) was lower in animals receiving the highest doses of adrenaline (difference: 22 [7-37]%, P = .015), dobutamine (20 [5-35]%, P = .024), milrinone (20 [6-34]%, P = .026), and levosimendan (36 [19-53]%, P < .001) than in controls. CONCLUSIONS: Although dobutamine and milrinone did not reduce cholinergic bronchoconstriction, they reversed the ACh-induced elevations in lung tissue resistance. In contrast, adrenaline, dopamine, and levosimendan exhibited both potent bronchodilatory action against ACh and diminished lung tissue damping. Further work is needed to determine whether these effects are clinically relevant in humans.


Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Cardiotônicos/farmacologia , Colinérgicos/farmacologia , Pulmão/efeitos dos fármacos , Acetilcolina/farmacologia , Resistência das Vias Respiratórias/fisiologia , Animais , Broncoconstrição/fisiologia , Broncodilatadores/farmacologia , Dobutamina/farmacologia , Pulmão/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Simendana/farmacologia
11.
Org Biomol Chem ; 17(35): 8166-8174, 2019 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-31464336

RESUMO

Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic M1 positive allosteric modulator 1 bearing an isoindolin-1-one ring system as a pharmacophore has been achieved using flow microreactors through selective I/Li exchange of 1-bromo-2-iodobenzene derivative 17 with BuLi and subsequent formylation at -40 °C of the highly reactive 2-bromophenyllithium intermediate using DMF, which is difficult to achieve by a conventional batch process due to the conversion of the highly reactive 2-bromophenyllithium intermediate into benzyne even at -78 °C. Late-stage cyclization to give the isoindolin-1-one ring system, through reductive amination of 18 followed by palladium-catalyzed carbonylation with carbon monoxide and intramolecular cyclization, efficiently afforded 1 for its further research and development.


Assuntos
Benzaldeídos/farmacologia , Colinérgicos/farmacologia , Receptor Muscarínico M1/metabolismo , Regulação Alostérica/efeitos dos fármacos , Benzaldeídos/síntese química , Benzaldeídos/química , Colinérgicos/síntese química , Colinérgicos/química , Humanos , Estrutura Molecular
12.
Arch Pharm Res ; 42(8): 722-731, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31350730

RESUMO

Isoorientin (ISO) is considered one of the most important flavonoids with various pharmacological effects such as antioxidant, anti-inflammatory, and anti-cancer activities. Despite these beneficial activities, the effects of ISO on learning and memory have not been investigated so far. The current study evaluated the memory-enhancing effects of ISO in a scopolamine-treated mouse model by using the Y-maze and passive avoidance tests. The results showed that ISO (5 and 10 mg/kg, p.o.) treatment significantly improved the cognitive impairments caused by scopolamine. Additionally, ISO significantly decreased scopolamine-induced acetylcholinesterase and thiobarbituric acid reactive substance activities in both the hippocampus and frontal cortex of mice. In addition, ISO significantly increased the levels of total superoxide dismutase induced by scopolamine in the hippocampus and frontal cortex. Moreover, Western blot results indicated that ISO reversed the decreases in expression of phosphorylated cAMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus and frontal cortex of scopolamine-treated mice. Thus, our results provide initial evidence that ISO ameliorates scopolamine-induced memory and cognitive impairments partly by restoring the cholinergic system, antioxidant defense, and p-CREB/BDNF signaling pathway, thereby exhibiting memory-enhancing activities.


Assuntos
Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colinérgicos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Luteolina/farmacologia , Animais , Colinérgicos/química , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Luteolina/química , Masculino , Memória/efeitos dos fármacos , Camundongos , Estrutura Molecular , Escopolamina , Transdução de Sinais/efeitos dos fármacos
13.
Methods Mol Biol ; 2011: 165-193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31273700

RESUMO

Tobacco kills every year approximately six million people as a direct result of direct use, and it is still considered one of the most excruciating threats for human health worldwide. The low successful rates of the currently available pharmacotherapies to assist in quitting tobacco use suggest there is a need for more effective treatments.The intravenous self-administration (IVSA) paradigm is considered the gold standard to study voluntary drug intake in animal models, including nicotine. The IVSA paradigm has been used to identify key mechanisms involved in the addictive properties of nicotine in both rodents and nonhuman primates. In this chapter we describe how the IVSA paradigm has served to further investigate the role of nicotinic acetylcholine receptors (nAChRs) in the reinforcing properties of nicotine. Notably, this review will cover recent advances (i.e., research carried out during the past decade) using the IVSA paradigm, with a focus on the status of research on current smoking cessation medications (such as varenicline and bupropion) and of other nAChR ligands.The combination of the IVSA paradigm with pharmacological and genetic tools (e.g., knockout animals) has greatly contributed to our understanding of the role of specific subtype nAChRs in nicotine reinforcement processes. We also discuss some of the limitations of the IVSA paradigm so these can be taken into consideration when interpreting and designing new studies.


Assuntos
Nicotina/administração & dosagem , Abandono do Hábito de Fumar , Animais , Comportamento Aditivo , Colinérgicos/farmacologia , Técnicas de Inativação de Genes , Humanos , Modelos Animais , Antagonistas Nicotínicos/administração & dosagem , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Autoadministração , Abandono do Hábito de Fumar/métodos , Vareniclina/administração & dosagem
14.
Neurotoxicology ; 74: 132-138, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31212017

RESUMO

Cockroach neurosecretory cells, dorsal unpaired median (DUM) neurons, express two distinct α-bungarotoxin-insensitive nicotinic acetylcholine receptor subtypes, nAChR1 and nAChR2 which are differently sensitive to the neonicotinoid insecticides and intracellular calcium pathways. The aim of this study is to determine whether sulfoxaflor acts as an agonist of nAChR1 and nAChR2 subtypes. We demonstrated that 1 mM sulfoxaflor induced high current amplitudes, compared to acetylcholine, suggesting that it was a full agonist of DUM neuron nAChR subtypes. Sulfoxaflor evoked currents were not inhibited by the nicotinic acetylcholine receptor antagonist d-tubocurarine (dTC) which reduced nAChR1. But, sulfoxaflor evoked currents were reduced in the presence of 5 µM mecamylamine which is known to reduce nAChR2 subtype. Interestingly, when 1 µM imidacloprid was added in the extracellular solution, sulfoxaflor-induced currents were significantly suppressed. Moreover, when extracellular calcium concentration was increased, bath application of 1 µM imidacloprid partially reduced sulfoxaflor activated currents when nAChR1 was inhibited with 20 µM dTC and completely suppressed sulfoxaflor currents when nAChR2 was inhibited with 5 µM mecamylamine. Our data demonstrated therefore that sulfoxaflor activates both nAChR1 and nAChR2 subtypes.


Assuntos
Bungarotoxinas/farmacologia , Colinérgicos/farmacologia , Baratas , Neonicotinoides/farmacologia , Agonistas Nicotínicos/farmacologia , Nitrocompostos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Compostos de Enxofre/farmacologia , Acetilcolina/farmacologia , Animais , Cálcio/farmacologia , Mecamilamina/farmacologia , Antagonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Piridinas/antagonistas & inibidores , Compostos de Enxofre/antagonistas & inibidores , Tubocurarina/toxicidade
15.
Rev Peru Med Exp Salud Publica ; 36(1): 54-61, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31116339

RESUMO

OBJECTIVES.: To determine and compare the effect of adrenergic and cholinergic agonist drugs on the production of reactive oxygen species (ROS) in neutrophils of healthy individuals. MATERIALS AND METHODS.: Whole blood samples were taken from five participants to purify neutrophils using the gelatin method. The production of chemiluminescent (QLM) ROS was measured using a scintillation counter and phorbol-12-myristat-13-acetate (PMA) as a stimulus. Non-PLA tests were also conducted to measure spontaneous production. Subsequently, with the same method, ROS formation was measured in the presence of nicotine (cholinergic agonist), salbutamol, and clonidine (adrenergic agonists), each in concentrations of 10-2 M, 10-3 M, 10-4 M, and 10-5 M. The area integrated under the QLM curves was calculated and the percentage of inhibition or stimulation was found as the case may be. The effect of the drugs was compared with their corresponding controls and statistical analysis was carried out. RESULTS.: A decrease in the production of ROS was obtained as an effect of the substances studied with a significant difference between the controls and the effect produced at 10-2 M, 10-3 M, and 10-4 M . This effect increased in intensity as drug concentration increased. The highest percentages of inhibition were shown at 10-2 M and 10-3 M. Salbutamol presented the maximum values with all the concentrations with a significant difference between its inhibition and that generated by the other drugs. CONCLUSIONS.: Adrenergic and cholinergic stimuli have an inhibitory effect on the production of ROS in neutrophils of healthy individuals.


Assuntos
Adrenérgicos/farmacologia , Colinérgicos/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio , Adolescente , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Psychopharmacology (Berl) ; 236(8): 2473-2484, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30982126

RESUMO

Many physiological and pathological changes in brain function manifest in eye-movement control. As such, assessment of oculomotion is an invaluable part of a clinical examination and affords a non-invasive window on several key aspects of neuronal computation. While oculomotion is often used to detect deficits of the sort associated with vascular or neoplastic events; subtler (e.g. pharmacological) effects on neuronal processing also induce oculomotor changes. We have previously framed oculomotor control as part of active vision, namely, a process of inference comprising two distinct but related challenges. The first is inferring where to look, and the second is inferring how to implement the selected action. In this paper, we draw from recent theoretical work on the neuromodulatory control of active inference. This allows us to simulate the sort of changes we would expect in oculomotor behaviour, following pharmacological enhancement or suppression of key neuromodulators-in terms of deciding where to look and the ensuing trajectory of the eye movement itself. We focus upon the influence of cholinergic and GABAergic agents on the speed of saccades, and consider dopaminergic and noradrenergic effects on more complex, memory-guided, behaviour. In principle, a computational approach to understanding the relationship between pharmacology and oculomotor behaviour affords the opportunity to estimate the influence of a given pharmaceutical upon neuronal function, and to use this to optimise therapeutic interventions on an individual basis.


Assuntos
Simulação por Computador , Movimentos Oculares/fisiologia , Modelos Neurológicos , Colinérgicos/farmacologia , Movimentos Oculares/efeitos dos fármacos , GABAérgicos/farmacologia , Humanos , Memória/efeitos dos fármacos , Memória/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Movimentos Sacádicos/efeitos dos fármacos , Movimentos Sacádicos/fisiologia
17.
Microb Pathog ; 132: 137-140, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028864

RESUMO

The role of cholinesterase in inflammatory reactions has been described in several infectious diseases. However, in Brucella spp. this has not yet been studied. Therefore, the objective of this study was to evaluate whether experimental infection by Brucella ovis alters the cholinergic activity in pro- or anti-inflammatory responses to the disease. For the study 48 mice were used, 24 infected by B. ovis and 24 non-infected. We collected samples of whole blood on days 7, 15, 30 and 60 post-infection (PI) by B. ovis. Acetylcholinesterase (AChE) activity in the blood increased on days 15 and 60 PI (P < 0.05). Butyrylcholinesterase (BChE) activity in serum increased on days 7 and 60 PI (P < 0.05). An increase in serum free radical levels occurred on days 7, 15 and 60 PI (P < 0.05), and consequently superoxide dismutase activity increased on day 15 PI (P < 0.05). A reduction in catalase activity occurred when the infection became chronic (60 PI). The increase in AChE and BChE characterized a pro-inflammatory response, since these enzymes regulate levels of acetylcholine (ACh) and butyrylcholine (BuSCh), molecules with anti-inflammatory properties. Therefore, with the increase of cholinesterase activity, there was an extracellular reduction of ACh, an inhibitor of several inflammatory mediators. This proinflammatory response of B. ovis infection leads to oxidative stress, and consequently to cellular damage.


Assuntos
Acetilcolinesterase/metabolismo , Brucella ovis/patogenicidade , Butirilcolinesterase/metabolismo , Colinesterases/metabolismo , Acetilcolina/metabolismo , Acetilcolinesterase/sangue , Animais , Brucelose/sangue , Butirilcolinesterase/sangue , Catalase , Colina/análogos & derivados , Colina/metabolismo , Colinérgicos/farmacologia , Colinesterases/sangue , DNA Bacteriano/análise , Modelos Animais de Doenças , Inflamação , Masculino , Camundongos , Estresse Oxidativo , Espécies Reativas de Oxigênio/sangue , Espécies Reativas de Oxigênio/metabolismo , Soro/enzimologia , Superóxido Dismutase
18.
Pharmacol Rep ; 71(3): 443-448, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003155

RESUMO

BACKGROUND: Chronic cerebral hypoperfusion (CCH) can induce the accumulation of reactive oxygen species, which leads to oxidative damage, neuronal injury, and central cholinergic dysfunction in vulnerable regions of the brain, such as the hippocampus and cerebral cortex. These effects can lead to significant cognitive impairments in clinical populations of vascular dementia (VaD). The present studies aimed to investigate the role of the cholinergic system in memory functions and hippocampal long-term potentiation (LTP) impairments induced by CCH in rats. METHODS: Male Sprague Dawley rats were subjected to permanent bilateral occlusion of common carotid arteries (PBOCCA) or sham surgery. Then, PBOCCA rats received ip injections with, either vehicle (control group), the muscarinic receptor agonist oxotremorine (0.1 mg/kg), or the acetylcholinesterase inhibitor physostigmine (0.1 mg/kg). Cognitive functions were evaluated using a passive avoidance task and the Morris water maze test. In addition, hippocampal LTP was recorded in vivo under anaesthesia. RESULTS: The PBOCCA rats exhibited significant deficits in passive avoidance retention and spatial learning and memory tests. They also showed a suppression of LTP formation in the hippocampus. Oxotremorine and physostigmine significantly improved the learning and memory deficits as well as the suppression of LTP in PBOCCA rats. CONCLUSIONS: The present data suggest that the cholinergic system plays an important role in CCH-induced cognitive deficits and could be an effective therapeutic target for the treatment of VaD.


Assuntos
Isquemia Encefálica/complicações , Colinérgicos/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Colinérgicos/farmacologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/etiologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
19.
Molecules ; 24(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836659

RESUMO

Researches on spicatoside A (SpiA)-containing natural products suggest the possibility of SpiA as a potential laxative to alleviate chronic constipation. However, no studies have been conducted with single compound administration of SpiA. To verify the laxative effects and mechanism of action of SpiA on chronic constipation, we investigated alterations in the excretion parameters, histological structure, and cholinergic regulation of the enteric nerve in the colons of Institute of Cancer Research (ICR) mice with loperamide (Lop)-induced constipation after exposure to 20 mg/kg of SpiA. Decrease in the number, weight and water contents of stools in the Lop+Vehicle treated group significantly recovered after SpiA treatment, and alterations in the histological structure and transmission electron microscopy (TEM) images were improved in the Lop+SpiA treated group. Similar recovery effects were observed in the ability for mucin secretion and expression of the membrane water channel gene (aquaporin 8, AQP8). Furthermore, significant improvements were observed in the acetylcholinesterase (AChE) activity and acetylcholine receptors' (AChRs) downstream signaling pathway after treatment of SpiA. The levels of gastrointestinal (GI) hormones including cholecystokinin (CCK) and gastrin were also remarkably enhanced in the Lop+SpiA treated group as compared to the Lop+Vehicle treated group. The expression of receptor tyrosine kinase (C-kit) and protein gene product 9.5 (PGP9.5) in Cajal and neural cells, as well as the phosphorylation of myosin light chain (MLC) in smooth muscle cells, were recovered after SpiA exposure. Taken together, the results of the present study provide the first strong evidence that SpiA improves chronic constipation through muscarinic cholinergic regulation of the enteric nerve in a Lop-induced constipation ICR mice model.


Assuntos
Colinérgicos/farmacologia , Constipação Intestinal/tratamento farmacológico , Sistema Nervoso Entérico/efeitos dos fármacos , Laxantes/farmacologia , Saponinas/farmacologia , Animais , Aquaporinas/metabolismo , Peso Corporal , Constipação Intestinal/induzido quimicamente , Modelos Animais de Doenças , Ingestão de Alimentos , Hormônios Gastrointestinais/metabolismo , Regulação da Expressão Gênica , Liliaceae/química , Loperamida , Camundongos , Camundongos Endogâmicos ICR , Mucinas/metabolismo , Extratos Vegetais/química , Raízes de Plantas/química , Proteínas Tirosina Quinases/metabolismo , Saponinas/isolamento & purificação , Transdução de Sinais
20.
J Vis Exp ; (144)2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30799845

RESUMO

Investigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A computerized and thoroughly validated battery of neuropsychological and neurophysiological tests has been shown to be sensitive to detect drug-induced effects of multiple new and existing compounds. The test battery covers the main CNS domains, which have been shown to respond to drug effects and can be repeatedly administered following drug administration to characterize the concentration-effect profile of a drug. The standard tests in the battery are saccadic eye movement, smooth pursuit eye movement, the Bowdle visual analog scale (VAS), the Bond and Lader VAS, body sway, adaptive tracking, visual verbal learning, and quantitative electroencephalography (qEEG). However, the test battery is adaptive in nature, meaning that it can be composed and adjusted with tests fit to investigate specific drug classes, or even specific receptors. Showing effects of new cholinergic drugs designed to have a pro-cognitive outcome has been difficult. The pharmacological challenge model is a tool for early proof-of-pharmacology. Here, a marketed drug is used to induce temporary and reversible disease-like symptoms in healthy subjects, via a pharmacological mechanism related to the disease that is targeted as indication for the new compound. The test battery was implemented to investigate the potential of the nicotinic receptor antagonist mecamylamine to be used as a challenge model for cholinergic dysfunction, as seen in neurodegenerative disorders. A worsening of scores in a dose dependent manner on the visual verbal learning test (VVLT; a test for learning and memory abilities) and the adaptive tracking test (a measure of visuomotor control and arousal), in particular, showed that the test battery is sensitive to showing acute pharmacodynamic effect after administration of anti-cholinergic drugs.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Colinérgicos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Adulto , Colinérgicos/farmacologia , Feminino , Humanos , Masculino
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