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1.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955902

RESUMO

In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer's disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer's disease has been placed on serotonin 5-HT6 receptor (5-HT6R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT6R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.


Assuntos
Doença de Alzheimer , Transtornos Cognitivos , Doença de Alzheimer/metabolismo , Animais , Transtornos Cognitivos/etiologia , Humanos , Ligantes , Receptores de Serotonina/metabolismo , Serotonina , Antagonistas da Serotonina/farmacologia
2.
J Cardiovasc Pharmacol ; 80(2): 314-322, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35939654

RESUMO

ABSTRACT: The 5-hydroxytryptamine 7 (5-HT 7 ) receptor is reported to have considerable constitutive activity when transfected into cells. Constitutive activity-receptor activity in the absence of known agonist-is important for understanding the contributions of a receptor to (patho)physiology. We test the hypothesis that the 5-HT 7 receptor possesses constitutive activity in a physiological situation. Isolated veins from male and female Sprague Dawley rats were used as models for measuring isometric force; the abdominal vena cava possesses a functional 5-HT 7 receptor that mediates relaxation, whereas the small mesenteric vein does not. Compounds reported to act as inverse agonists were investigated for their ability to cause contraction (moving a constitutively active relaxant receptor to an inactive state, removing relaxation). Compared with a vehicle control, clozapine, risperidone, ketanserin, and SB269970 caused no contraction in the isolated male abdominal vena cava. By contrast, methiothepin caused a concentration-dependent contraction of the male but not female abdominal vena cava, although with low potency (-log EC 50 [M] = 5.50 ± 0.45) and efficacy (∼12% of contraction to endothelin-1). Methiothepin-induced contraction was not reduced by the 5-HT 7 receptor antagonist (SB269970, 1 µM, not active in the vena cava). These same compounds showed little to no effect in the isolated mesenteric vein. We conclude that the 5-HT 7 receptor in the isolated veins of the Sprague Dawley rat does not possess constitutive activity. We raise the question of the physiological relevance of constitutive activity of this receptor important to such diverse physiological functions as sleep, circadian rhythm, temperature, and blood pressure regulation.


Assuntos
Antagonistas da Serotonina , Serotonina , Animais , Pressão Sanguínea , Masculino , Metiotepina/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Vasoconstrição
3.
Bioorg Med Chem ; 70: 116917, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35839536

RESUMO

Herein, a series of novel 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)- 1H-indole derivatives were designed and synthesized via hybridization strategy of idalopirdine and SB-271046. The optimal compound C14 (Ki = 0.085 nM), with difluoromethyl on C3 position on indole scaffold, increased the affinity for the 5-HT6R up to 10-folds than idalopirdine (Ki = 0.83 nM). Additionally, C14 had good pharmacokinetic properties and in vitro metabolic properties. Finally, C14 could efficiently reverse the scopolamine induced emotional memory deficits in novel object recognition assay in rats. Thus, we propose C14 might be considered as a new cognition-enhancing agent and the further studies are now underway in our laboratory.


Assuntos
Receptores de Serotonina , Serotonina , Animais , Cognição , Indóis/farmacologia , Piperazina , Ratos , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 23(13)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35806448

RESUMO

Some diseases that are associated with dopamine deficiency are accompanied by psychiatric symptoms, including Parkinson's disease. However, the mechanism by which this occurs has not been clarified. Previous studies found that dopamine-deficient (DD) mice exhibited hyperactivity in a novel environment. This hyperactivity is improved by clozapine and donepezil, which are used to treat psychiatric symptoms associated with dopamine deficiency (PSDD). We considered that DD mice could be used to study PSDD. In the present study, we sought to identify the pharmacological mechanism of PSDD. We conducted locomotor activity tests by administering quetiapine and drugs that have specific actions on serotonin (5-hydroxytryptamine [5-HT]) receptors and muscarinic receptors. Changes in neuronal activity that were induced by drug administration in DD mice were evaluated by examining Fos immunoreactivity. Quetiapine suppressed hyperactivity in DD mice while the 5-HT1A receptor antagonist WAY100635 inhibited this effect. The number of Fos-positive neurons in the median raphe nucleus increased in DD mice that exhibited hyperactivity and was decreased by treatment with quetiapine and 5-HT1A receptor agonists. In conclusion, hyperactivity in DD mice was ameliorated by quetiapine, likely through 5-HT1A receptor activation. These findings suggest that 5-HT1A receptors may play a role in PSDD, and 5-HT1A receptor-targeting drugs may help improve PSDD.


Assuntos
Antipsicóticos , Dopamina , Fumarato de Quetiapina , Receptor 5-HT1A de Serotonina , Agonistas do Receptor 5-HT1 de Serotonina , Animais , Antipsicóticos/farmacologia , Dopamina/deficiência , Dopamina/metabolismo , Camundongos , Fumarato de Quetiapina/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia
5.
Int J Neuropsychopharmacol ; 25(9): 786-793, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35882205

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS. METHODS: We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats. RESULTS: Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment. CONCLUSIONS: ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.


Assuntos
Síndrome do Cromossomo X Frágil , Metanfetamina , Animais , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Guanidinas , Isoquinolinas , Masculino , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Knockout , Fenciclidina/uso terapêutico , Ratos , Ratos Transgênicos , Receptores de Serotonina , Escopolamina/uso terapêutico , Serotonina , Antagonistas da Serotonina/farmacologia
6.
Int J Mol Sci ; 23(10)2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35628547

RESUMO

Comorbid diabetes and depression constitutes a major health problem, worsening associated cardiovascular diseases. Fluoxetine's (antidepressant) role on cardiac diabetic complications remains unknown. We determined whether fluoxetine modifies cardiac vagal input and its serotonergic modulation in male Wistar diabetic rats. Diabetes was induced by alloxan and maintained for 28 days. Fluoxetine was administered the last 14 days (10 mg/kg/day; p.o). Bradycardia was obtained by vagal stimulation (3, 6 and 9 Hz) or i.v. acetylcholine administrations (1, 5 and 10 µg/kg). Fluoxetine treatment diminished vagally-induced bradycardia. Administration of 5-HT originated a dual action on the bradycardia, augmenting it at low doses and diminishing it at high doses, reproduced by 5-CT (5-HT1/7 agonist). 5-CT did not alter the bradycardia induced by exogenous acetylcholine. Decrease of the vagally-induced bradycardia evoked by high doses of 5-HT and 5-CT was reproduced by L-694,247 (5-HT1D agonist) and blocked by prior administration of LY310762 (5-HT1D antagonist). Enhancement of the electrical-induced bradycardia by 5-CT (10 µg/kg) was abolished by pretreatment with SB269970 (5-HT7 receptor antagonist). Thus, oral fluoxetine treatment originates a decrease in cardiac cholinergic activity and changes 5-HT modulation of bradycardic responses in diabetes: prejunctional 5-HT7 receptors augment cholinergic-evoked bradycardic responses, whereas prejunctional 5-HT1D receptors inhibit vagally-induced bradycardia.


Assuntos
Diabetes Mellitus Experimental , Fluoxetina , Acetilcolina/farmacologia , Animais , Bradicardia/tratamento farmacológico , Bradicardia/etiologia , Colinérgicos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Masculino , Ratos , Ratos Wistar , Receptores de Serotonina/fisiologia , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia
7.
Eur J Neurosci ; 56(1): 3674-3686, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35445439

RESUMO

The intrinsic electrical properties of motoneurons strongly affect motoneuron excitability to fast-acting excitatory ionotropic inputs. Serotonin (5-HT) is a neurochemical that alters the intrinsic properties of motoneurons, whereby animal models and in vitro experiments indicate that 5-HT increases motoneuron excitability by activating 5-HT2 receptors on the somato-dendritic compartment. In the current study, we examined how antagonism of the 5-HT2 receptor affects motoneuron excitability in humans. We hypothesised that motoneuron excitability would be reduced. The 5-HT2 antagonist cyproheptadine was administered to 10 healthy participants in a double-blinded, placebo-controlled, crossover trial. Electrical cervicomedullary stimulation was used to deliver a synchronised excitatory volley to motoneurons to elicit cervicomedullary motor evoked potentials (CMEPs) in the surface electromyography (EMG) signal of the resting biceps brachii. Likewise, electrical peripheral nerve stimulation was used to generate antidromic spikes in motoneurons and cause recurrent discharges, which were recorded with surface EMG as F-waves in a resting hand muscle. Compared with placebo, we found that 5-HT2 antagonism reduced the amplitude and persistence of F-waves but did not affect CMEP amplitude. 5-HT2 antagonism also reduced maximal contraction strength. The reduced recurrent discharge of motoneurons with 5-HT2 antagonism suggests that 5-HT2 receptors modulate the electrical properties of the initial segment or soma to promote excitability. Conversely, as cyproheptadine did not affect motoneuron excitability to brief synaptic input, but affected maximal contractions requiring sustained input, it seems likely that the 5-HT2 -mediated amplification of synaptic input at motoneuron dendrites is functionally significant only when excitatory input activates persistent inward currents.


Assuntos
Neurônios Motores , Serotonina , Axônios/fisiologia , Ciproeptadina/farmacologia , Método Duplo-Cego , Estimulação Elétrica , Potencial Evocado Motor/fisiologia , Humanos , Neurônios Motores/fisiologia , Músculo Esquelético/fisiologia , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia
8.
Can J Physiol Pharmacol ; 100(6): 521-533, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35395172

RESUMO

Anxiety and depression are common mental disorders affecting millions of people worldwide. Unsatisfactory clinical outcomes with the use of the available pharmacological interventions among some patients demand newer drugs with proven efficacy, safety, and tolerability profile. In this study, the LQFM211, LQFM213, and LQFM214 were designed from the piperazine scaffold and administered orally in mice. These mice were later evaluated in the open field, elevated plus maze, and forced swimming tests to assess the exploratory, anxiolytic, and antidepressant-like activities, respectively. The mechanism of action of these new derivatives was evaluated using flumazenil (benzodiazepine antagonist) and WAY100635 (5-HT1A receptor antagonist). Unlike LQFM214, the LQFM211 and LQFM213 elicited anxiolytic and antidepressant-like effects. The blockade of the effect of LQFM213 by WAY100635 suggests the involvement of the serotonergic pathway.


Assuntos
Ansiolíticos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Humanos , Camundongos , Piperazina/farmacologia , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Relação Estrutura-Atividade
9.
Int J Mol Sci ; 23(5)2022 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-35269729

RESUMO

While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbß3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.


Assuntos
Transtorno Depressivo Maior , Trombose , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Cloridrato de Duloxetina/farmacologia , Cloridrato de Duloxetina/uso terapêutico , Hemostasia , Humanos , Camundongos , Norepinefrina/farmacologia , Ativação Plaquetária , Agregação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Trombose/tratamento farmacológico , Trombose/metabolismo , Trombose/prevenção & controle
10.
Biol Pharm Bull ; 45(6): 738-742, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35314522

RESUMO

Nutmeg, a dried seed kernel of a tall evergreen Myristicaceae tree, is widely used as a spice and herbal medicine and is known to have antidepressant-like effects. This study evaluates the mechanisms underlying this antidepressant-like effect and safety of nutmeg n-hexane extract (NNE) in mice. Tail suspension and open field tests showed that NNE (10 mg/kg, per OS (p.o.)) significantly decreased the immobility time of mice without effecting their spontaneous locomotor activity. The reduction of immobility time of mice elicited by NNE was significantly inhibited by ketanserin (5-hydroxytryptamine (5-HT)2A/2C receptor antagonist), ondansetron (5-HT3 receptor antagonist), and yohimbine (α2 receptor antagonist). WAY100635 (5-HT1A receptor antagonist) tended to inhibit the effect of NNE but without significance. Testing according to the Organisation for Economic Co-operation and Development Guidelines, no mice died due to administrated NNE (2000 mg/kg, p.o.), and behavioral and weight changes were not seen in the acute toxicity test. In the Ames test, no increase in the number of revertant colonies for each bacterial strain test strains TA98 and TA100 by nutmeg powder was observed either with or without metabolic activity by S9 mix. These results suggest that NNE shows an antidepressant-like effect involving various serotonergic and noradrenergic nervous systems and maybe a highly safe natural preparation.


Assuntos
Myristica , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Elevação dos Membros Posteriores/métodos , Camundongos , Myristica/metabolismo , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Natação
11.
J Integr Neurosci ; 21(1): 17, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164453

RESUMO

Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Acatisia Induzida por Medicamentos/prevenção & controle , Anfetamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/farmacologia , Psicoses Induzidas por Substâncias/prevenção & controle , Antagonistas da Serotonina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Acatisia Induzida por Medicamentos/etiologia , Anfetamina/administração & dosagem , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Fenciclidina/administração & dosagem , Psicoses Induzidas por Substâncias/etiologia , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/administração & dosagem
12.
J Med Chem ; 65(5): 4201-4217, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35195401

RESUMO

The 5-HT5A receptor (5-HT5AR), for which no selective agonists and a few antagonists exist, remains the least understood serotonin receptor. A single commercial antagonist, SB-699551, has been widely used to investigate the 5-HT5AR function in neurological disorders, including pain, but this molecule has substantial liabilities as a chemical probe. Accordingly, we sought to develop an internally controlled probe set. Docking over 6 million molecules against a 5-HT5AR homology model identified 5 mid-µM ligands, one of which was optimized to UCSF678, a 42 nM arrestin-biased partial agonist at the 5-HT5AR with a more restricted off-target profile and decreased assay liabilities versus SB-699551. Site-directed mutagenesis supported the docked pose of UCSF678. Surprisingly, analogs of UCSF678 that lost the 5-HT5AR activity revealed that 5-HT5AR engagement is nonessential for alleviating pain, contrary to studies with less-selective ligands. UCSF678 and analogs constitute a selective probe set with which to study the function of the 5-HT5AR.


Assuntos
Antagonistas da Serotonina , Serotonina , Humanos , Ligantes , Dor , Receptores de Serotonina , Antagonistas da Serotonina/farmacologia
13.
Life Sci ; 293: 120335, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35051421

RESUMO

AIMS: This study investigated whether fluoxetine treatment changes the 5-HT regulation on vascular sympathetic neurotransmission in type 1 diabetes. MAIN METHODS: Four-week diabetes was obtained by a single alloxan s.c. administration in male Wistar rats, administering fluoxetine for 14 days (10 mg/kg/day; p.o.). Systolic blood pressure, heart rate, glycaemia, body weight (BW) evolution, creatinine, and blood urea nitrogen (BUN) were monitored. Afterward, rats were pithed to perform the vascular sympathetic stimulation. 5-HT1A/1D/2A receptors expression was analysed by Western blot in thoracic aorta. Both i.v. norepinephrine and the electrical stimulation of the spinal sympathetic drive evoked vasoconstrictor responses. KEY FINDINGS: Fluoxetine treatment significantly reduced the BW gain, hyperglycaemia, creatinine, and BUN in diabetic rats. The electrical-produced vasopressor responses were greater in untreated than in fluoxetine-treated diabetic rats. 5-HT decreased the sympathetic-produced vasopressor responses. While 5-CT, 8-OH-DPAT and L-694,247 (5-HT1/7, 5-HT1A and 5-HT1D agonists, respectively) reproduced 5-HT-evoked inhibition, the 5-HT2 activation by α-methyl-5-HT augmented the vasoconstrictions. The 5-CT sympatho-inhibition was reversed by 5-HT1A plus 5-HT1D antagonists (WAY-100,635 and LY310762, respectively), whereas ritanserin (5-HT2A antagonist) blocked the α-methyl-5-HT potentiating effect. Norepinephrine-generated vasoconstrictions were increased or diminished by α-methyl-5-HT or 5-CT, respectively. 5-HT1A/1D/2A receptors were expressed at vascular level, being 5-HT1A expression increased by fluoxetine in diabetic rats. SIGNIFICANCE: Our findings suggest that fluoxetine improves metabolic and renal profiles, changes the vasopressor responses, and 5-HT receptors modulating sympathetic activity in diabetic rats: 5-HT1A/1D are involved in the sympatho-inhibition, while 5-HT2A is implicated in the sympatho-potentiation, being both effects pre and/or postjunctional in nature.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Fluoxetina/administração & dosagem , Receptores de Serotonina/metabolismo , Inibidores de Captação de Serotonina/administração & dosagem , Serotonina/metabolismo , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Masculino , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia
14.
Eur J Pharmacol ; 918: 174774, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35077674

RESUMO

Deficits in the translation between egocentric-allocentric strategies may become another diagnostic mark for neurodegenerative disorders, especially Alzheimer's disease. Regarding the specific regional distribution of serotonin-1A receptor in brain areas mediating allocentric (externally-centered) spatial navigation to the escape location, here we studied the effects of median raphe nucleus serotonin-1A autoreceptors stimulation, [8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT); 4 µg/0.5 µl saline], of a selective cholinergic denervation by intracerebroventricular administration of the 192IgG saporin (1µl/each ventricle), on male Wistar rats search strategies in a Morris maze during acquisition, and before probe sessions. Despite some evidence of spatial hippocampal dependent knowledge to those PBS/Saline animals, their performance dropped to chance levels on probe trial. Therefore, we considered two probabilities and first analyzed the ability of the rats to make better use of one or more strategies. We showed statistically significant increases in the distances associated with egocentric (body-centered) non-spatial strategies, random searching in particular, in 192IgG/8OH rats, which led to their improved performance. Second, considering to what extent a shift in search strategy use improves performance indicated that 8-OH-DPAT alone did not affect learning since it appeared the related performance was impaired over days. However, the strategy choices made by 192IgG/8OH rats increased performance by more than 12% compared to 192IgG/Saline rats, an effect reversed with pre-treatment by serotonin-1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635). The results strongly suggest the potential role of serotonergic system, via the serotonin-1A receptors, in spatial navigation. We argue that the receptors are of interest as therapeutic targets that can be used against age-related cognitive decline.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anticorpos Monoclonais/farmacologia , Encéfalo , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Saporinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Navegação Espacial , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colinérgicos/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Infusões Intraventriculares , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Navegação Espacial/efeitos dos fármacos , Navegação Espacial/fisiologia
15.
Biochem Pharmacol ; 197: 114908, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34999054

RESUMO

The diacylglycerol kinase (DGK) family of lipid enzymes catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Both DAG and PA are lipid signaling molecules that are of notable importance in regulating cell processes such as proliferation, apoptosis, and migration. There are ten mammalian DGK enzymes that appear to have distinct biological functions. DGKα has emerged as a promising therapeutic target in numerous cancers including glioblastoma (GBM) and melanoma as treatment with small molecule DGKα inhibitors results in reduced tumor sizes and prolonged survival. Importantly, DGKα has also been identified as an immune checkpoint due to its promotion of T cell anergy, and its inhibition has been shown to improve T cell activation. There are few small molecule DGKα inhibitors currently available, and the application of existing compounds to clinical settings is hindered by species-dependent variability in potency, as well as concerns regarding isotype specificity particularly amongst other type I DGKs. In order to resolve these issues, we have screened a library of compounds structurally analogous to the DGKα inhibitor, ritanserin, in an effort to identify more potent and specific alternatives. We identified two compounds that more potently and selectively inhibit DGKα, one of which (JNJ-3790339) demonstrates similar cytotoxicity in GBM and melanoma cells as ritanserin. Consistent with its inhibitor profile towards DGKα, JNJ-3790339 also demonstrated improved activation of T cells compared with ritanserin. Together our data support efforts to identify DGK isoform-selective inhibitors as a mechanism to produce pharmacologically relevant cancer therapies.


Assuntos
Diacilglicerol Quinase/antagonistas & inibidores , Diacilglicerol Quinase/metabolismo , Ritanserina/análogos & derivados , Ritanserina/farmacologia , Antagonistas da Serotonina/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Células Jurkat
16.
Int J Neuropsychopharmacol ; 25(5): 425-431, 2022 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-35022720

RESUMO

Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R and/or serotonergic 5-HT2A/1A-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT3-R/5-HT6-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT3-R and 5-HT6-R antagonists ondansetron and SB-399 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT3R and 5-HT6-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.


Assuntos
Antipsicóticos , Encéfalo , Fenciclidina , Quinolinas , Antagonistas da Serotonina , Animais , Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Fenciclidina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Quinolinas/farmacologia , Ratos , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia
17.
Biochem Biophys Res Commun ; 587: 131-138, 2022 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-34872001

RESUMO

BACKGROUND/AIM: Previously, we showed that transcription factor 21 (TCF21) promotes chicken preadipocyte differentiation. However, the genome-wide TCF21 binding sites and its downstream target genes in chicken adipogenesis were unknown. METHODS: ChIP-Seq and RNA-Seq were used to screen candidate targets of TCF21. qPCR and luciferase reporter assay were applied to verify the sequencing results. Western blotting, oil red-O staining and pharmacological treatments were performed to investigate the function of 5-hydroxytryptamine receptor 2A (HTR2A), one of the bonafide direct downstream binding targets of TCF21. RESULTS: A total of 94 candidate target genes of TCF21 were identified. ChIP-qPCR, RT-qPCR, and luciferase reporter assay demonstrated that HTR2A is one of the bonafide direct downstream binding targets of TCF21. HTR2A expression in adipose tissue was upregulated in fat line broilers. Also, the abundance of HTR2A gradually increased during the adipogenesis process. Interestingly, pharmacological enhancement or inhibition of HTR2A promoted or attenuated the differentiation of preadipocytes, respectively. Furthermore, HTR2A inhibition impaired the TCF21 promoted adipogenesis. CONCLUSIONS: We profiled the genome-wide TCF21 binding sites in chicken differentiated preadipocytes revealing HTR2A as the direct downstream target of TCF21 in adipogenesis.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Proteínas Aviárias/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Galinhas/genética , Genoma , Receptor 5-HT2A de Serotonina/genética , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Anfetaminas/farmacologia , Animais , Proteínas Aviárias/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Transformada , Galinhas/crescimento & desenvolvimento , Galinhas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Ketanserina/farmacologia , Luciferases/genética , Luciferases/metabolismo , Masculino , Ligação Proteica , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Transdução de Sinais
18.
Int J Neurosci ; 132(1): 23-30, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32677492

RESUMO

INTRODUCTION: Antidepressants increase the level of 5-HT in the somatodendritic region of the serotonergic dorsal raphe nucleus (DRN) neurons in the first few days of their usage, which, in turn, inhibits the serotonergic neurons locally. Pindolol may eliminate this inhibition when used in combination with antidepressants. MATERIAL AND METHODS: We aimed to determine the effect of pindolol on 5-HT1A receptor response in the DRN neurons, using voltage clamp recordings and prove the potentiation of antidepressant effect of venlafaxine by pindolol through behavior experiments. Balb/c mice, 28-35 days-old were used. RESULTS: 5-HT application (25 µM) induced an outward current by 23.36 ± 3.79 pA at the neurons in the dorsal subnucleus of DRN. This effect was inhibited by pre-administration of WAY-100135 (21 µM) and pindolol (10 µM) separately. The current induced by 5-HT and 8-OHDPAT have no statistically significance. 8-OHDPAT (30 µM) induced a 5-HT-like outward current, which was inhibited by pre-administration of pindolol (10 µM). Combination of venlafaxine (20 mg/kg/day) and pindolol (15 mg/kg/day) significantly reduced immobilization time when compared to the control group in tail suspension test and forced swim test without any significant change in locomotor activity. Administration of venlafaxine (20 mg/kg/day) alone or pindolol (15 mg/kg/day) alone did not significantly reduce immobilization time. CONCLUSION: Pindolol has the potential to prevent the inhibition of serotonergic neurons after antidepressant use. Hence, we, for the first time, demonstrated that pindolol can potentiate antidepressant effect of venlafaxine. In the mood disorders, pindolol is likely to increase the effectiveness of antidepressant drugs when given in combination.


Assuntos
Antidepressivos/farmacologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Pindolol/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Sinergismo Farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Pindolol/administração & dosagem , Piperazinas/farmacologia , Antagonistas da Serotonina/administração & dosagem , Cloridrato de Venlafaxina/administração & dosagem
19.
Artigo em Inglês | MEDLINE | ID: mdl-34748864

RESUMO

INTRODUCTION: Recent studies have observed that patients with treatment-resistant schizophrenia as well as patients with schizophrenia who do not respond within a medication trial exhibit excess activity of the glutamate system. In this study we sought to replicate the within-trial glutamate abnormality and to investigate the potential for structural differences and treatment-induced changes to improve identification of medication responders and non-responders. METHODS: We enrolled 48 medication-naïve patients in a 4-week trial of risperidone and classified them retrospectively into responders and non-responders using clinical criteria. Proton magnetic resonance spectroscopy and T1-weighted structural MRI were acquired pre- and post-treatment to quantify striatal glutamate levels and several measures of subcortical brain structure. RESULTS: Patients were classified as 29 responders and 19 non-responders. Striatal glutamate was higher in the non-responders than responders both pre- and post-treatment (F1,39 = 7.15, p = .01). Volumetric measures showed a significant group x time interaction (t = 5.163, <1%FDR), and group x time x glutamate interaction (t = 4.23, <15%FDR) were seen in several brain regions. Striatal volumes increased at trend level with treatment in both groups, and a positive association of striatal volumes with glutamate levels was seen in the non-responders. CONCLUSIONS: Combining anatomic measures with glutamate levels offers the potential to enhance classification of responders and non-responders to antipsychotic medications as well as to provide mechanistic understanding of the interplay between neuroanatomical and neurochemical changes induced by these medications. Ethical statement The study was approved by the Ethics and Scientific committees of the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All participants over 18 years fully understood and signed the informed consent; in case the patient was under 18 years, informed consent was obtained from both parents. Participants did not receive a stipend.


Assuntos
Corpo Estriado , Ácido Glutâmico/metabolismo , Transtornos Psicóticos , Risperidona/administração & dosagem , Antagonistas da Serotonina/administração & dosagem , Adulto , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Estudos Retrospectivos , Risperidona/farmacologia , /metabolismo , Antagonistas da Serotonina/farmacologia , Inquéritos e Questionários , Adulto Jovem
20.
Int J Mol Sci ; 22(21)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34769511

RESUMO

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT4Rs). Ever since the discovery of their expression in the hippocampus, 5-HT4Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT4Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT4Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT4Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level.


Assuntos
Hipocampo/efeitos dos fármacos , Aprendizagem/fisiologia , Transtornos da Memória/tratamento farmacológico , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Receptores 5-HT4 de Serotonina/química , Antagonistas da Serotonina/farmacologia , Animais , Hipocampo/metabolismo , Humanos , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Receptores 5-HT4 de Serotonina/metabolismo
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