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1.
Neuropsychopharmacology ; 49(4): 747-756, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38212441

RESUMO

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A-/- mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A-/- mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.


Assuntos
Transtorno Depressivo Maior , Alucinógenos , Humanos , Animais , Camundongos , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Serotonina , Receptor 5-HT2A de Serotonina , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Lisurida/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico
2.
Pharmacol Biochem Behav ; 233: 173659, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37844631

RESUMO

Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HT2AR) agonists demonstrated rapid and sustained antidepressant actions in patients with treatment-resistant depression. The new antidepressant arketamine is reported to cause long-lasting prophylactic effects in lipopolysaccharide (LPS)-treated mice and mice exposed to chronic restrain stress (CRS). However, no study has compared the prophylactic effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonism), and arketamine on depression-like behaviors in mice. Saline (10 ml/kg), DOI (2.0 or 4.0 mg/kg), lisuride (1.0 or 2.0 mg/kg), or arketamine (10 mg/kg) was administered intraperitoneally (i.p.) to male mice 6 days before administration of LPS (1.0 mg/kg). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated body weight loss, splenomegaly, the increased immobility time of forced swimming test (FST), and the decreased expression of PSD-95 in the prefrontal cortex (PFC) of LPS-treated mice. In another test, male mice received the same treatment one day before CRS (7 days). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated the increased FST immobility time, the reduced sucrose preference in the sucrose preference test, and the decreased expression of PSD-95 in the PFC of CRS-exposed mice. These findings suggest that, unlike to arketamine, both DOI and lisuride did not exhibit long-lasting prophylactic effects in mouse models of depression.


Assuntos
Alucinógenos , Humanos , Camundongos , Masculino , Animais , Alucinógenos/farmacologia , Lipopolissacarídeos/farmacologia , Lisurida , Serotonina/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Sacarose , Depressão/tratamento farmacológico , Depressão/prevenção & controle , Depressão/metabolismo
3.
J Psychiatr Res ; 165: 205-218, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37517241

RESUMO

In the present study, nanoemulsion (NE) loaded with lisuride were formulated for delivering drug to brain via intranasal route. Dopamine levels, pharmacokinetic, and antioxidant activity were estimated. Antioxidant effect of lisuride NE was assessed in-vivo using oxidative stress models revealing symptoms like those of Parkinson's disease. Intranasally administered lisuride NE-treated group revealed a greater number of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione (GSH) as compared to the intravenously administered lisuride suspension in haloperidol rat model. Additionally, it was observed that lisuride NE can decrease dopamine loss. When lisuride NE was administered intranasally resulted in considerably higher dopamine concentrations (17.48 ± 0.05 ng/mL) in comparison to rats receiving haloperidol (7.28 ± 0.02 ng/mL). From study, it is suggested that NE is a possible strategy to deliver lisuride intranasally to lower free radical damage and prevent the biochemical alterations associated with Parkinson's disease.


Assuntos
Lisurida , Doença de Parkinson , Ratos , Animais , Lisurida/farmacologia , Lisurida/uso terapêutico , Dopamina , Doença de Parkinson/tratamento farmacológico , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Encéfalo , Estresse Oxidativo , Antioxidantes/farmacologia
4.
Pharmacol Biochem Behav ; 222: 173500, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36476377

RESUMO

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.


Assuntos
Alucinógenos , Ketamina , Camundongos , Animais , Alucinógenos/farmacologia , Lipopolissacarídeos/farmacologia , Lisurida , Ketamina/farmacologia , Serotonina , Antidepressivos/farmacologia , Depressão/tratamento farmacológico
5.
Psychopharmacology (Berl) ; 239(11): 3551-3565, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36107207

RESUMO

RATIONALE: The 5-HT2A receptor is the major target of classic hallucinogens. Both DOI (2,5-dimethoxy-4-iodoamphetamine) and lisuride act at 5-HT2A receptors, and lisuride shares comparable affinity with DOI and acts as a partial agonist at 5-HT2A receptors. However, not like DOI, lisuride lacks hallucinogenic properties. Impulsive decision-making refers to the preference for an immediate small reinforcer (SR) over a delayed large reinforcer (LR). OBJECTIVES: The current study aims to compare the effects of DOI and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs. METHODS: Impulsive decision-making was evaluated in male Sprague-Dawley rats by the percentage of choice for the LR in delay discounting task (DDT). Delay to the LR changed in an ascending order (0, 4, 8, 16, and 32 s) across one session. RESULTS: DOI (0.5 and 1.0 mg/kg) increased impulsive decision-making, and the effects of DOI (1.0 mg/kg) were blocked by the 5-HT2A receptor antagonist ketanserin (1.0 mg/kg) rather than the 5-HT2C receptor antagonist SB-242084 (1.0 mg/kg). Contrarily, lisuride (0.1, 0.3, and 0.5 mg/kg) decreased impulsive decision-making. The effects of lisuride (0.3 mg/kg) were not antagonized by ketanserin (1.0 mg/kg), selective 5-HT1A antagonist WAY-100635 (1.0 mg/kg), or selective dopamine D4 receptor antagonist L-745870 (1.0 mg/kg) but were attenuated by the selective dopamine D2/D3 receptor antagonist tiapride (40 mg/kg). CONCLUSIONS: DOI and lisuride have contrasting effects on impulsive decision-making via distinct receptors. DOI-induced increase of impulsivity is mediated by the 5-HT2A receptor, while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor.


Assuntos
Desvalorização pelo Atraso , Alucinógenos , Animais , Masculino , Ratos , Dopamina/farmacologia , Alucinógenos/farmacologia , Comportamento Impulsivo , Ketanserina/farmacologia , Lisurida/farmacologia , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptor 5-HT2C de Serotonina , Serotonina/farmacologia , Cloridrato de Tiaprida/farmacologia
6.
Biochem Biophys Res Commun ; 598: 20-25, 2022 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-35149433

RESUMO

5- HT2A receptor is a member of the family A G-protein-coupled receptor. It is involved in many psychiatric disorders, such as depression, addiction and Parkinson's disease. 5-HT2AR targeted drugs play an important role in regulating cognition, memory, emotion and other physiological function by coupling G proteins, and their most notable function is stimulating the serotonergic hallucination. However, not all 5-HT2AR agonists exhibit hallucinogenic activity, such as lisuride. Molecular mechanisms of these different effects are not well illustrated. This study suggested that 5-HT2AR coupled both Gs and Gq protein under hallucinogenic agonists DOM and 25CN-NBOH stimulation, but nonhallucinogenic agonist lisuride and TBG only activates Gq signaling. Moreover, in head twitch response (HTR) model, we found that cAMP analogs 8-Bromo-cAMP and PDE4 inhibitor Rolipram could increase HTR, while Gs protein inhibitor Melittin could reduce HTR. Collectively, these results revealed that Gs signaling is a key signaling pathway that may distinguish hallucinogenic agonists and nonhallucinogenic agonists.


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Alucinógenos/farmacologia , Movimentos da Cabeça/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , AMP Cíclico/metabolismo , Células HEK293 , Movimentos da Cabeça/fisiologia , Humanos , Lisurida/farmacologia , Masculino , Meliteno/farmacologia , Camundongos Endogâmicos C57BL , Rolipram/farmacologia , Transdução de Sinais/efeitos dos fármacos
7.
Science ; 375(6579): 403-411, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35084960

RESUMO

Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR ß-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.


Assuntos
Antidepressivos/farmacologia , Desenho de Fármacos , Alucinógenos/química , Alucinógenos/farmacologia , Receptor 5-HT2A de Serotonina/química , Animais , Antidepressivos/química , Antidepressivos/metabolismo , Arrestina/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Alucinações/induzido quimicamente , Alucinógenos/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Ligantes , Lisurida/química , Lisurida/metabolismo , Dietilamida do Ácido Lisérgico/química , Dietilamida do Ácido Lisérgico/metabolismo , Camundongos , Conformação Proteica , Psilocibina/análogos & derivados , Psilocibina/química , Psilocibina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/química , Serotonina/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
8.
Front Endocrinol (Lausanne) ; 12: 791633, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35095761

RESUMO

Pituitary neuroendocrine tumors (PitNET) are commonly benign tumors accounting for 10-25% of intracranial tumors. Prolactin-secreting adenomas represent the most predominant type of all PitNET and for this subtype of tumors, the medical therapy relies on the use of dopamine agonists (DAs). DAs yield an excellent therapeutic response in reducing tumor size and hormonal secretion targeting the dopamine receptor type 2 (D2DR) whose higher expression in prolactin-secreting adenomas compared to other PitNET is now well established. Moreover, although DAs therapy does not represent the first-line therapy for other PitNET, off-label use of DAs is considered in PitNET expressing D2DR. Nevertheless, DAs primary or secondary resistance, occurring in a subset of patients, may involve several molecular mechanisms, presently not fully elucidated. Dopamine receptors (DRs) expression is a prerequisite for a proper DA function in PitNET and several molecular events may negatively modify DR membrane expression, through the DRs down-regulation and intracellular trafficking, and DR signal transduction pathway. The current mini-review will summarise the presently known molecular events that underpin the unsuccessful therapy with DAs.


Assuntos
Adenoma/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hipofisárias/tratamento farmacológico , Receptores de Dopamina D2/metabolismo , Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/metabolismo , Aminoquinolinas/uso terapêutico , Bromocriptina/uso terapêutico , Cabergolina/uso terapêutico , Filaminas/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Lisurida/uso terapêutico , MicroRNAs/metabolismo , Pergolida/uso terapêutico , Neoplasias Hipofisárias/metabolismo , Prolactinoma/tratamento farmacológico , Prolactinoma/metabolismo , Receptores de Dopamina D2/agonistas , beta-Arrestinas/metabolismo
9.
Biochem Biophys Res Commun ; 531(4): 609-614, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32814630

RESUMO

The 5-HT2A receptor is a target for hallucinogenic and non-hallucinogenic ligands that evoke unique behavioral, electrophysiological and molecular consequences. Here, we explored the differential effects of distinct 5-HT2A receptor ligands on signaling pathways downstream to the 5-HT2A receptor. The hallucinogenic 5-HT2A receptor agonist DOI evoked an enhanced signaling response compared to the non-hallucinogenic 5-HT2A receptor agonist lisuride in human/rat 5-HT2AR-EGFP receptor expressing HEK293 cell lines and cortical neuronal cultures. We noted higher levels of phospho-PLC, pPKC, pERK, pCaMKII, pCREB, as well as higher levels of IP3 and DAG production following 5-HT2A receptor stimulation with DOI. Our study reveals distinct signaling signatures, differing in magnitude and kinetics at the 5-HT2A receptor in response to DOI versus lisuride.


Assuntos
Anfetaminas/farmacologia , Lisurida/farmacologia , Neurônios/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Células Cultivadas , Córtex Cerebral/citologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Alucinógenos/farmacologia , Humanos , Neurônios/metabolismo , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/genética , Receptores de Glutamato Metabotrópico/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Can J Physiol Pharmacol ; 98(8): 511-521, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32268074

RESUMO

In vitro studies have suggested that terguride blocks the contractile and relaxant responses produced by 5-hydroxytryptamine (5-HT) via 5-HT2A/2B receptors. This study has now investigated terguride's blocking properties on central/peripheral 5-HT2 receptors in anaesthetized or pithed rats. Male Wistar anaesthetized/pithed rats were cannulated for recording blood pressure and heart rate and for i.v. administration of several compounds. In both groups of rats, i.v. bolus injections of 5-HT or (±)-DOI (a 5-HT2 receptor agonist; 1-1000 µg/kg) produced dose-dependent increases in diastolic blood pressure and heart rate. These responses were dose-dependently antagonized by terguride (10-3000 µg/kg). In anaesthetized rats, i.v. bolus injections of BW723C86 (a 5-HT2B receptor agonist; 1-1000 µg/kg) produced dose-dependent increases in diastolic blood pressure and not dose-dependent increases in heart rate, while in pithed rats, these responses were attenuated. The vasopressor responses elicited by BW723C86 in anaesthetized rats were dose-dependently blocked by terguride (10-300 µg/kg), whereas its the tachycardic responses were dose-independently blocked. These results, taken together, suggest that terguride behaved as an antagonist at the 5-HT2 receptors located in the central nervous system and (or) the systemic vasculature. This is the first evidence demonstrating that terguride can block central/peripheral 5-HT2 receptors mediating cardiovascular responses in anaesthetized or pithed rats.


Assuntos
Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Lisurida/análogos & derivados , Receptores 5-HT2 de Serotonina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Lisurida/farmacologia , Masculino , Ratos , Ratos Wistar
11.
Int J Rheum Dis ; 21(12): 2128-2138, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30207074

RESUMO

BACKGROUND: Release of 5-hydroxytryptamine (5-HT; serotonin) from activated platelets following microvascular injury leads to tissue fibrosis. 5-HT strongly induces extracellular matrix synthesis in dermal fibroblasts in a transforming growth factor beta 1 (TGF-ß1)-dependent manner. AIM: To evaluate anti-fibrotic properties of inhibitors of 5-HT2 and 5-HT2B (terguride, SB204741) respectively in human adult dermal fibroblasts (HADF) derived from a patient with scleroderma. METHODS: Anti-fibrotic efficacy of 5-HT2 and 5-HT2B inhibitors was evaluated as per two strategies: HADF were incubated with 5-HT (1 µM)/TGF-ß1 (10 ng/mL) for 1 hour followed by 5-HT (1 µM)/TGF-ß1 (10 ng/mL) and terguride or SB204741 (1 µM, each) for 24 hours (post-treatment strategy) and HADF were treated with terguride or SB204741 (1 µM, each) for 1 hour followed by 5-HT (1 µM)/TGF-ß1 (10 ng/mL) for 24 hours (pre-treatment strategy). Real time quantitative polymerase chain reaction for expression of pro-fibrotic (TGFΒ1, COL1A1, COL1A2, ACTA2, CTGF and FN1) and anti-fibrotic genes (MMP2/TIMP1) was performed. Expression of type I collagen, alpha smooth muscle actin (α-SMA), phosphorylation of Smad3, ERK1/2 and STAT3 was examined by immunoblotting. RESULTS: Stimulation of HADF cells with 5-HT/TGF-ß1 led to the increased expression of pro-fibrotic genes which was significantly reduced by both terguride and SB204741. Expression of anti-fibrotic genes was not affected upon incubation with the inhibitors. In 5-HT-stimulated HADF, treatment with terguride and SB204741 decreased type I collagen and α-SMA. In 5-HT/TGF-ß1 stimulated HADF, terguride and SB204741 treatment reduced ERK1/2 and STAT3 phosphorylation but did not influence Smad3 phosphorylation. CONCLUSION: Terguride and SB204741 reduce pro-fibrotic potential of HADF cells and suppress TGF-ß1-mediated non-canonical pathways, ERK1/2 and STAT3 which have been implicated in the regulation of pro-fibrotic genes and in the development of fibrosis. Taken together, our data suggest that 5-HT inhibitors might reduce fibrosis via suppression of TGF-beta1-mediated non-canonical signaling pathways. These observations have important therapeutic implications for fibrotic disorders like scleroderma.


Assuntos
Fibroblastos/efeitos dos fármacos , Indóis/farmacologia , Lisurida/análogos & derivados , Receptor 5-HT2B de Serotonina/efeitos dos fármacos , Escleroderma Sistêmico/tratamento farmacológico , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Ureia/análogos & derivados , Adulto , Células Cultivadas , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Lisurida/farmacologia , Fenótipo , Fosforilação , Receptor 5-HT2B de Serotonina/metabolismo , Fator de Transcrição STAT3/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Serotonina/farmacologia , Pele/metabolismo , Pele/patologia , Ureia/farmacologia
12.
Transpl Immunol ; 49: 43-53, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29649585

RESUMO

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. METHODS: CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. RESULTS: Elevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. CONCLUSION: Inhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use.


Assuntos
Aorta/cirurgia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Lisurida/análogos & derivados , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas da Serotonina/uso terapêutico , Succinatos/uso terapêutico , Animais , Aorta/patologia , Proliferação de Células , Feminino , Rejeição de Enxerto/imunologia , Humanos , Indóis/uso terapêutico , Lisurida/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Modelos Animais , Serotonina/metabolismo , Migração Transendotelial e Transepitelial , Transplante Homólogo , Ureia/análogos & derivados , Ureia/uso terapêutico
13.
Psychopharmacology (Berl) ; 235(1): 99-108, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28971230

RESUMO

RATIONALE: 2-Bromoterguride, a dopamine D2 receptor partial agonist with antagonist properties at serotonin 5-HT2A receptors and α2C-adrenoceptors, meets the prerequisites of a putative atypical antipsychotic drug (APD). We recently showed that 2-bromoterguride is effective in tests of positive symptoms of schizophrenia in rats without inducing extrapyramidal side effects or metabolic changes. OBJECTIVE: In continuation of our recent work, we now investigated the effect of 2-bromoterguride on apomorphine and phencyclidine (PCP)-induced disruptions of prepulse inhibition (PPI) of the acoustic startle response, a measure of sensory gating. In addition, we used subchronic PCP treatment to produce cognitive deficits and social aversion, and assessed the effect of 2-bromoterguride on the performance in the novel object recognition (NOR) task (model for studying cognitive deficit symptoms of schizophrenia) and the social interaction test (model for studying negative symptoms of schizophrenia). Finally, we extended the side effect profile of 2-bromoterguride by measuring the prolactin response to systemic administration of the drug in rats. RESULTS: Treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) reversed PPI deficits induced by apomorphine and PCP, respectively. Subchronic PCP induced impairments in object memory and social interaction behavior which were ameliorated by 2-bromoterguride but not by clozapine and aripiprazole, respectively. Prolactin concentration in blood serum was not elevated at 1, 2, or 4 h post-2-bromoterguride treatment, which further supports the safe and effective use of this drug. CONCLUSIONS: Our data support 2-bromoterguride as a promising APD candidate due to its beneficial effect on cognitive impairments and negative symptoms of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Transtornos Cognitivos/psicologia , Agonistas de Dopamina/farmacologia , Lisurida/análogos & derivados , Receptores de Dopamina D2/agonistas , Comportamento Social , Animais , Apomorfina/farmacologia , Transtornos Cognitivos/induzido quimicamente , Agonistas de Dopamina/efeitos adversos , Lisurida/efeitos adversos , Lisurida/farmacologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Fenciclidina/farmacologia , Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Psicologia do Esquizofrênico
14.
Eur J Pharmacol ; 814: 114-123, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28821451

RESUMO

The neurotransmitter 5-hydroxytryptamine (5-HT) is involved in regulation of local tissue inflammation and repair through a set of receptors (5-HT1-7 receptors), which are expressed in the lung. Considering the protective importance of 5-HT receptor antagonists against development of pulmonary fibrosis, we evaluated whether 5-HT7 receptor antagonist (SB-269970) modulates lung inflammatory and fibrogenic processes in comparison with 5-HT2A/B receptor antagonist (terguride), in bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) model. IPF model induced by a single dose of intra-tracheal BLM instillation (5mg/kg), and rats were treated with intraperitoneal injection of SB-269970 (1mg/kg day) or terguride (1.2mg/kg/d). The experiment was carried out on two separate sets of rats that were killed at day 7th and day 21st to evaluate the endpoint of the IPF inflammatory and fibrogenic phases, respectively. During the inflammatory phase 5-HT2A/B and 5-HT7 receptor antagonists attenuated the BLM-induced increase in the lung fluid content, the inflammatory cytokines levels and oxidative stress burden. In the fibrogenic phase, both SB-269970 and terguride reduced the serotonin concentrations in lung homogenates and significantly protected against IPF fibrogenic phase by attenuating collagen deposition and mRNA expression of both transforming growth factor-ß1 (TGF- ß1), and procollagen type Ӏ (PINP). 5-hydroxytryptamine 5-HT7 receptor antagonist showed more benefits than 5-HT2A/B receptor antagonist on the deleterious effects accompanied BLM instillation. The present study showed involvement of 5-HT7 receptor in the pathophysiology of BLM-induced IPF in rats and identified it as a potential therapeutic target in lung fibrotic disorders.


Assuntos
Bleomicina/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Lisurida/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Receptores de Serotonina/metabolismo , Sulfonamidas/farmacologia , Animais , Colágeno/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Lisurida/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fenóis/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos , Sulfonamidas/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Água/metabolismo
15.
Neuropharmacology ; 117: 14-20, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28131770

RESUMO

Dopamine (DA) contributes to the regulation of voluntary movement, and a deficiency in DAergic neurons leads to movement disorders. The objective of this study was to examine the neuroprotective effect of DA D2-like receptor agonist, lisuride, and the role of DA receptors in this protection. Treatment with lisuride alleviated loss of tyrosine hydroxylase (TH) both direct and intraperitoneal injection in 6-hydroxydopamine (6-OHDA) mouse model. Similar results were obtained in primary neuronal cultures treated with lisuride. Lisuride protected TH expression against 6-OHDA-induced cytotoxicity in a concentration-dependent manner. Then, we evaluated the role of DA D2 and D3 receptor in neuroprotective effect of lisuride. Treatment of neuronal cultures with L-741,626, a DA D2 receptor-selective antagonist, did not alter neuroprotective effect of lisuride. However, protective effect of lisuride on TH expression was abolished when cells were treated with GR103691, a D3 receptor selective antagonist. Furthermore, whether lisuride can alleviate mitochondrial damage of DAergic neurons induced by 6-OHDA, we investigated the expression of the mitochondrial regulatory protein, paraplegin, and changes in mitochondria morphology. Treatment with lisuride countered a 6-OHDA-induced reduction in paraplegin and TH expression, and co-treatment with GR103691 blocked this effect of lisuride. Transmission electron microscopy confirmed the lisuride mitigation of 6-OHDA-induced damage to the mitochondrial membrane and cristae. These results suggest that the DA D3 receptor mediates the neuroprotective effects of lisuride by preventing mitochondrial damage.


Assuntos
Lisurida/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores de Dopamina D3/agonistas , ATPases Associadas a Diversas Atividades Celulares , Animais , Compostos de Bifenilo/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Relação Dose-Resposta a Droga , Feminino , Indóis/farmacologia , Lisurida/antagonistas & inibidores , Masculino , Metaloendopeptidases/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Fármacos Neuroprotetores/antagonistas & inibidores , Oxidopamina/antagonistas & inibidores , Piperazinas/farmacologia , Piperidinas/farmacologia , Cultura Primária de Células , Receptores de Dopamina D3/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismo
16.
Expert Rev Clin Immunol ; 13(5): 469-482, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27899043

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.


Assuntos
Produtos Biológicos/uso terapêutico , Fibrinolíticos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Articulações/patologia , Pulmão/patologia , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Abatacepte/uso terapêutico , Acetamidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos como Assunto , Fibrose , Humanos , Indóis/uso terapêutico , Inflamação , Lisurida/análogos & derivados , Lisurida/uso terapêutico , PubMed , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
17.
Psychopharmacology (Berl) ; 233(15-16): 3041-50, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27317020

RESUMO

RATIONALE: Recently, we showed that 2-bromoterguride acted as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A and α2C-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy. OBJECTIVE: To extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT2A receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs). RESULTS: Acute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity. CONCLUSIONS: Our data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Lisurida/análogos & derivados , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Anfetaminas/farmacologia , Animais , Encéfalo/metabolismo , Agonistas de Dopamina/farmacologia , Lisurida/farmacologia , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/agonistas , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
18.
Pharmacol Ther ; 164: 195-203, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27133570

RESUMO

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.


Assuntos
Estudos Clínicos como Assunto/métodos , Hipertensão Pulmonar/tratamento farmacológico , Animais , Biomarcadores , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Lisurida/análogos & derivados , Lisurida/farmacologia , Fenótipo , Fentolamina/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Peptídeo Intestinal Vasoativo/farmacologia
19.
Mol Cell Proteomics ; 13(5): 1273-85, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24637012

RESUMO

The serotonin 5-HT(2A) receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline, and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT(2A) receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture with enrichment in phosphorylated peptides by means of hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT(2A) receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the nonhallucinogenic 5-HT(2A) agonist lisuride. Among the 5995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI versus lisuride. These include a serine (Ser(280)) located in the third intracellular loop of the 5-HT(2A) receptor, a region important for its desensitization. The specific phosphorylation of Ser(280) by hallucinogens was further validated by quantitative mass spectrometry analysis of immunopurified receptor digests and by Western blotting using a phosphosite specific antibody. The administration of DOI, but not of lisuride, to mice, enhanced the phosphorylation of 5-HT(2A) receptors at Ser(280) in the prefrontal cortex. Moreover, hallucinogens induced a less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than did nonhallucinogenic agonists. The mutation of Ser(280) to aspartic acid (to mimic phosphorylation) reduced receptor desensitization by nonhallucinogenic agonists, whereas its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals a biased phosphorylation of the 5-HT(2A) receptor in response to hallucinogenic versus nonhallucinogenic agonists, which underlies their distinct capacity to desensitize the receptor.


Assuntos
Anfetaminas/farmacologia , Alucinógenos/farmacologia , Lisurida/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Serina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Neurônios/metabolismo , Fosforilação , Córtex Pré-Frontal/metabolismo , Proteômica/métodos , Transdução de Sinais/efeitos dos fármacos
20.
Artigo em Inglês | MEDLINE | ID: mdl-23909604

RESUMO

Cutaneous fibrosis seen in systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities. Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter and immune modulator, is also an important mediator of bidirectional interactions between the vasoactive amines and the skin.5-HT, a commonly secreted amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the microenvironment are unclear. We review that as serotonin has powerful vasodilator, immunomodulator, and growth factor actions, this pathway could be involved in skin fibrotic. Since serotoninergic system play a role in skin fibrotic, and 5-HTs drugs, an usual treatment for this type of patients. These provides a future perspective for research and drug development.


Assuntos
Agonistas de Dopamina/uso terapêutico , Lisurida/análogos & derivados , Escleroderma Sistêmico/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Serotonina/metabolismo , Pele/patologia , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Fibrose , Humanos , Lisurida/uso terapêutico , Medicina de Precisão , Receptor 5-HT1A de Serotonina/metabolismo , Pele/efeitos dos fármacos
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