RESUMO
Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the effect of the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) on anxiety and seizure behavior in adult zebrafish and its possible mechanisms of action. The acute toxicity of 96 h of HTMCX was analyzed, and the open and light/dark field tests (n = 6 animals/group) were used to assess the anxiety behavior of animals treated with HTMCX. In addition, the mechanisms of action were investigated with antagonists of the GABAA, 5-HT receptors, and molecular anchorage study. Pentylenetetrazole (PTZ) was used to induce seizure by immersion. As a result, acetophenone HTMCX (1, 3 and 10 mg/kg; v.o.) was non-toxic and affected locomotor activity. The higher doses (3 and 10 mg/kg; v.o.) produced signs of anxiolytic action in the light/dark test, and this effect was reversed by the pizotifen (antagonist 5HTR1 and 5HTR2A/2C), having the potential to form a complex with 5HTR1B. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABAA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A/3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.
Assuntos
Acetofenonas/uso terapêutico , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Croton , Neurotransmissores/uso terapêutico , Acetofenonas/farmacologia , Acetofenonas/toxicidade , Animais , Ansiolíticos/farmacologia , Ansiolíticos/toxicidade , Ansiedade/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/toxicidade , Feminino , Masculino , Simulação de Acoplamento Molecular , Neurotransmissores/farmacologia , Neurotransmissores/toxicidade , Pentilenotetrazol , Receptores de Serotonina/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Serotonina/metabolismo , Peixe-ZebraRESUMO
Selenium is an essential micronutrient with several biological roles in the human body, but supra nutritional consumption can cause toxic effects. The potential deleterious effects of organoselenium compounds are controversial. The compound α-(phenylselanyl) acetophenone (PSAP) exhibits antioxidant, antidepressant-like and glutathione peroxidase-like activity, which makes important the elucidation of any toxic effects. Hence, the present study aims to investigate the in vitro toxicity of PSAP in Chinese Hamster ovary cells (through MTT assay) and analyse its genotoxicity using the comet assay in mice leukocytes after acute or chronic treatments, alongside with biochemical analyses. Our results demonstrate that the oral administration of PSAP in acute (1, 5, 10, 50, 200 mg/kg) and chronic (1, 10, 50, 200 mg/kg) doses did not cause genotoxicity. The compound presented cytotoxic effect in the MTT assay just at 500 µM after 24 h of administration and at 250 and 500 µM after 48 and 72 h of administration. According to biochemical analysis, PSAP presented a minor toxic effect by altering δ-ALA-D activity in liver and catalase activity in kidney at the highest tested concentration. Taking together, these data indicate that PSAP has low toxic effects after chronic administration in mice.
Assuntos
Acetofenonas/toxicidade , Antidepressivos/toxicidade , Antioxidantes/toxicidade , Compostos Organosselênicos/toxicidade , Acetofenonas/administração & dosagem , Administração Oral , Animais , Antidepressivos/administração & dosagem , Antioxidantes/administração & dosagem , Células CHO , Catalase , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Cricetulus , Dano ao DNA , Relação Dose-Resposta a Droga , Esquema de Medicação , Rim/efeitos dos fármacos , Rim/enzimologia , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Compostos Organosselênicos/administração & dosagem , Sintase do Porfobilinogênio/metabolismo , Medição de RiscoRESUMO
Apocynin, a methoxy-substituted catechol (4-hydroxy-3-methoxyacetophenone), originally extracted from the roots of Picrorhiza kurroa, has been extensively used as a non-toxic inhibitor of the multienzymatic complex NADPH oxidase. We discovered that the analogous methoxy-substituted catechol, 4-Fluoro-2-methoxyphenol (F-apocynin), in which the acetyl group present in apocynin was changed to a fluorine atom, was significantly more potent as an inhibitor of NADPH oxidase activity, myeloperoxidase (MPO) chlorinating activity and phagocytosis of microorganisms by neutrophils; it was also as potent as apocynin in inhibiting tumor necrosis factor-alpha (TNFα) release by peripheral blood mononuclear cells. We attribute the increased potency of F-apocynin to its increased lipophilicity, which could facilitate the passage of the drug through the cell membrane. The inhibition of MPO chlorination activity, phagocytosis and TNFα release shows that apocynin and F-apocynin actions are not restricted to reactive oxygen species inhibition, but further studies are needed to clarify if these mechanisms are related. Like apocynin, F-apocynin did not show cell toxicity, and is a strong candidate for use in the treatment of inflammatory diseases.