RESUMO
Trichomoniasis is a great public health burden worldwide and the increase in treatment failures has led to a need for finding alternative molecules to treat this disease. In this study, we present in vitro and in silico analyses of two 2,8-bis(trifluoromethyl) quinolines (QDA-1 and QDA-2) against Trichomonas vaginalis. For in vitro trichomonacidal activity, up to seven different concentrations of these drugs were tested. Molecular docking, biochemical, and cytotoxicity analyses were performed to evaluate the selectivity profile. QDA-1 displayed a significant effect, completely reducing trophozoites viability at 160 µM, with an IC50 of 113.8 µM, while QDA-2 at the highest concentration reduced viability by 76.9%. QDA-1 completely inhibited T. vaginalis growth and increased reactive oxygen species production and lipid peroxidation after 24 h of treatment, but nitric oxide accumulation was not observed. In addition, molecular docking studies showed that QDA-1 has a favorable binding mode in the active site of the T. vaginalis enzymes purine nucleoside phosphorylase, lactate dehydrogenase, triosephosphate isomerase, and thioredoxin reductase. Moreover, QDA-1 presented a level of cytotoxicity by reducing 36.7% of Vero cells' viability at 200 µM with a CC50 of 247.4 µM and a modest selectivity index. In summary, the results revealed that QDA-1 had a significant anti-T. vaginalis activity. Although QDA-1 had detectable cytotoxicity, the concentration needed to eliminate T. vaginalis trophozoites is lower than the CC50 encouraging further studies of this compound as a trichomonacidal agent.
Assuntos
Quinolinas , Tricomoníase , Trichomonas vaginalis , Animais , Chlorocebus aethiops , Humanos , Simulação de Acoplamento Molecular , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Tricomoníase/tratamento farmacológico , Trofozoítos , Células VeroRESUMO
The 3-[(4-methoxyphenyl)selanyl]-2-phenylimidazo[1,2-a] pyridine (MPI), a novel organic selenium compound, has been receiving increased attention due to its antioxidant effects and its ability to protect against depression-like behaviours. However, it remains elusive whether MPI is able to reverse depressive-like symptoms and biochemical alterations in mice. In the present work, we explored the ability of MPI (10 mg/kg, i.g.) to reverse inflammation- and stress-induced depression-like behaviours in mice injected with tumour necrosis factor (TNF-α) or submitted to acute restraint stress. Depression-like behaviours were evaluated by the tail suspension and splash test and the open field test was used to evaluate the locomotor activity of mice. The prefrontal cortex and hippocampus of mice were used for the evaluation of parameters of oxidonitrosative stress. Here, we showed that a single administration of MPI abolished the depressive-like behaviours induced by TNF-α and acute restraint stress. The oxidative and nitrosative stress presented in mice with depression-like behaviours were also decreased by MPI in the prefrontal cortex and hippocampus. Our findings suggest that MPI presents antidepressant-like activity which is associated with the biochemical regulation of oxidative stress in prefrontal cortex and hippocampus of mice, arising as a promising strategy for the management of depressive symptoms.
Assuntos
Depressão , Hipocampo/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Compostos de Selênio/farmacologia , Estresse Psicológico , Animais , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Inflamação/metabolismo , Camundongos , Restrição Física , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/etiologia , Estresse Psicológico/metabolismoRESUMO
Extensive data have reported the involvement of oxidative stress in the pathogenesis of neuropsychiatric disorders, prompting the pursuit of antioxidant molecules that could become adjuvant pharmacological agents for the management of oxidative stress-associated disorders. The 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) has been reported as an antioxidant and immunomodulatory compound that improves depression-like behavior and cognitive impairment in mice. However, the exact effect of CMI on specific brain cells is yet to be studied. In this context, the present study aimed to evaluate the antioxidant activity of CMI in H2O2-induced oxidative stress on human dopaminergic neuroblastoma cells (SH-SY5Y) and to shed some light into its possible mechanism of action. Our results demonstrated that the treatment of SH-SY5Y cells with 4 µM CMI protected them against H2O2 (343 µM)-induced oxidative stress. Specifically, CMI prevented the increased number of reactive oxygen species (ROS)-positive cells induced by H2O2 exposure. Furthermore, CMI treatment increased the levels of reduced glutathione in SH-SY5Y cells. Molecular docking studies demonstrated that CMI might interact with enzymes involved in glutathione metabolism (i.e., glutathione peroxidase and glutathione reductase) and H2O2 scavenging (i.e., catalase). In silico pharmacokinetics analysis predicted that CMI might be well absorbed, metabolized, and excreted, and able to cross the blood-brain barrier. Also, CMI was not considered toxic overall. Taken together, our results suggest that CMI protects dopaminergic neurons from H2O2-induced stress by lowering ROS levels and boosting the glutathione system. These results will facilitate the clinical application of CMI to treat nervous system diseases associated with oxidative stress.
Assuntos
Peróxido de Hidrogênio/toxicidade , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Compostos de Selênio/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Glutationa/metabolismo , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacocinética , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Oxirredutases/química , Oxirredutases/metabolismo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Compostos de Selênio/química , Compostos de Selênio/metabolismo , Compostos de Selênio/farmacocinéticaRESUMO
Despite the severity and the high prevalence of depression and anxiety and the efforts that have been done to improve their treatment, the available pharmacotherapy still has several limitations. Therefore, the investigation of novel agents and the characterization of the molecular signaling pathways underlying their effects are needed. The organoselenium compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) has emerged as a promising antidepressant and anxiolytic molecule in several animal models of depression through the modulation of neuroinflammation and oxidative stress. In light of this, the present study aimed to dive into the mechanism of action of CMI in ameliorating anhedonic- and anxiogenic-like behaviors induced by repeated corticosterone administration in mice. A single administration of CMI (1 âmg/kg, i.g.) abrogated the behavioral alterations induced by corticosterone in the open field test, splash test, and elevated plus maze test. Additionally, CMI treatment decreased the levels of reactive species and lipid peroxidation in the plasma of corticosterone-treated mice and normalized the expression of GR, BDNF, synaptophysin, GSK-3ß, Nrf 2 , and IDO in the hippocampi of stressed mice. Noteworthy, the pre-treatment of mice with LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor) abrogated the anti-anhedonic- and anxiolytic-like effects elicited by CMI in corticosterone-treated mice, while ZnPP (HO-1 inhibitor) counteracted the anxiolytic-like effect of CMI. These findings suggest that CMI might ameliorate behavioral and biochemical alterations in the depression-anxiety comorbidity induced by corticosterone, highlighting the potential of CMI as a possible adjuvant therapy.
RESUMO
The contribution of oxidative stress has been described in numerous studies as one of the main pathways involved in the pathophysiology of anxiety and its comorbidities, such as chronic pain. Therefore, in this study, we investigated the anxiolytic-like, antiallodynic, and anti-hyperalgesic effects of 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazole (SePy) in response to acute restraint stress (ARS) in mice through the modulation of oxidative stress and neuroendocrine responses. Mice were restrained for 2 h followed by SePy (1 or 10 mg/kg, intragastrically) treatment. Behavioral, and biochemical tests were performed after further 30 min. The treatment with SePy reversed (i) the decreased time spent and the number of entries in the open arms of the elevated plus-maze apparatus, (ii) the decreased time spent in the central zone of the open field test and the increased number of grooming, (iii) the increased number of marbles buried, (iv) the increased response frequency of Von Frey Hair stimulation, and (v) the decreased latency time to nociceptive response in the hot plate test stress induced by ARS. Biochemically, SePy reversed ARS-induced increased levels of plasma corticosterone, and reversed the ARS-induced alterations in the levels of reactive species, lipid peroxidation, and superoxide dismutase and catalase activities in the prefrontal cortices and hippocampi of mice. Moreover, a molecular docking approach suggested that SePy may interact with the active site of the glucocorticoid receptor. Altogether, these results indicate that SePy attenuated anxiolytic-like behavior, hyperalgesia, and mechanical allodynia while modulating oxidative stress and neuroendocrine responses in stressed mice.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Sistemas Neurossecretores/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Animais , Ansiolíticos/administração & dosagem , Corticosterona/sangue , Masculino , Camundongos , Pirazóis , Restrição Física , SelênioRESUMO
Only in the last decade the long-term consequences of sepsis started to be studied and even less attention has been given to the treatment of psychological symptoms of sepsis survivors. It is estimated that 60% of sepsis survivors have psychological disturbances, including depression, anxiety, and cognitive impairment. Although the causative factors remain largely poorly understood, blood-brain barrier (BBB) disturbances, neuroinflammation, and oxidative stress have been investigated. Therefore, we sought to explore if the immunomodulatory and antioxidant selenocompound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) would be able to ameliorate long-term behavioral and biochemical alterations in sepsis survivors male Swiss mice. CMI treatment (1 mg/kg, given orally for seven consecutive days) attenuated depression- and anxiogenic-like behaviors and cognitive impairment present one month after the induction of sepsis (lipopolysaccharide, 5 mg/kg intraperitoneally). Meantime, CMI treatment modulated the number of neutrophils and levels of reactive species in neutrophils, lymphocytes, and monocytes. In addition, peripheral markers of liver and kidneys dysfunction (AST, ALT, urea, and creatinine) were reduced after CMI treatment in post-septic mice. Notably, CMI treatment to non-septic mice did not alter AST, ALT, urea, and creatinine levels, indicating the absence of acute hepatotoxicity and nephrotoxicity following CMI treatment. Noteworthy, CMI ameliorated BBB dysfunction induced by sepsis, modulating the expression of inflammation-associated genes (NFκB, IL-1ß, TNF-α, IDO, COX-2, iNOS, and BDNF) and markers of oxidative stress (reactive species, nitric oxide, and lipid peroxidation levels) in the prefrontal cortices and hippocampi of mice. In conclusion, we unraveled crucial molecular pathways that are impaired in post-septic mice and we present CMI as a promising therapeutic candidate aimed to manage the long-lasting behavioral alterations of sepsis survivors to improve their quality of life.
Assuntos
Comportamento Animal , Indóis/química , Estresse Oxidativo , Sepse/patologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Indóis/farmacologia , Indóis/uso terapêutico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/citologia , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicaçõesRESUMO
Major depressive disorder (MDD) is a chronic mental illness affecting a wide range of people worldwide. The pathophysiology of MDD is not completely elucidated, but it is believed that oxidative stress and neuroinflammation are involved. In light with this, the aim of the present study was to investigate whether a single administration of the antioxidant 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) was able to reverse the streptozotocin-induced depression-like behavior, oxidative stress, and neuroinflammation in mice. MFSeI (10 mg/kg) was administered intragastrically (i.g.) 24 h after the intracerebroventricular injection of STZ (0.2 mg/4 µL/per mouse). Thirty minutes after MFSeI administration, behavioral tests and neurochemical analyses were performed. Fluoxetine (10 mg/kg, i.g.) was used as a positive control. MFSeI and fluoxetine were able to reverse the STZ-induced depression-like behavior, as evidenced by decreased immobility time in the forced swimming test and increased grooming time in the splash test. Mechanistically, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortices and hippocampi of STZ-treated mice. Additionally, neuroinflammation (i.e. expression of NF-κB, IL-1ß, and TNF-α) and the reduced mRNA levels of BDNF in the and hippocampi of depressed mice were reversed by treatment with MFSeI. Fluoxetine did not improve the STZ-induced alterations at the levels of reactive species, NF-κB and BDNF in the prefrontal cortices neither the levels of TNF-α in both brain regions. Together, these data suggest that the MFSeI may be a promising compound with antidepressant-like action, reducing oxidative stress and modulating inflammatory pathways in the brain of depressed mice.
Assuntos
Antidepressivos/administração & dosagem , Antioxidantes/administração & dosagem , Depressão/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Compostos de Selênio/administração & dosagem , Estreptozocina/toxicidade , Animais , Antidepressivos/química , Antioxidantes/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intraventriculares , Masculino , Camundongos , Estresse Oxidativo/fisiologia , Compostos de Selênio/química , Estreptozocina/administração & dosagemRESUMO
BACKGROUND: Trichomonas vaginalis is the causative agent of trichomoniasis, which is one of the most common sexually transmitted diseases worldwide. Trichomoniasis has a high incidence and prevalence and is associated with serious complications such as HIV transmission and acquisition, pelvic inflammatory disease and preterm birth. Although trichomoniasis is treated with oral metronidazole (MTZ), the number of strains resistant to this drug is increasing (2.5-9.6%), leading to treatment failure. Therefore, there is an urgent need to find alternative drugs to combat this disease. METHODS: Herein, we report the in vitro and in silico analysis of 12 furanyl N-acylhydrazone derivatives (PFUR 4, a-k) against Trichomonas vaginalis. Trichomonas vaginalis ATCC 30236 isolate was treated with seven concentrations of these compounds to determine the minimum inhibitory concentration (MIC) and 50% inhibitory concentration (IC50). In addition, compounds that displayed anti-T. vaginalis activity were analyzed using thiobarbituric acid reactive substances (TBARS) assay and molecular docking. Cytotoxicity analysis was also performed in CHO-K1 cells. RESULTS: The compounds PFUR 4a and 4b, at 6.25 µM, induced complete parasite death after 24 h of exposure with IC50 of 1.69 µM and 1.98 µM, respectively. The results showed that lipid peroxidation is not involved in parasite death. Molecular docking studies predicted strong interactions of PFUR 4a and 4b with T. vaginalis enzymes, purine nucleoside phosphorylase, and lactate dehydrogenase, while only PFUR 4b interacted in silico with thioredoxin reductase and methionine gamma-lyase. PFUR 4a and 4b led to a growth inhibition (< 20%) in CHO-K1 cells that was comparable to the drug of choice, with a promising selectivity index (> 7.4). CONCLUSIONS: Our results showed that PFUR 4a and 4b are promising molecules that can be used for the development of new trichomonacidal agents for T. vaginalis.
Assuntos
Antiprotozoários , Hidrazonas , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Antiprotozoários/toxicidade , Células CHO , Cricetulus , Humanos , Hidrazonas/farmacologia , Hidrazonas/toxicidade , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular/métodos , Tricomoníase/tratamento farmacológicoRESUMO
Oxidative stress and neuroinflammation are found both in diabetes mellitus and major depressive disorder (MDD). In addition to damage in peripheral organs, such as liver and kidney, diabetic patients have a higher risk of developing depression. In this sense, the objective of the present study was to characterize the antidepressant-like effect of a selenium-containing compound, the 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI), in streptozotocin (STZ)-induced diabetic mice. STZ (200â¯mg/kg, i.p.) was used to induce diabetes mellitus type I, and after seven days, the administration of MFSeI (10â¯mg/kg, i.g.) was initiated and followed for the next 14 days. Twenty-four hours after the last administration of MFSeI, the behavioral tests were performed, followed by euthanasia. The treatment with MFSeI was able to reverse the hyperglycemia induced by STZ. MFSeI also decreased the plasma levels of biomarkers of liver and kidney damage. Importantly, MFSeI reversed the depression-like behavior induced by STZ in the tail suspension test and forced swimming test without promoting locomotor alterations. Furthermore, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortex (PFC), hippocampus (HC), liver, and kidney of STZ-treated mice. Treatment with MFSeI also decreased the expression of tumor necrosis factor-alpha, inducible nitric oxide synthase and indoleamine 2,3-dioxygenase, while increasing the expression of interleukin-10, insulin receptor substrate-1 and glucose transport-4 in the PFC and HC of mice. Taken together, the results indicate the effectiveness of MFSeI against depression-like behavior and central and peripheral complications caused by diabetes in mice.
Assuntos
Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Indóis/farmacologia , Inflamação/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Animais , Depressão/sangue , Depressão/imunologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/imunologia , Hipocampo/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/imunologia , Indóis/administração & dosagem , Inflamação/sangue , Inflamação/imunologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Compostos Organosselênicos/administração & dosagem , SelênioRESUMO
Psychiatric alterations are often found in patients with breast cancer even before the initiation of adjuvant therapy, resulting in a poor quality of life. It has become accepted that neuroinflammation and oxidative stress are involved in the pathophysiology of depression and cognitive impairment. Herein, we tested the hypothesis that treatment with the antioxidant and immunomodulatory selenium-containing compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI)could attenuate behavioral and neurochemical alterations in a mammary (4T1) tumor model. Female BALB/c mice were subcutaneously inoculated with 4T1 cancer cells (1 × 105 cells/mice) or PBS. From days 14 to 20, mice received daily gavage with canola oil or CMI. On day 21, mice were submitted to behavioral tests followed by euthanasia. We found that CMI did not alter tumor growth, body weight, and body temperature in tumor-bearing mice. Importantly, treatment with CMI abrogated tumor-induced depression-like behavior and cognitive impairment. By the time CMI improved the behavioral alterations, it had reduced tumor-induced neuroinflammation (altered expression of NFκB, IL-1ß, TNF-α, IL-10, IDO, and COX-2) and oxidative stress (altered expression of iNOS and Nrf2, and levels of reactive species, nitric oxide, lipid peroxidation, and superoxide dismutase activity) in the prefrontal cortices and hippocampi of mice. A molecular docking approach suggested the ability of CMI to inhibit the activity of iNOS and COX-2. Together, our results indicate that CMI treatment may attenuate depression and cognitive impairment in 4T1 tumor-bearing mice, and be a groundbreaking strategy for the treatment of cancer-related psychiatric symptoms to improve the quality of life of cancer patients.