RESUMO
Hydrocephalus is a neurological condition with altered cerebrospinal fluid flow (CSF). The treatment is surgical and the most commonly used procedure is ventricle-peritoneal shunt. However, not all patients can undergo immediate surgery or achieve complete lesion reversal. Neuroprotective measures are valuable in such cases. It was evaluated whether the use of celecoxib, a selective inhibitor of COX-2, associated or not with ventricular-subcutaneous derivation, could offer benefits to the brain structures affected by experimental hydrocephalus. Seven-day-old male Wistar Hannover rats induced by intracisternal injection of kaolin 15% were used, divided into five groups with ten animals each: intact control (C), untreated hydrocephalus (H), hydrocephalus treated with celecoxib 20 mg/kg intraperitoneal (HTC), hydrocephalus treated with shunt (HTS) and hydrocephalus treated with shunt and celecoxib 20 mg/kg intraperitoneal (HTCS). Celecoxib was administered for 21 consecutive days, starting the day after hydrocephalus induction and continuing until the end of the experimental period. The surgery was performed seven days after inducing hydrocephalus. Multiple assessment methods were used, such as behavioral tests (water maze and open field), histological analysis (hematoxylin and eosin), immunohistochemistry (caspase-3, COX-2, and GFAP), and ELISA analysis of GFAP. The results of the behavioral and memory tests indicated that celecoxib improves the neurobehavioral response. The improvement can be attributed to the reduced neuroinflammation (p < 0.05), and astrogliosis (p < 0.05) in different brain regions. In conclusion, the results suggest that celecoxib holds great potential as an adjuvant neuroprotective drug for the treatment of experimental hydrocephalus.
Assuntos
Gliose , Hidrocefalia , Humanos , Ratos , Animais , Masculino , Ratos Wistar , Celecoxib/efeitos adversos , Gliose/tratamento farmacológico , Gliose/patologia , Neuroproteção , Doenças Neuroinflamatórias , Ciclo-Oxigenase 2 , Hidrocefalia/tratamento farmacológico , Hidrocefalia/patologia , Inflamação/tratamento farmacológicoRESUMO
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2.0 °C. The micromolar dissociation constant (Kd) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV Kd value accounted to 6.6 µM in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Dieta , Epigênese Genética , Lisina/metabolismo , Proteínas Nucleares/metabolismo , Proteínas/antagonistas & inibidores , Estilbenos/farmacologia , Fatores de Transcrição/metabolismo , Acetilação , Proteínas de Ciclo Celular , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Neoplasias/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , ResveratrolRESUMO
AIM: This work aimed to evaluate the activity of 3'-hydroxychalcone against Cryptococcus gattii in planktonic and biofilm forms and their toxicity using alternative animal models. MATERIALS & METHODS: Minimum inhibitory concentration and minimum fungicide concentration were determined. Biofilm formation and the susceptibility tests were performed by the 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-5-[carbonyl(phenylamino)]-2H-tetrazolium hydroxide assay. Toxicity and efficacy were checked in Danio rerio and Galleria mellonella models. RESULTS: The compound 3'-hydroxychalcone showed fungicidal activity against C. gattii in both planktonic and biofilm forms. The toxicity in zebrafish embryos revealed a low lethal concentration. In G. mellonella, the compound did not show antifungal activity and larvae toxicity. CONCLUSION: Because of the activity of 3'-hydroxychalcone against C. gattii in vitro, molecular modifications should be made to improve efficacy and to reduce toxicity in vivo. [Formula: see text].
Assuntos
Antifúngicos/farmacologia , Cryptococcus gattii/efeitos dos fármacos , Modelos Animais de Doenças , Animais , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Criptococose/microbiologia , Cryptococcus gattii/citologia , Lepidópteros/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Peixe-ZebraRESUMO
N-oxide derivatives compounds such as furoxan and benzofuroxan are promising scaffolds for designing of new antileishmanial drugs. A series of furoxan (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-b, and 14a-f) and benzofuroxan (benzo[c][1,2,5]oxadiazole1-N-oxide) (compounds 8a-c) derivatives were evaluated against in vitro cultured L. infantum promastigotes and amastigotes. The compounds exhibited activity against promastigote and intracellular amastigote forms with EC50 values ranging from 2.9 to 71.2µM and 2.1 to 18.2µM, respectively. The most promising compound, 14e, showed good antileishmanial activity (EC50=3.1µM) against intracellular amastigote forms of L. infantum with a selectivity index, based on murine macrophages (SI=66.4), almost 3-times superior to that presented by the standard drug amphotericin B (AmpB). The efficacy of 14e to eliminate the parasites in vivo was also demonstrated. Treatment of L. infantum-infected hamsters with compound 14e at 3.0mg/Kg/day led to a meaningful reduction of parasite load in spleen (49.9%) and liver (54.2%), respectively; these data were corroborated by histopathological analysis, which also revealed reduction in the number of inflammatory cells in the liver of the treated animals. Moreover, histological analysis of the spleen and kidney of treated animals did not reveal alterations suggestive of toxic effects. The parasite load reduction might be related to NO production, since this molecule is a NO-donor. We observed neither side effects nor elevation of hepatic/renal biomarker levels in the plasma. The data herein presented suggest that the compound should be considered in the development of new drugs for treatment of visceral leishmaniasis.
Assuntos
Antiprotozoários/uso terapêutico , Benzoxazóis/uso terapêutico , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Anfotericina B/toxicidade , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Benzoxazóis/toxicidade , Biomarcadores/metabolismo , Cricetinae , Rim/efeitos dos fármacos , Rim/parasitologia , Rim/patologia , Rim/fisiopatologia , Leishmaniose Visceral/parasitologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Fígado/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Macrófagos/patologia , Masculino , Camundongos , Óxido Nítrico/biossíntese , Baço/efeitos dos fármacos , Baço/parasitologia , Baço/patologia , Resultado do TratamentoRESUMO
Resveratrol (RVT) is a stilbene with a protective effect on the cardiovascular system; however, drawbacks including low bioavailability and fast metabolism limit its efficacy. In this work we described new resveratrol derivatives with nitric oxide (NO) release properties, ability to inhibit platelet aggregation and in vivo antithrombotic effect. Compounds (4a-f) were able to release NO in vitro, at levels ranging from 24.1% to 27.4%. All compounds (2a-f and 4a-f) have exhibited platelet aggregation inhibition using as agonists ADP, collagen and arachidonic acid. The most active compound (4f) showed reduced bleeding time compared to acetylsalicylic acid (ASA) and protected up to 80% against in vivo thromboembolic events. These findings suggest that hybrid resveratrol-furoxan (4f) is a novel lead compound able to prevent platelet aggregation and thromboembolic events.
Assuntos
Fibrinolíticos/farmacologia , Hidrazonas/farmacologia , Doadores de Óxido Nítrico/farmacologia , Oxidiazóis/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Difosfato de Adenosina/farmacologia , Animais , Ácido Araquidônico/farmacologia , Aspirina/farmacologia , Tempo de Sangramento , Colágeno/farmacologia , Fibrinolíticos/síntese química , Hidrazonas/síntese química , Dinitrato de Isossorbida/farmacologia , Masculino , Camundongos , Doadores de Óxido Nítrico/síntese química , Nitritos/análise , Oxidiazóis/síntese química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Ratos WistarRESUMO
Chalcones form a class of compounds that belong to the flavonoid family and are widely distributed in plants. Their simple structure and the ease of preparation make chalcones attractive scaffolds for the synthesis of a large number of derivatives enabling the evaluation of the effects of different functional groups on biological activities. In this Letter, we report the successful synthesis of a series of novel prenylated chalcones via Claisen-Schmidt condensation and the evaluation of their effect on the viability of the Trypanosomatidae parasites Leishmania amazonensis, Leishmania infantum and Trypanosoma cruzi.
Assuntos
Chalcona/síntese química , Chalcona/farmacologia , Leishmania infantum/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Chalcona/química , Concentração Inibidora 50 , Prenilação , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/farmacologiaRESUMO
A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis.
Assuntos
Antiprotozoários/farmacologia , Benzoxazóis/farmacologia , Leishmania mexicana/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Oxidiazóis/farmacologia , Anfotericina B/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Benzoxazóis/síntese química , Benzoxazóis/química , Concentração de Íons de Hidrogênio , Leishmania mexicana/crescimento & desenvolvimento , Estágios do Ciclo de Vida/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Masculino , Camundongos , Óxido Nítrico/biossíntese , Nitritos/metabolismo , Oxidiazóis/síntese química , Oxidiazóis/química , Testes de Sensibilidade Parasitária , Pentamidina/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of anti-inflammatory derivatives containing an N-acyl hydrazone subunit (4a-e) were synthesized and characterized. Docking studies were performed that suggest that compounds 4a-e bind to cyclooxygenase (COX)-1 and COX-2 isoforms, but with higher affinity for COX-2. The compounds display similar anti-inflammatory activities in vivo, although compound 4c is the most effective compound for inhibiting rat paw edema, with a reduction in the extent of inflammation of 35.9% and 52.8% at 2 and 4 h, respectively. The anti-inflammatory activity of N-acyl hydrazone derivatives was inferior to their respective parent drugs, except for compound 4c after 5 h. Ulcerogenic studies revealed that compounds 4a-e are less gastrotoxic than the respective parent drug. Compounds 4b-e demonstrated mucosal damage comparable to celecoxib. The in vivo analgesic activities of the compounds are higher than the respective parent drug for compounds 4a-b and 4d-e. Compound 4a was more active than dipyrone in reducing acetic-acid-induced abdominal constrictions. Our results indicate that compounds 4a-e are anti-inflammatory and analgesic compounds with reduced gastrotoxicity compared to their respective parent non-steroidal anti-inflammatory drugs.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Hidrazonas/farmacologia , Animais , Celecoxib , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Hemorragia Gastrointestinal/induzido quimicamente , Hidrazonas/efeitos adversos , Hidrazonas/química , Inflamação/tratamento farmacológico , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação Proteica , Pirazóis/farmacologia , Ratos , Ratos Wistar , Sulfonamidas/farmacologiaRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) 1-5 containing an N-acyl hydrazone subunit were prepared and their antiplatelet and antithrombotic activities assessed in vitro and in vivo. Compounds 1-5 inhibited the platelet aggregation induced by adenosine diphosphate and/or arachidonic acid, with inhibition rates of 18.0%-61.1% and 65.9%-87.3%, respectively. Compounds 1 and 5 were the most active compounds, inhibiting adenosine-diphosphate-induced platelet aggregation by 57.2% and 61.1%, respectively. The inhibitory rates for arachidonic-acid-induced platelet aggregation were similar for compound 2 (80.8%) and acetylsalicylic acid (ASA, 80%). After their oral administration to mice, compounds 1, 3, and 5 showed shorter mean bleeding times than ASA. Compounds 1 and 5 also protected against thromboembolic events, with survival rates of 40% and 33%, respectively, compared with 30% for ASA. In conclusion, these results indicate that these novel NSAIDs containing an NAH subunit may offer better antiplatelet and antithrombotic activities than ASA.