RESUMEN
Parkinson's disease (PD) induced by environmental toxins involves a multifactorial cascade of harmful factors, thus motivating the search for therapeutic agents able to act on the greatest number of molecular targets. This study evaluated the efficacy of 50 mg/kg purified anacardic acids (AAs), isolated from cashew nut shell liquid, on multiple steps of oxidative stress and inflammation induced by rotenone in the substantia nigra (SN) and striatum. Adult mice were divided into four groups: Control, rotenone, AAs + rotenone, and AAs alone. Lipoperoxidation, nitric oxide (NO) levels, and reduced glutathione (GSH)/oxidized gluthatione (GSSG) ratio were evaluated. NF-kB-p65, pro-IL-1ß, cleaved IL-1ß, metalloproteinase-9, Tissue Inhibitory Factor-1 (TIMP-1), tyrosine hydroxylase (TH), and glial fibrillary acidic protein (GFAP) levels were assessed by Western blot. In silico studies were also made using the SwissADME web tool. Rotenone increased lipoperoxidation and NO production and reduced TH levels and GSH/GSSG ratio in both SN and striatum. It also enhanced NF-kB-p65, pro, and cleaved IL-1ß, MMP-9, GFAP levels compared to control and AAs groups. The AAs alone reduced pro-IL-1ß in the striatum while they augmented TIMP1 and reduced MMP-9 amounts in both regions. AAs reversed rotenone-induced effects on lipoperoxidation, NO production, and GSH/GSSG ratio, as well as increased TH and attenuated pro-IL-1ß and MMP-9 levels in both regions, NF-kB-p65 in the SN and GFAP in the striatum. Altogether, the in vivo and in silico analysis reinforced multiple and defined molecular targets of AAs, identifying that they are promising neuroprotective drug candidates for PD, acting against oxidative and inflammatory conditions induced by rotenone.
Asunto(s)
Ácidos Anacárdicos/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Plaguicidas/toxicidad , Ácidos Anacárdicos/química , Ácidos Anacárdicos/aislamiento & purificación , Animales , Simulación por Computador , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Proteína Ácida Fibrilar de la Glía/genética , Glutatión/metabolismo , Disulfuro de Glutatión/metabolismo , Humanos , Interleucina-1beta/genética , Peroxidación de Lípido/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/genética , Ratones , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/genética , Enfermedad de Parkinson Secundaria/patología , Inhibidor Tisular de Metaloproteinasa-1/genética , Factor de Transcripción ReIA/genética , Tirosina 3-Monooxigenasa/genéticaRESUMEN
Bufotenine (1, 5-hydroxy-N,N-dimethyltryptamine) was isolated from seeds of Anadenanthera spp., a tree widespread in the Brazilian cerrado, using an efficient acid-base shakeout protocol. The conversion of bufotenine into N,N-dimethyltryptamine (4) and 5-methoxy-N,N-dimethyltryptamine (5) was accomplished through an innovative and short approach featuring the use of novel bufotenine-aminoborane complex (7). Furthermore, an easy methodology for conversion of bufotenine into 5-hydroxy-N,N,N-trimethyltryptamine (6) was well-established. This is the first study that highlights bufotenine as a resource for the production of N,N-dimethyltryptamines for either pharmacological and toxicological investigations or for synthetic purposes.
Asunto(s)
Bufotenina/química , Fabaceae/química , Metoxidimetiltriptaminas/síntesis química , N,N-Dimetiltriptamina/síntesis química , Brasil , Metoxidimetiltriptaminas/química , Modelos Moleculares , Estructura Molecular , N,N-Dimetiltriptamina/química , Semillas/químicaRESUMEN
This work is part of a large program, which seeks to discover new antitumor isobenfuranones designed from anacardic acids. The synthetic strategy for the construction of the title compounds takes into consideration the use of inexpensive anacardic acids (2), the major natural cashew (Anacardium occidentale) nut-shell phenolic lipid, and features one-pot construction of fused-ring aromatic gamma-lactones, phthalides. The cytotoxicity screening in different human cancer cell lines (HL-60 leukemia, SF295 glioblastoma and MDA-MB435 melanoma) by the MTT assay showed that acyclic precursor (6), and isobenfuranones (1a and 1b) are active compounds. Interestingly, 1a exhibits significant antiproliferative effect against HL-60 cells and moderate activity against SF295 and MDA-MB435 cell lines. Analysis of mechanisms involved in the cytotoxic activity showed that active compounds were leading to DNA damage, triggering apoptosis or necrosis induction.
Asunto(s)
Ácidos Anacárdicos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Animales , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Benzofuranos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Oxígeno/químicaRESUMEN
Cutaneous secretions of toad species are an important source of bufadienolides, compounds that exhibit interesting structural features and biopharmacological properties. Here we describe the isolation of bufadienolides from the Brazilian toad Rhinella schneideri parotoid glands secretion, including: marinobufagin (1), bufalin (2), telocinobufagin (3), hellebrigenin (4), and the atypical 20S,21R-epoxymarinobufagin (5) besides the widespread beta-sitosterol (6). Starting from natural bufadienolides four derivatives were prepared: 3beta-acetoxy-marinobufagin (7), 3beta-acetoxy-bufalin (8), 3beta-acetoxy-telocinobufagin (9), and 3beta-acetoxy-20S,21R-epoxymarinobufagin (10). The cytotoxic evaluation showed that all natural bufadienolides and their derivatives exhibited moderate to strong activity against human HL-60, SF-295, MDA-MB-435, and HCT-8 cancer cell strains without hemolysis of mouse erythrocytes. The acetylated bufadienolides (7-9) and the epoxide 10 showed lesser peripheral blood lymphocytes (PBLs) inhibitory activity than their precursors, suggesting that chemical modifications on such compounds can play an important role on the modulation of their cytotoxic profile.