RESUMO
Temporal lobe epilepsy is the most common type of pharmacoresistant epilepsy in adults. Epigallocatechin-3-gallate has aroused much interest because of its multiple therapeutic effects, but its instability compromises the potential effectiveness. PEGylated-PLGA nanoparticles of Epigallocatechin-3-gallate were designed to protect the drug and to increase the brain delivery. Nanoparticles were prepared by the double emulsion method and cytotoxicity, behavioral, Fluoro-Jade C, Iba1 and GFAP immunohistochemistry studies were carried out to determine their effectiveness. Nanoparticles showed an average size of 169 nm, monodisperse population, negative surface charge, encapsulation efficiency of 95% and sustained release profile. Cytotoxicity assays exhibited that these nanocarriers were non-toxic. Behavioral test showed that nanoparticles reduced most than free drug the number of epileptic episodes and their intensity. Neurotoxicity and immunohistochemistry studies confirmed a decrease in neuronal death and neuroinflammation. In conclusion, Epigallocatechin-3-gallate PEGylated-PLGA nanoparticles could be a suitable strategy for the treatment of temporal lobe epilepsy.
Assuntos
Catequina/análogos & derivados , Epilepsia do Lobo Temporal/tratamento farmacológico , Nanopartículas/química , Polietilenoglicóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Catequina/química , Catequina/uso terapêutico , Portadores de Fármacos/química , Emulsões , Epilepsia do Lobo Temporal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células PC12 , Tamanho da Partícula , Ratos , Convulsões/tratamento farmacológicoRESUMO
Aim: To compare free and nanoparticle (NP)-encapsulated epigallocatechin-3-gallate (EGCG) for the treatment of Huntington's disease (HD)-like symptoms in mice. Materials & methods: EGCG was incorporated into PEGylated poly(lactic-co-glycolic) acid NPs with ascorbic acid (AA). HD-like striatal lesions and motor deficit were induced in mice by 3-nitropropionic acid-intoxication. EGCG and EGCG/AA NPs were co-administered and behavioral motor assessments and striatal histology performed after 5 days. Results: EGCG/AA NPs were significantly more effective than free EGCG in reducing motor disturbances and depression-like behavior associated with 3-nitropropionic acid toxicity. EGCG/AA NPs treatment also mitigated neuroinflammation and prevented neuronal loss. Conclusion: NP encapsulation enhances therapeutic robustness of EGCG in this model of HD symptomatology. Together with our previous findings, this highlights the potential of EGCG/AA NPs in the symptomatic treatment of neurodegenerative diseases.
Assuntos
Nanopartículas , Animais , Catequina/análogos & derivados , Camundongos , Nitrocompostos , Polietilenoglicóis , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , PropionatosRESUMO
Epigallocatechin-3-gallate (EGCG) is a candidate for treatment of Alzheimer's disease (AD) but its inherent instability limits bioavailability and effectiveness. We found that EGCG displayed increased stability when formulated as dual-drug loaded PEGylated PLGA nanoparticles (EGCG/AA NPs). Oral administration of EGCG/AA NPs in mice resulted in EGCG accumulation in all major organs, including the brain. Pharmacokinetic comparison of plasma and brain accumulation following oral administration of free or EGCG/AA NPs showed that, whilst in both cases initial EGCG concentrations were similar, long-term (5-25â¯h) concentrations were ca. 5 fold higher with EGCG/AA NPs. No evidence was found that EGCG/AA NPs utilised a specific pathway across the blood-brain barrier (BBB). However, EGCG, empty NPs and EGCG/AA NPs all induced tight junction disruption and opened the BBB in vitro and ex vivo. Oral treatment of APPswe/PS1dE9 (APP/PS1) mice, a familial model of AD, with EGCG/AA NPs resulted in a marked increase in synapses, as judged by synaptophysin (SYP) expression, and reduction of neuroinflammation as well as amyloid ß (Aß) plaque burden and cortical levels of soluble and insoluble Aß(1-42) peptide. These morphological changes were accompanied by significantly enhanced spatial learning and memory. Mechanistically, we propose that stabilisation of EGCG in NPs complexes and a destabilized BBB led to higher therapeutic EGCG concentrations in the brain. Thus EGCG/AA NPs have the potential to be developed as a safe and strategy for the treatment of AD.