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1.
Biol Res ; 56(1): 27, 2023 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-37226204

RESUMEN

BACKGROUND: The underlying mechanism of Parkinson's disease are still unidentified, but excitotoxicity, oxidative stress, and neuroinflammation are considered key actors. Proliferator activated receptors (PPARs) are transcription factors involved in the control of numerous pathways. Specifically, PPARß/δ is recognized as an oxidative stress sensor, and we have previously reported that it plays a detrimental role in neurodegeneration. METHODS: Basing on this concept, in this work, we tested the potential effects of a specific PPARß/δ antagonist (GSK0660) in an in vitro model of Parkinson's disease. Specifically, live-cell imaging, gene expression, Western blot, proteasome analyses, mitochondrial and bioenergetic studies were performed. Since we obtained promising results, we tested this antagonist in a 6-hydroxydopamine hemilesioned mouse model. In the animal model, behavioral tests, histological analysis, immunofluorescence and western blot of substantia nigra and striatum upon GSK0660 were assayed. RESULTS: Our findings suggested that PPARß/δ antagonist has neuroprotective potential due to neurotrophic support, anti-apoptotic and anti-oxidative effects paralleled to an amelioration of mitochondria and proteasome activity. These findings are strongly supported also by the siRNA results demonstrating that by silencing PPARß/δ a significative rescue of the dopaminergic neurons was obtained, thus indicating an involvement of PPARß/δ in PD's pathogenesis. Interestingly, in the animal model, GSK0660 treatment confirmed neuroprotective effects observed in the in vitro studies. Neuroprotective effects were highlighted by the behavioural performance and apomorphine rotation tests amelioration and the reduction of dopaminergic neuronal loss. These data were also confirmed by imaging and western blotting, indeed, the tested compound decreased astrogliosis and activated microglia, concomitant with an upregulation of neuroprotective pathways. CONCLUSIONS: In summary, PPARß/δ antagonist displayed neuroprotective activities against 6-hydroxydopamine detrimental effects both in vitro and in vivo models of Parkinson's disease, suggesting that it may represent a novel therapeutic approach for this disorder.


Asunto(s)
Fármacos Neuroprotectores , PPAR-beta , Enfermedad de Parkinson , Animales , Ratones , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Oxidopamina , Complejo de la Endopetidasa Proteasomal
2.
Biol. Res ; 56: 27-27, 2023. tab, graf, ilus
Artículo en Inglés | LILACS | ID: biblio-1513739

RESUMEN

BACKGROUND: The underlying mechanism of Parkinson's disease are still unidentified, but excitotoxicity, oxidative stress, and neuroinflammation are considered key actors. Proliferator activated receptors (PPARs) are transcription factors involved in the control of numerous pathways. Specifically, PPARß/δ is recognized as an oxidative stress sensor, and we have previously reported that it plays a detrimental role in neurodegeneration. METHODS: Basing on this concept, in this work, we tested the potential effects of a specific PPARß/δ antagonist (GSK0660) in an in vitro model of Parkinson's disease. Specifically, live-cell imaging, gene expression, Western blot, proteasome analyses, mitochondrial and bioenergetic studies were performed. Since we obtained promising results, we tested this antagonist in a 6-hydroxydopamine hemilesioned mouse model. In the animal model, behavioral tests, histological analysis, immunofluorescence and western blot of substantia nigra and striatum upon GSK0660 were assayed. RESULTS: Our findings suggested that PPARß/δ antagonist has neuroprotective potential due to neurotrophic support, anti-apoptotic and anti-oxidative effects paralleled to an amelioration of mitochondria and proteasome activity. These findings are strongly supported also by the siRNA results demonstrating that by silencing PPARß/δ a significative rescue of the dopaminergic neurons was obtained, thus indicating an involvement of PPARß/δ in PD's pathogenesis. Interestingly, in the animal model, GSK0660 treatment confirmed neuroprotective effects observed in the in vitro studies. Neuroprotective effects were highlighted by the behavioural performance and apomorphine rotation tests amelioration and the reduction of dopaminergic neuronal loss. These data were also confirmed by imaging and western blotting, indeed, the tested compound decreased astrogliosis and activated microglia, concomitant with an upregulation of neuroprotective pathways. CONCLUSIONS: In summary, PPARß/δ antagonist displayed neuroprotective activities against 6-hydroxydopamine detrimental effects both in vitro and in vivo models of Parkinson's disease, suggesting that it may represent a novel therapeutic approach for this disorder.


Asunto(s)
Animales , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , PPAR-beta , Oxidopamina , Complejo de la Endopetidasa Proteasomal
3.
J Biomed Mater Res A ; 106(6): 1585-1594, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29424473

RESUMEN

Novel two-dimensional films and three-dimensional (3D) scaffolds based on chitosan (CHI), apatite (Ap), and graphene oxide (GO) were developed by an in situ synthesis in which self-assembly process was conducted to direct partial reduction of GO by CHI in acidic medium. Physical-chemical characterization was carried out by optical microscopy, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy. In vitro biological studies using murine fibroblast (MC3T3) and human neuroblastoma (SH-SY5Y) cell lines were also performed. Cell growth and adherence on composites was also checked using SEM. Live and death staining by confocal microscope and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium of the samples were investigated. The results confirmed the incorporation of both Ap and GO sheets, into CHI polymeric matrix. Furthermore, it was confirmed a physical integration between inorganic Ap and organic CHI and strong chemical interaction between CHI and GO in the obtained composites. SH-SY5Y cell line showed preferential adherence on CHI/GO films surface while MC3T3 cell line displayed a good compatibility for all 3D scaffolds. This study confirms the biocompatibility of materials based on CHI, Ap, and GO for future tissues applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1585-1594, 2018.


Asunto(s)
Apatitas/química , Materiales Biocompatibles/química , Quitosano/análogos & derivados , Grafito/química , Andamios del Tejido/química , Animales , Adhesión Celular , Línea Celular , Proliferación Celular , Humanos , Ratones , Ingeniería de Tejidos
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