Neuroprotective effects of the PPARβ/δ antagonist GSK0660 in in vitro and in vivo Parkinson's disease models.
GSK0660
Mitochondrial impairment
Neurotrophic support
Oxidative stress
Parkinson’s disease
Proteasome
Journal
Biological research
ISSN: 0717-6287
Titre abrégé: Biol Res
Pays: England
ID NLM: 9308271
Informations de publication
Date de publication:
25 May 2023
25 May 2023
Historique:
received:
12
09
2022
accepted:
29
04
2023
medline:
26
5
2023
pubmed:
25
5
2023
entrez:
24
5
2023
Statut:
epublish
Résumé
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, PPARβ/δ is recognized as an oxidative stress sensor, and we have previously reported that it plays a detrimental role in neurodegeneration. Basing on this concept, in this work, we tested the potential effects of a specific PPARβ/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. Our findings suggested that PPARβ/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 PPARβ/δ a significative rescue of the dopaminergic neurons was obtained, thus indicating an involvement of PPARβ/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. In summary, PPARβ/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.
Sections du résumé
BACKGROUND
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, PPARβ/δ is recognized as an oxidative stress sensor, and we have previously reported that it plays a detrimental role in neurodegeneration.
METHODS
METHODS
Basing on this concept, in this work, we tested the potential effects of a specific PPARβ/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
RESULTS
Our findings suggested that PPARβ/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 PPARβ/δ a significative rescue of the dopaminergic neurons was obtained, thus indicating an involvement of PPARβ/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
CONCLUSIONS
In summary, PPARβ/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.
Identifiants
pubmed: 37226204
doi: 10.1186/s40659-023-00438-1
pii: 10.1186/s40659-023-00438-1
pmc: PMC10210307
doi:
Substances chimiques
PPAR-beta
0
Neuroprotective Agents
0
GSK0660
0
Oxidopamine
8HW4YBZ748
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
27Informations de copyright
© 2023. The Author(s).
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