Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson's Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice.
Parkinson’s disease
methylphenidate analogues
motor recovery effect
threo methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride
α-synuclein/synapsin III complex
Journal
Pharmaceutics
ISSN: 1999-4923
Titre abrégé: Pharmaceutics
Pays: Switzerland
ID NLM: 101534003
Informations de publication
Date de publication:
30 Jul 2022
30 Jul 2022
Historique:
received:
17
05
2022
revised:
20
07
2022
accepted:
26
07
2022
entrez:
26
8
2022
pubmed:
27
8
2022
medline:
27
8
2022
Statut:
epublish
Résumé
Parkinson's disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative
Identifiants
pubmed: 36015221
pii: pharmaceutics14081595
doi: 10.3390/pharmaceutics14081595
pmc: PMC9414221
pii:
doi:
Types de publication
Journal Article
Langues
eng
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