1. |
- Corsi, Sara, et al.
(författare)
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Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease
- 2023
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 363
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Tidskriftsartikel (refereegranskat)abstract
- Growing preclinical and clinical evidence highlights neurosteroid pathway imbalances in Parkinson's Disease (PD) and L-DOPA-induced dyskinesias (LIDs). We recently reported that 5α-reductase (5AR) inhibitors dampen dyskinesias in parkinsonian rats; however, unraveling which specific neurosteroid mediates this effect is critical to optimize a targeted therapy. Among the 5AR-related neurosteroids, striatal pregnenolone has been shown to be increased in response to 5AR blockade and decreased after 6-OHDA lesions in the rat PD model. Moreover, this neurosteroid rescued psychotic-like phenotypes by exerting marked antidopaminergic activity. In light of this evidence, we investigated whether pregnenolone might dampen the appearance of LIDs in parkinsonian drug-naïve rats. We tested 3 escalating doses of pregnenolone (6, 18, 36 mg/kg) in 6-OHDA-lesioned male rats and compared the behavioral, neurochemical, and molecular outcomes with those induced by the 5AR inhibitor dutasteride, as positive control. The results showed that pregnenolone dose-dependently countered LIDs without affecting L-DOPA-induced motor improvements. Post-mortem analyses revealed that pregnenolone significantly prevented the increase of validated striatal markers of dyskinesias, such as phospho-Thr-34 DARPP-32 and phospho-ERK1/2, as well as D1-D3 receptor co-immunoprecipitation in a fashion similar to dutasteride. Moreover, the antidyskinetic effect of pregnenolone was paralleled by reduced striatal levels of BDNF, a well-established factor associated with the development of LIDs. In support of a direct pregnenolone effect, LC/MS-MS analyses revealed that striatal pregnenolone levels strikingly increased after the exogenous administration, with no significant alterations in downstream metabolites. All these data suggest pregnenolone as a key player in the antidyskinetic properties of 5AR inhibitors and highlight this neurosteroid as an interesting novel tool to target LIDs in PD.
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2. |
- Faustini, Gaia, et al.
(författare)
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Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinsons disease-like phenotype
- 2022
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Ingår i: Molecular Therapy. - : Cell Press. - 1525-0016 .- 1525-0024. ; 30:4, s. 1465-1483
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Tidskriftsartikel (refereegranskat)abstract
- Fibrillary aggregated alpha-synuclein (alpha-syn) deposition in Lewy bodies (LB) characterizes Parkinsons disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with alpha-syn to regulate dopamine (DA) release and can be found in the insoluble alpha-syn fibrils composing LB. Moreover, we showed that a-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human alpha-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates alpha-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human alpha-syn transgenic mice at PD-like stage with advanced alpha-syn aggregation and overt striatal synaptic failure, we could lower alpha-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates alpha-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.
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