Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease
(2023) In Experimental Neurology 363.- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2023-05
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 6-OHDA-lesion, Dyskinesia, Neurosteroids, Parkinson's disease, Pregnenolone
- in
- Experimental Neurology
- volume
- 363
- article number
- 114370
- publisher
- Elsevier
- external identifiers
-
- pmid:36878398
- scopus:85149991045
- ISSN
- 0014-4886
- DOI
- 10.1016/j.expneurol.2023.114370
- language
- English
- LU publication?
- yes
- id
- ac90b591-ad2e-47e6-8a67-578a2ede9cb0
- date added to LUP
- 2023-04-24 12:01:26
- date last changed
- 2024-06-15 02:07:22
@article{ac90b591-ad2e-47e6-8a67-578a2ede9cb0,
abstract = {{<p>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-ERK<sub>1/2</sub>, as well as D<sub>1</sub>-D<sub>3</sub> 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.</p>}},
author = {{Corsi, Sara and Scheggi, Simona and Pardu, Alessandra and Braccagni, Giulia and Caruso, Donatella and Cioffi, Lucia and Diviccaro, Silvia and Gentile, Mauro and Fanni, Silvia and Stancampiano, Roberto and Gambarana, Carla and Melcangi, Roberto Cosimo and Frau, Roberto and Carta, Manolo}},
issn = {{0014-4886}},
keywords = {{6-OHDA-lesion; Dyskinesia; Neurosteroids; Parkinson's disease; Pregnenolone}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Experimental Neurology}},
title = {{Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease}},
url = {{http://dx.doi.org/10.1016/j.expneurol.2023.114370}},
doi = {{10.1016/j.expneurol.2023.114370}},
volume = {{363}},
year = {{2023}},
}