Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease

Sara Corsi; Simona Scheggi; Alessandra Pardu; Giulia Braccagni; Donatella Caruso; Lucia Cioffi; Silvia Diviccaro; Mauro Gentile; Silvia Fanni; Roberto Stancampiano; Carla Gambarana; Roberto Cosimo Melcangi; Roberto Frau; Manolo Carta

doi:10.1016/j.expneurol.2023.114370

Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease

Exp Neurol. 2023 May:363:114370. doi: 10.1016/j.expneurol.2023.114370. Epub 2023 Mar 5.

Affiliations

¹ Department of Biomedical Sciences, University of Cagliari, Cagliari, CA, Italy.
² Department of Molecular and Developmental Medicine, University of Siena, Siena, SI, Italy.
³ Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, MI, Italy.
⁴ Department of Biomedical Sciences, University of Cagliari, Cagliari, CA, Italy; Basal Ganglia Pathophysiology Unit, Department Experimental Medical Science, Lund University, Sweden.
⁵ Department of Biomedical Sciences, University of Cagliari, Cagliari, CA, Italy; "Guy Everett Laboratory", Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. Electronic address: roberto.frau@unica.it.
⁶ Department of Biomedical Sciences, University of Cagliari, Cagliari, CA, Italy. Electronic address: manolocarta@unica.it.

PMID: 36878398
DOI: 10.1016/j.expneurol.2023.114370

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-ERK_1/2, 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.

Keywords: 6-OHDA-lesion; Dyskinesia; Neurosteroids; Parkinson's disease; Pregnenolone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiparkinson Agents / adverse effects
Corpus Striatum / metabolism
Disease Models, Animal
Dutasteride / metabolism
Dutasteride / pharmacology
Dutasteride / therapeutic use
Dyskinesia, Drug-Induced* / metabolism
Levodopa / adverse effects
Male
Neurosteroids* / metabolism
Neurosteroids* / pharmacology
Neurosteroids* / therapeutic use
Oxidopamine / toxicity
Parkinson Disease* / pathology
Rats
Rats, Sprague-Dawley

Substances

Levodopa
Dutasteride
Oxidopamine
Neurosteroids
Antiparkinson Agents