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

• Published in: Experimental neurology Vol. 363; p. 114370
• Main Authors: Corsi, Sara, Scheggi, Simona, Pardu, Alessandra, Braccagni, Giulia, Caruso, Donatella, Cioffi, Lucia, Diviccaro, Silvia, Gentile, Mauro, Fanni, Silvia, Stancampiano, Roberto, Gambarana, Carla, Melcangi, Roberto Cosimo, Frau, Roberto, Carta, Manolo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2023
• Subjects: 6-OHDA-lesion; Animals; Antiparkinson Agents - adverse effects; Basic Medicine; Corpus Striatum - metabolism; Disease Models, Animal; Dutasteride - metabolism; Dutasteride - pharmacology; Dutasteride - therapeutic use; Dyskinesia; Dyskinesia, Drug-Induced - metabolism; Levodopa - adverse effects; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Neurosciences; Neurosteroids; Neurosteroids - metabolism; Neurosteroids - pharmacology; Neurosteroids - therapeutic use; Neurovetenskaper; Oxidopamine - toxicity; Parkinson Disease - pathology; Parkinson's disease; Pregnenolone; Rats; Rats, Sprague-Dawley; Parkinson's disease; Neurosteroids; 6-OHDA-lesion; Pregnenolone; Dyskinesia
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2023.114370

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. •PREG administration dampened development of LID in a rat model of PD.•PREG administration counteracted striatal dopaminergic signaling alterations.•PREG normalized striatal BDNF levels and D1-D3 receptor interaction.