Neuroprotective Mechanisms of Dehydroepiandrosterone in Parkinson’s Disease: Preliminary Results of a Scoping Review.

Abstract

Background. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, dysfunction of nigrostriatal circuits, and progressive motor impairment. Although current treatments provide symptomatic control, their efficacy may decrease over the long term and may be associated with motor, metabolic, or psychiatric complications; therefore, identifying strategies with neuroprotective potential remains relevant. Dehydroepiandrosterone (DHEA) is a steroid hormone produced in the adrenal glands and synthesized de novo in the central nervous system. In nervous tissue, it may exert genomic and non-genomic actions through its interaction with androgenic, estrogenic, and neurosteroidal pathways. In addition, its age-related decline has been linked to increased vulnerability to neurodegenerative processes. In experimental models, DHEA has shown potentially protective effects by modulating dopaminergic neurotransmission, reducing GABAergic inhibition in striatal circuits, promoting local conversion to estradiol, and participating in antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. However, clinical evidence in humans with PD remains limited. Objective. To describe the neuroprotective mechanisms associated with the therapeutic potential of DHEA in Parkinson’s disease. Materials and methods. A literature search was conducted using algorithms based on the following Medical Subject Headings (MeSH) and search terms: (“Dehydroepiandrosterone” AND “Parkinson Disease”). Published studies evaluating the relationship between DHEA, Parkinson’s disease, parkinsonian models, or neuroprotective mechanisms were included. Study selection was performed in two stages, title/abstract and full-text screening, in duplicate. Finally, a narrative synthesis was conducted under PRISMA-ScR parameters considering study type, experimental model, intervention, motor outcomes, and proposed neurobiological mechanisms. Results. A total of 50 articles were identified, of which 5 studies met the inclusion criteria: 4 reviews and 1 primary study in an animal model. The experimental study in non-human primates with MPTP-induced lesions reported that DHEA administration at doses of 1, 5, and 15 mg/kg significantly improved parkinsonian motor scores in subjects with moderate to severe impairment. At the mechanistic level, DHEA showed a possible modulatory effect on basal ganglia circuits by reducing GABAergic inhibition in striatal output pathways, which could promote motor activity. Likewise, its cerebral conversion to estradiol could enhance dopaminergic signaling and activate antioxidant and anti-inflammatory mechanisms. DHEA also acted as an adjuvant to low-dose L-Dopa, increasing its therapeutic effect and prolonging the motor response by 15 to 45 minutes, without increasing dyskinesias when combined with high-dose L-Dopa. Conclusions.
Preliminary evidence suggests that DHEA has neuroprotective potential in PD through modulation of dopaminergic and GABAergic neurotransmission, local conversion to estrogenic metabolites, and regulation of oxidative, inflammatory, and apoptotic processes. Although preclinical findings are promising, the scarcity of primary studies and the lack of robust clinical evidence prevent definitive conclusions regarding its therapeutic efficacy in humans.