Araújo, BrunaCampos, JonasSilva, Rita CaridadePinheiro, Bárbara MendesMarques, RaquelBarata, SandraLima, RuiMacedo, Joana MartinsGomes, EduardoLarrat, BenoitSalgado, AntónioMériaux, SébastienDomingues, SofiaTeixeira, FábioGomes, Eduardo2025-10-282025-10-282023-10Araújo, B., Campos, J., Caridade-Silva, R., Mendes-Pinheiro, B., Marques, R., Barata, S., Lima, R., Martins-Macedo, J., Gomes, E., Larrat, B., Salgado, A., Mériaux, S., Domingues, S., & Teixeira, F. (2023). Modulation of brain structure and motor function by safinamide multimodal actions in a pre-clinical model of Parkinson’s Disease. IBRO Neuroscience Reports, 15, S212. https://doi.org/10.1016/j.ibneur.2023.08.3372667-2421http://hdl.handle.net/10400.22/30696To date, no neuroprotective/disease-modifying strategy has been approved as a Parkinson’s Disease (PD) therapy, because of the‘one-disease-one-target’ view that has been followed. New drug-based therapeutic routes, namely Safinamide, have been introduced as a promising multimodal drug combining dopaminergic and non-dopaminergic (neuroprotective) actions, representing a new potential alternative therapy to prevent or delay PD progression. Thus, the present work addressed Safinamide's impact on PD, relying on the possibility of potentiating dopaminergic neurons (DAn) survival by tackling cellular/molecular impairments responsible for its failure. Safinamide (10mg/kg) was given by oral gavage to a 6-OHDA pre-clinical rat model. DAn survival, neuroinflammation, and redox system homeostasis were assessed by histological and molecular analysis. Additionally, to overpass the selective blood-brain barrier (BBB) permeability, which reduces drug bioavailability reaching PD brain regions, we conducted magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) to transiently open the BBB to precisely deliver Safinamide in PD-affected areas. Results revealed that Safinamide monotherapy was able to potentiate the densities of DAn and fibers, revealing a protective effect when compared to the untreated group. To understand possible pathways associated with this improvement, we found that Safinamide appears to be a modulator of the antioxidant and autophagy systems since an increase in the expression levels of DJ-1, SOD-1, and LC3B was observed when compared to the non-treated group. Furthermore, Safinamide presents a potential modulatory activity on neuroinflammation and astrogliosis, as a decrease in microglia (CD11b+) and astrocytic (GFAP+) cells number was observed when compared to 6-OHDA group. Additionally, the anatomical and functional MRI analysis exhibited connectivity and metabolite alterations. Collectively, these data demonstrate the promising therapeutic potential of Safinamide as a neuroprotection strategy for PD, which may open new therapeutic opportunities for individuals in prodromal stages, potentially delaying clinical manifestation in high-risk patients.engNeuronsGliaconference poster