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- From the gut to the brain: Is microbiota a new paradigm in Parkinson’s disease treatment?Publication . Vilela, Cristiana; Araújo, Bruna; Guedes, Carla; Silva, Rita Caridade; Macedo, Joana Martins; Teixeira, Catarina; Gomes, Eduardo; Prudêncio, Cristina; Vieira, Mónica; Teixeira, Fábio G.Parkinson’s disease (PD) is recognized as the second most prevalent primary chronic neurodegenerative disorder of the central nervous system. Clinically, PD is characterized as a movement disorder, exhibiting an incidence and mortality rate that is increasing faster than any other neurological condition. In recent years, there has been a growing interest concerning the role of the gut microbiota in the etiology and pathophysiology of PD. The establishment of a brain–gut microbiota axis is now real, with evidence denoting a bidirectional communication between the brain and the gut microbiota through metabolic, immune, neuronal, and endocrine mechanisms and pathways. Among these, the vagus nerve represents the most direct form of communication between the brain and the gut. Given the potential interactions between bacteria and drugs, it has been observed that the therapies for PD can have an impact on the composition of the microbiota. Therefore, in the scope of the present review, we will discuss the current understanding of gut microbiota on PD and whether this may be a new paradigm for treating this devastating disease.
- Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablationPublication . Martins-Macedo, Joana; Araújo, Bruna; Anjo, Sandra I.; Silveira-Rosa, Tiago; Patrício, Patrícia; Alves, Nuno Dinis; Silva, Joana M.; Teixeira, Fábio G.; Manadas, Bruno; Rodrigues, Ana J.; Lepore, Angelo C.; Salgado, António J.; Gomes, Eduardo D.; Pinto, Luísa; Gomes, EduardoAdult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.
- From peripheral to central (Neuro)degeneration: Is heart-kidney a new axial paradigm for Parkinson’s disease?Publication . Teixeira, Catarina; Caridade-Silva, Rita; Martins-Macedo, Joana; Araújo, Bruna; Gomes, Eduardo; Vilela, Cristiana; Soares-Guedes, Carla; Pires, Inês Falcão; Alencastre, Inês; G. Teixeira, Fábio; Gomes, EduardoParkinson’s Disease (PD) is primarily characterized by the accumulation of alpha-synuclein (αSyn) and the loss of dopaminergic neurons (DAn). The most evident repercussions of the disease include sympathetic and parasympathetic dysfunction, decreased dopamine (DA) levels, and impaired voluntary movements. Given the multifactorial nature of PD, it is now recognized that several systemic diseases may predispose individuals to the onset and progression of PD as well as influence its therapeutic outcomes. Recent studies have highlighted that patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) face an increased risk of developing PD, independent of the shared risk factors. Indeed, substantial evidence supports the connections between the brain, heart, and kidneys. Elements such as the dopaminergic system, blood pressure regulation, inflammation, autophagy, oxidative stress, and calcium (Ca2+) signaling are recognized as crucial for the functioning of each organ individually. However, these factors may also significantly impact the overall health of the triad. Understanding the interconnection between the brain, heart, and kidneys would be groundbreaking in enhancing our knowledge about their interactions, enabling prompt interventions in the early stages of the disease. With this perspective, this review analyzes the current understanding of the brain-heart-kidney axis as a potential new paradigm for diagnosing and managing PD.
- Modulation of brain structure and motor function by safinamide multimodal actions in a pre-clinical model of Parkinson’s DiseasePublication . Araújo, Bruna; Campos, Jonas; Silva, Rita Caridade; Pinheiro, Bárbara Mendes; Marques, Raquel; Barata, Sandra; Lima, Rui; Macedo, Joana Martins; Gomes, Eduardo; Larrat, Benoit; Salgado, António; Mériaux, Sébastien; Domingues, Sofia; Teixeira, Fábio; Gomes, EduardoTo 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.