Browsing by Author "Rodrigues, Tiago M."
Now showing 1 - 7 of 7
Results Per Page
Sort Options
- Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effectsPublication . Mahú, Inês; Barateiro, Andreia; Rial-Pensado, Eva; Martinéz-Sánchez, Noelia; Vaz, Sandra H.; Cal, Pedro M.S.D.; Jenkins, Benjamin; Rodrigues, Tiago M.; Cordeiro, Carlos; Costa, Miguel F.; Mendes, Raquel; Seixas, Elsa; Pereira, Mafalda M.A.; Kubasova, Nadiya; Gres, Vitka; Morris, Imogen; Temporão, Carolina; Olivares, Marta; Sanz, Yolanda; Koulman, Albert; Corzana, Francisco; Sebastião, Ana M; López, Miguel; Bernardes, Gonçalo J. L.; Domingos, Ana I.Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.
- Challenges and promises in the development of neurotrophic factor-based therapies for Parkinson’s diseasePublication . Rodrigues, Tiago M.; Jerónimo-Santos, André; Outeiro, Tiago; Sebastião, Ana M; Diógenes, Maria JoséParkinson's disease (PD) is a chronic movement disorder typically coupled to progressive degeneration of dopaminergic neurons in the substantia nigra (SN). The treatments currently available are satisfactory for symptomatic management, but the efficacy tends to decrease as neuronal loss progresses. Neurotrophic factors (NTFs) are endogenous proteins known to promote neuronal survival, even in degenerating states. Therefore, the use of these factors is regarded as a possible therapeutic approach, which would aim to prevent PD or to even restore homeostasis in neurodegenerative disorders. Intriguingly, although favorable results in in vitro and in vivo models of the disease were attained, clinical trials using these molecules have failed to demonstrate a clear therapeutic benefit. Therefore, the development of animal models that more closely reproduce the mechanisms known to underlie PD-related neurodegeneration would be a major step towards improving the capacity to predict the clinical usefulness of a given NTF-based approach in the experimental setting. Moreover, some adjustments to the design of clinical trials ought to be considered, which include recruiting patients in the initial stages of the disease, improving the efficacy of the delivery methods, and combining synergetic NTFs or adding NTF-boosting drugs to the already available pharmacological approaches. Despite the drawbacks on the road to the use of NTFs as pharmacological tools for PD, very relevant achievements have been reached. In this article, we review the current status of the potential relevance of NTFs for treating PD, taking into consideration experimental evidence, human observational studies, and data from clinical trials.
- Challenges of BDNF-based therapies : from common to rare diseasesPublication . Miranda-Lourenço, Catarina; Ribeiro Rodrigues, Leonor; Fonseca-Gomes, João; Tanqueiro, Sara; Belo, Rita F.; Ferreira, Catarina B.; Rei, Nádia; Ferreira-Manso, Mafalda; de Almeida-Borlido, Carolina; Costa-Coelho, Tiago; Freitas, Céline; Zavalko, Svitlana; Mouro, Francisco; Sebastião, Ana M; Xapelli, Sara; Rodrigues, Tiago M.; Diógenes, Maria JoséNeurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75NTR). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.
- Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signallingPublication . Miranda-Lourenço, Catarina; Duarte, Sofia T.; Palminha, Cátia; Gaspar, Cláudia; Rodrigues, Tiago M.; Magalhães-Cardoso, Teresa; Rei, Nádia; Colino-Oliveira, Mariana; Gomes, Rui; Ferreira, Sara; Rosa, Jéssica; Xapelli, Sara; Armstrong, Judith; García-Cazorla, Àngels; Correia-de-Sá, Paulo; Sebastião, Ana M; Diógenes, Maria JoséRett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.
- Macular OCT-angiography parameters to predict the clinical stage of nonproliferative diabetic retinopathy: an exploratory analysisPublication . Rodrigues, Tiago M.; Marques, João P.; Soares, Mário; Simão, Sílvia; Melo, Pedro; Martins, Amélia; Figueira, João; Murta, Joaquim N.; Silva, RufinoBackground: To test whether a single or a composite set of macular vascular density parameters, evaluated with optical coherence tomography angiography (OCTA), are able to predict nonproliferative diabetic retinopathy (NPDR) staging according to the gold-standard ETDRS-grading scheme. Methods: Prospectively defined, cross-sectional study in which macular structural and vascular parameters of diabetic eyes with nonproliferative DR (up to ETDRS Level 53) were evaluated with OCTA (Avanti RTVue-XR 100, Optovue Inc, Fremont, CA). Seven-field photographs of the fundus were taken for DR staging according to the ETDRS-grading scheme. The vessel density in the superficial and deep capillary plexus (SCP and DCP, respectively), as well as in the choriocapillaris (CC), were calculated using automated software. Univariate and multivariate ordered logistic regression models were used in the analysis. P < 0.05 was considered statistically significant. Results: We included 101 eyes from 56 subjects (mean (SD) age 62.64 (11.74) years; 57.4% were male). On univariate analysis, several OCTA parameters were found to be associated with higher ETDRS level (parafoveal SCP density: OR = 0.87 (95% CI 0.76-0.99), p = 0.039; parafoveal DCP density: OR = 0.79 (95% CI 0.72-0.87), p < 0.001; CC density: OR = 0.89 (95% CI 0.80-0.99)), p = 0.036). In the final model, while also adjusting for relevant clinical features, only parafoveal vessel density in the DCP remained as a significant predictor of NPDR ETDRS level (OR = 0.54 (95% CI 0.32-0.92), p = 0.024). Conclusion: Our results suggest that parafoveal vessel density in the DCP is the parameter most robustly associated with ETDRS level. OCTA analysis may provide objective imaging biomarkers to monitor NPDR clinical progression.
- Peripapillary neurovascular coupling in the early stages of diabetic retinopathyPublication . Rodrigues, Tiago M.; Marques, João P.; Soares, Mário; Dolan, Michael-John; Melo, Pedro; Simão, Sílvia; Teles, João; Figueira, João; Murta, Joaquim N.; Silva, RufinoPurpose: To study radial peripapillary capillary (RPC) density in the early stages of diabetic retinopathy (DR), using optical coherence tomography angiography. Methods: A cross-sectional evaluation of RPCs was performed using optical coherence tomography angiography (Avanti RTVue-XR 100, Optovue Inc, Fremont, CA). Annular RPC density was the primary outcome. Global density and retinal nerve fiber layer thickness were secondary outcomes. Diabetic eyes were divided into three groups: no DR, mild nonproliferative DR (mild NPDR), and moderate NPDR. Multilevel mixed-effects univariate and multivariate linear regression models were used. Results: We included 155 eyes (n = 42 control; n = 27 no DR; n = 28 mild NPDR; and n = 58 moderate NPDR) from 86 subjects (mean [SD] age 63.39 [10.70] years; 46.45% male). When compared with controls, a significant decrease in annular RPC density was found in all groups of diabetic eyes on multivariate analysis (no DR: β = -2.95, P < 0.001; mild NPDR: β = -1.76, P = 0.017; and moderate NPDR: β = -2.82, P < 0.001). We also detected a significant decrease in retinal nerve fiber layer thickness in diabetic eyes (even in the no DR group). Furthermore, in diabetic eyes, annular RPC density and retinal nerve fiber layer thickness correlated significantly (R = 0.4874, P < 0.001). Conclusion: Peripapillary neurovascular changes occur early in the course of DR. Their significance in the progression of DR warrants further research.
- A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's diseasePublication . Fonseca-Gomes, João; Costa-Coelho, Tiago; Ferreira-Manso, Mafalda; Inteiro-Oliveira, Sara; Vaz, Sandra H.; Alemãn-Serrano, Nuno; Atalaia Barbacena, Henrique; Ribeiro Rodrigues, Leonor; Ramalho, Rita Mira; Climaco Pinto, Rui; Vicente Miranda, Hugo; Tanqueiro, Sara; de Almeida-Borlido, Carolina; Ramalho, Maria João; Miranda-Lourenço, Catarina; Belo, Rita F.; Ferreira, Catarina B.; Neves, Vera; Rombo, Diogo M.; Viais, Ricardo; Umemori, Juzoh; Martins, Ivo C.; Jerónimo-Santos, André; Caetano, António; Manso, Nuno; Mäkinen, Petra; Marttinen, Mikael; Takalo, Mari; Bremang, Michael; Pike, Ian; Haapasalo, Annakaisa; Loureiro, Joana A.; Pereira, Maria Carmo; Santos, Nuno C.; Outeiro, Tiago; Castanho, Miguel A. R. B.; Fernandes, Adelaide; Hiltunen, Mikko; Duarte, Carlos B.; Castrén, Eero; De Mendonça, Alexandre; Sebastião, Ana M; Rodrigues, Tiago M.; Diógenes, Maria JoséIn Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.