Influência dos receptores A2a da adenosina no efeito neuroprotector do BDNF na morte neuronal induzida

Tese de mestrado, Bioquímica (Bioquímica Médica), Universidade de Lisboa, Faculdade de Ciências, 2009O factor neurotrófico derivado do cérebro (BDNF) é uma neurotrofina que promove sobrevivência neuronal através da activação do seu receptor TrkB. Na doença de Alzheimer ocorre deposição do péptido Aβ (amyloid-beta) e consequente morte neuronal. Dado que os níveis de BDNF se encontram diminuídos nesta doença, a administração directa desta neurotrofina ao cérebro tem sido sugerida como terapêutica. Contudo esta abordagem revelou-se difícil de implementar pelo que são necessárias alternativas, como por exemplo, o uso de pequenas moléculas que potenciem os efeitos do BDNF endógeno no cérebro. É sabido que o receptor A2A da adenosina pode trans-activar os receptores TrkB na ausência de BDNF. Do ponto de vista funcional, sabe-se que os efeitos desta neurotrofina na transmissão sináptica e plasticidade sináptica são dependentes da activação do receptor A2A. Assim, na presente dissertação, pretendeu-se avaliar a influência dos receptores A2A no efeito neuroprotector do BDNF na morte neuronal induzida pelo péptido Aβ, e também, analisar o efeito deste péptido nos níveis dos receptores TrkB. Os resultados mostram que o BDNF diminui a morte neuronal por apoptose induzida pelo péptido Aβ, e que essa protecção é superior em culturas primárias de neurónios com 10 DIV (days in-vitro) do que com 4 DIV.Por outro lado, a activação do receptor A2A da adenosina, em culturas com 4 DIV, bloqueou o efeito protector do BDNF. Contudo, em culturas com 10 DIV, o efeito protector do BDNF não é influenciado pela activação do receptor A2A. Em ambas as culturas (4 e 10 DIV) a activação do receptor A2A, por si só, não altera os níveis de apoptose induzida pelo Aβ. Durante a presente dissertação também se observou que o péptido Aβ provoca uma diminuição na isoforma completa do receptor TrkB concomitante com um aumento na isoforma truncada do receptor. Este aumento na isoforma truncada é dependente da síntese proteica e é prevenido pela administração exógena de BDNF. Em conclusão, os resultados sugerem que o péptido Aβ poderá reduzir a neuroprotecção endógena exercida pelo BDNF devido às alterações nas isoformas do receptor TrkB, e que a activação dos receptores A2A de adenosina pode diminuir o efeito protector do BDNF na apoptose induzida pelo péptido Aβ.Brain-derived neurotrophic factor (BDNF) is a neurotrophin which promotes neuronal survival through activation of TrkB receptor. In Alzheimer’s disease (AD), the deposition of amyloid-beta peptide (Aβ) contributes to neuronal death. Since the levels of BDNF are reduced in this disorder, direct administration of this neurotrophin into the brain was considered a promising therapeutic approach. It is, however, not simple and therefore, new approaches, like the use of small molecules which can potentiate the endogenous BDNF effects in the brain, were proposed. It is known that adenosine A2A receptors can trans-activate TrkB receptors even in the absence of BNDF. In a functional point of view, the effects of BDNF in synaptic plasticity and transmission are dependent of A2A receptors activation. The objective in this work was to evaluate the influence of A2A receptors upon BDNF neuroprotective effect against neuronal death induced by Aβ peptide, and also, to analyse the effect of this peptide in the levels of TrkB receptor. The results obtained show that BDNF reduces neuronal apoptotic death induced by Aβ, and that this neuroprotection is more pronounced in 10 days in-vitro primary neuronal cultures (10DIV) than in 4 DIV cultures. On the other hand, in 4 DIV cells, A2A receptors activation blocked the protective effect of BDNF. However, in 10 DIV cultures, A2A receptors activation did not influence the BDNF-induced neuroprotection. In both cultures (4 and 10 DIV), the activation of A2A receptors did not changed the apoptosis levels induced by Aβ peptide. In the present work it was also observed that Aβ peptide administration produced a decrease in the full length isoform of TrkB receptor concomitantly with an increase in the truncated isoform of TrkB receptor. This increase in truncated receptor is dependent on protein synthesis and was prevented if BDNF was added to the cultures. In conclusion, these results suggest that Aβ peptide can reduce neuroprotection caused by endogenous BDNF because it induces TrkB isoform changes, and that the BDNF-induced protection against neuronal death can be diminished by activation of adenosine A2A receptor

Brain-derived neurotrophic factor and adenosine signalling on amyloid-β peptide induced toxicity : impact on hippocampal function

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2014Brain-derived neurotrophic factor (BDNF) and its high-affinity full-length receptor, TrkB-FL, play a central role in the nervous system by providing trophic support to neurons and by regulating synaptic transmission and plasticity. BDNF signalling is impaired in Alzheimer’s disease (AD), a neurodegenerative disorder characterized, among other features, by the accumulation of the amyloid-β (Aβ) peptide. Although the mechanisms implicated in the reduction of BDNF signalling in AD were not clarified, the reestablishment of BDNF actions is considered as a promising strategy for AD treatment. In last decade it became clear that most of synaptic actions of BDNF, including the ones upon synaptic transmission, plasticity or upon neurotransmitter release, are fully dependent on adenosine A2A receptors (A2AR) activation. However, evidences indicate that A2AR antagonists can prevent the deficits in AD animal models. Given the lack of data clarifying the mechanisms behind the changes on BDNF signalling, namely changes on TrkB receptors, and the knowledge that A2AR activation facilitates most of BDNF synaptic actions, the main goal of this project was to study the impact of Aβ peptides and A2AR on BDNF signalling. This work revealed that in rat primary neuronal cultures Aβ selectively increases mRNA levels for the truncated TrkB-T1 and TrkB-T2 isoforms without affecting TrkB fulllength (TrkB-FL) mRNA levels. Moreover, Aβ increases protein levels of total pool of truncated TrkB receptors (TrkB-Tc) and decreases TrkB-FL protein levels. This effect is explained by the Aβ-induced calpain-mediated cleavage on TrkB-FL receptors, downstream of Shc binding site, which results in the formation of a new truncated TrkB receptor (TrkB-T’) and a new intracellular fragment (TrkB-ICD), which is also detected in post-mortem human brain samples. In hippocampal slices it was observed that Aβ impairs BDNF function in a calpaindependent way, upon modulation of GABA and glutamate release from hippocampal nerve terminals, and upon modulation of long-term potentiation (LTP). Finally, the exogenous BDNF strongly reduces the Aβ-induced activation of caspase-3 and calpain in neuronal cultures, an effect not affected by A2AR agonist or antagonist. Moreover, for the first time it was shown that chronic in vivo blockade of A2AR by a selective antagonist, prevents the facilitatory action of BDNF upon ex-vivo CA1 hippocampal LTP and decreases both mRNA and protein levels of the TrkB-FL receptor in rat hippocampus. In conclusion, the present work shows that Aβ induces a TrkB-FL cleavage mediated by calpain and impairs BDNF-mediated effects in synaptic plasticity and neurotransmitter release in a calpain-dependent way. While the BDNF action upon synaptic plasticity is abolished under chronic in vivo A2AR blocking conditions, the protective actions of this neurotrophin against Aβ toxicity were found to be dependent on A2AR activation.O factor neurotrófico derivado do cérebro (Brain-derived neurotrophic factor- BDNF) e o seu receptor de alta afinidade, TrkB-FL, desempenham um papel central no sistema nervoso, dado que promovem suporte trófico aos neurónios e que regulam a transmissão e plasticidade sinápticas. A sinalização mediada pelo BDNF encontra-se diminuída na doença de Alzheimer (Alzheimer’s disease -AD), uma doença neurodegenerativa na qual ocorre acumulação do péptido beta amilóide (amyloid-beta -Aβ). Apesar dos mecanismos envolvidos na redução da sinalização mediada pelo BDNF na AD não serem totalmente conhecidos, o restabelecimento das acções do BDNF tem sido considerado como uma estratégia promissora para a terapêutica desta doença. Na última década tornou-se claro que a maioria das acções sinápticas do BDNF, incluindo as acções na transmissão e plasticidade sinápticas e também na libertação de neurotransmissores, é dependente da activação dos receptores A2A da adenosina (A2AR). Contudo, o uso de antagonistas dos A2AR tem sido apontado como uma possível estratégia terapêutica para o tratamento da AD. Dada a falta de evidências que clarifiquem os mecanismos envolvidos nas alterações da sinalização mediada pelo BDNF e o conhecimento de que a activação dos A2AR facilita a maioria das acções sinápticas do BDNF, o objectivo principal desta tese foi estudar o impacto dos péptidos Aβ e dos A2AR na sinalização mediada pelo BDNF. Este trabalho revelou que, em culturas primárias de neurónios corticais, o Aβ aumenta os níveis de mRNA dos receptores TrkB truncados, TrkB-T1 e TrkB-T2, sem afectar os níveis de mRNA dos receptores TrkB completos, TrkB-FL. Por outro lado, verificou-se que o Aβ aumenta os níveis proteicos do conjunto de receptores TrkB truncados e que diminui os níveis proteicos dos receptores TrkB-FL, por um mecanismo independente da proliferação glial e da activação de caspases. Foi ainda possível concluir que o Aβ induz a clivagem, mediada por calpaínas, dos receptores TrkB-FL, esta clivagem dá-se após o local de ligação da Shc e antes do início do domínio de cinase de tirosina, pelo que origina um novo receptor TrkB truncado (TrkB-T’), contendo o local de ligação à Shc, e um novo fragmento intracelular (TrkBintracellular domain- ICD), contendo a totalidade do domínio da cinase. No entanto, a presença destes fragmentos, não mostrou afectar a fosforilação do receptor TrkB-FL induzida pela exposição ao BDNF. Interessantemente, foi possível detectar o fragmento TrkB-ICD em uma amostra, post-mortem, de cérebro humano. Mostrou-se também que a inibição das calpaínas previne as alterações dos níveis proteicos das isoformas do TrkB, induzidas pelo Aβ, sem afectar as alterações ao nível do mRNA do TrkB. Por outro lado, este trabalho revelou que o BDNF exógeno reduz a activação da caspase-3 e das calpaínas induzida pelo Aβ, de uma forma independentemente dos A2AR. Em fatias de hipocampo de ratos adultos, este trabalho mostrou que o Aβ diminui as acções do BDNF na plasticidade sináptica, nomeadamente na potenciação de longa duração (Long-term potentiation, LTP) na área CA1 do hipocampo, bem como no seu efeito sobre libertação de neurotransmissores (GABA e glutamato) de sinaptosomas. Notavelmente, o inibidor das calpaínas, MDL28170, mostrou restabelecer os efeitos do BDNF, na presença do péptido Aβ, tanto na plasticidade sináptica como na libertação de neurotransmissores. Este trabalho permitiu ainda concluir que o bloqueio crónico dos A2AR, in-vivo, através da administração de um antagonista selectivo (KW-6002), previne o efeito potenciador do BDNF na LTP, registada ex-vivo na área CA1 do hipocampo, e que diminui os níveis de mRNA e de proteína do receptor TrkB-FL, no hipocampo de rato. Em suma, o presente trabalho revelou que o péptido Aβ induz a clivagem dos receptores TrkB-FL, mediada pelas calpaínas, e que bloqueia as acções mediadas pelo BDNF na plasticidade sináptica e na libertação de GABA e glutamato por um mecanismo dependente da actividade das calpaínas. Se por um lado, o efeito do BDNF na plasticidade sináptica é perdido aquando da inibição crónica dos A2AR, o efeito protector desta neurotrofina contra a toxicidade induzida pelo Aβ mostrou-se independente da activação dos A2AR.Fundação para a Ciência e a Tecnologia (FCT

Anotação automática e interativa de documentos PDF

Mestrado em Engenharia de Computadores e TelemáticaO aumento acelerado da literatura biomédica levou ao desenvolvimento de vários esforços para extrair e armazenar, de forma estruturada, a informação relativa aos conceitos e relações presentes nesses textos, oferecendo aos investigadores e clínicos um acesso rápido e fácil à informação. No entanto, este processo de "curadoria de conhecimento" é uma tarefa extremamente exaustiva, sendo cada vez mais comum o uso de ferramentas de anotação automática, fazendo uso de técnicas de mineração de texto. Apesar de já existirem sistemas de anotação bastante completos e que apresentam um alto desempenho, estes não são largamente usados pela comunidade biomédica, principalmente por serem complexos e apresentarem limitações ao nível de usabilidade. Por outro lado, o PDF tornou-se nos últimos anos num dos formatos mais populares para publicar e partilhar documentos visto poder ser apresentado exatamente da mesma maneira independentemente do sistema ou plataforma em que é acedido. A maioria das ferramentas de anotação foram principalmente desenhadas para extrair informação de texto livre, contudo hoje em dia uma grande parte da literatura biomédica é publicada e distribuída em PDF, e portanto a extração de informação de documentos PDF deve ser um ponto de foco para a comunidade de mineração de texto biomédico. O objetivo do trabalho descrito nesta dissertação foi a extensão da framework Neji, permitindo o processamento de documentos em formato PDF, e a integração dessas funcionalidades na plataforma Egas, permitindo que um utilizador possa visualizar e anotar, simultaneamente, o artigo original no formato PDF e o texto extraído deste. Os sistemas desenvolvidos apresentam bons resultados de desempenho, tanto em termos de velocidade de processamento como de representação da informação, o que também contribui para uma melhor experiência de utilizador. Além disso, apresentam várias vantagens para a comunidade de mineração de texto e curadores, permitindo a anotação direta de artigos no formato PDF e simplificando o uso e configuração destes sistemas de anotação por parte de investigadores.The accelerated increase of the biomedical literature has led to various efforts to extract and store, in a structured way, the information related with the concepts and relations presented in those texts, providing to investigators and researchers a fast and easy access to knowledge. However, this process of “knowledge curation” is an extremely exhaustive task, being more and more common demanding the application of automatic annotation tools, that make use of text mining techniques. Even thought complete annotation systems already exist and produce high performance results, they are not widely used by the biomedical community, mainly because of their complexity and also due to some limitations in usability. On the other hand, the PDF has become in the last years one of the most popular formats for publishing and sharing documents because of it can be displayed exactly in the same way independently of the system or platform where it is accessed. The majority of annotation tools were mainly designed to extract information from raw text, although a big part of the biomedical literature is published and distributed in PDF, and thus the information extraction from PDF documents should be a focus point for the biomedical text mining community. The objective of the work described in this document is the extension of Neji framework, allowing the processing of documents in PDF format, and the integration of these features in Egas platform, allowing a user to simultaneously visualize the original article in PDF format and its extracted text. The improved and developed systems present good performing results, both in terms of processing speed and representation of the information, contributing also for a better user experience. Besides that, they present several advantages for the biomedical community, allowing the direct annotation of PDF articles and simplifying the use and configuration of these annotation systems by researchers

TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins

The signaling of brain-derived neurotrophic factor (BDNF) has been suggested to be impaired in Alzheimer's disease (AD), which may compromise the function of BDNF upon neuronal activity and survival. Accordingly, decreased levels of BDNF and its tropomyosin-receptor kinase B-full-length (TrkB-FL) have been detected in human brain samples of AD patients. We have previously found that neuronal exposure to amyloid-beta (A beta) peptide, a hallmark of AD, leads to calpain overactivation and subsequent TrkB-FL cleavage leading to decreased levels of TrkB-FL and the generation of two new fragments: a membrane-bound truncated receptor (TrkB-T') and an intracellular fragment (TrkB-ICD). Importantly, we identified this TrkB-FL cleavage and TrkB-ICD presence in human brain samples, which indicates that this molecular mechanism contributes to the loss of BDNF signaling in humans. The exact role of this TrkB-ICD fragment is, however, unknown. Here, we used a human neuroglioma cell line and rat cortical primary neuronal cultures to track TrkB-ICD intracellularly. Our data show that TrkB-ICD is a relatively stable fragment that accumulates in the nucleus over time, through a phosphorylation-dependent process. We also found that TrkB-ICD has tyrosine kinase activity, inducing the phosphorylation of nuclear and axonal proteins. These findings suggest that TrkB-ICD may lead to a dysregulation of the activity of several proteins, including proteins in the nucleus, to where TrkB-ICD migrates. Since TrkB-ICD is formed by A beta peptide-induced cleavage of TrkB-FL, the present data highlights a new mechanism that may have a role in AD pathophysiology.Peer reviewe

TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins

The signaling of brain-derived neurotrophic factor (BDNF) has been suggested to be impaired in Alzheimer’s disease (AD), which may compromise the function of BDNF upon neuronal activity and survival. Accordingly, decreased levels of BDNF and its tropomyosin-receptor kinase B-full-length (TrkB-FL) have been detected in human brain samples of AD patients. We have previously found that neuronal exposure to amyloid-β (Aβ) peptide, a hallmark of AD, leads to calpain overactivation and subsequent TrkB-FL cleavage leading to decreased levels of TrkB-FL and the generation of two new fragments: a membrane-bound truncated receptor (TrkB-T′) and an intracellular fragment (TrkB-ICD). Importantly, we identified this TrkB-FL cleavage and TrkB-ICD presence in human brain samples, which indicates that this molecular mechanism contributes to the loss of BDNF signaling in humans. The exact role of this TrkB-ICD fragment is, however, unknown. Here, we used a human neuroglioma cell line and rat cortical primary neuronal cultures to track TrkB-ICD intracellularly. Our data show that TrkB-ICD is a relatively stable fragment that accumulates in the nucleus over time, through a phosphorylation-dependent process. We also found that TrkB-ICD has tyrosine kinase activity, inducing the phosphorylation of nuclear and axonal proteins. These findings suggest that TrkB-ICD may lead to a dysregulation of the activity of several proteins, including proteins in the nucleus, to where TrkB-ICD migrates. Since TrkB-ICD is formed by Aβ peptide-induced cleavage of TrkB-FL, the present data highlights a new mechanism that may have a role in AD pathophysiology

Single photon emission computed tomography, invasive coronary angiography and cardiac computed tomography angiography

Introduction: Diagnostic tests that use ionizing radiation play a central role in cardiology and their use has grown in recent years, leading to increasing concerns about their potential stochas-tic effects. The aims of this study were to compare the radiation dose of three diagnostic tests: single photon emission computed tomography (SPECT), invasive coronary angiography (ICA) and cardiac computed tomography (cardiac CT) and their evolution over time, and to assess the influence of body mass index on radiation dose. Methods: We assessed consecutive patients included in three prospective registries (SPECT, ICA and cardiac CT) over a period of two years. Radiation dose was converted to mSv and compared between the three registries. Differences over time were evaluated by comparing the first with the fourth semester. Results: A total of 6196 exams were evaluated: 35% SPECT, 53% ICA and 22% cardiac CT. Mean radiation dose was 10.7±1.2 mSv for SPECT, 8.1±6.4 mSv for ICA, and 5.4±3.8 mSv for cardiac CT (p<0.001 for all). With regard to the radiation dose over time, there was a very small reduction in SPECT (10.7 to 10.5 mSv, p=0.004), a significant increase (25%) in ICA (7.0 to 8.8mSv; p<0.001), and a significant reduction (29%) in cardiac CT (6.5 to 4.6 mSv, p<0.001). Obesity was associated with a significantly higher radiation dose in all three exams. Conclusions: Cardiac CT had a lower mean effective radiation dose than invasive coronary angiography, which in turn had a lower mean effective dose than SPECT. There was a significant increase in radiation doses in the ICA registry and a significant decrease in the cardiac CT registry over time.publishersversionpublishe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Diversificação das Visitas ao Parque Arqueológico do Vale do Côa

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Challenges and promises in the development of neurotrophic factor-based therapies for Parkinson’s disease

© Springer International Publishing Switzerland 2014Parkinson'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.This work was supported by a Fundação para a Ciência e a Tecnologia (FCT) project grant. André Jerónimo-Santos is supported by an FCT fellowship grant (SFRH/BD/62828/2009) and Tiago Fleming Outeiro is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain.info:eu-repo/semantics/publishedVersio