Carla P. Fonseca

The redox switch/redox coupling hypothesis.

We provide an integrative interpretation of neuroglial metabolic coupling including the presence of subcellular compartmentation of pyruvate and monocarboxylate recycling through the plasma membrane of both neurons and glial cells. The subcellular compartmentation of pyruvate allows neurons and astrocytes to select between glucose and lactate as alternative substrates, depending on their relative extracellular concentration and the operation of a redox switch. This mechanism is based on the inhibition of glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase by NAD(+) limitation, under sufficiently reduced cytosolic NAD(+)/NADH redox conditions. Lactate and pyruvate recycling through the plasma membrane allows the return to the extracellular medium of cytosolic monocarboxylates enabling their transcellular, reversible, exchange between neurons and astrocytes. Together, intracellular pyruvate compartmentation and monocarboxylate recycling result in an effective transcellular coupling between the cytosolic NAD(+)/NADH redox states of both neurons and glial cells. Following glutamatergic neurotransmission, increased glutamate uptake by the astrocytes is proposed to augment glycolysis and tricarboxylic acid cycle activity, balancing to a reduced cytosolic NAD(+)/NADH in the glia. Reducing equivalents are transferred then to the neuron resulting in a reduced neuronal NAD(+)/NADH redox state. This may eventually switch off neuronal glycolysis, favoring the oxidation of extracellular lactate in the lactate dehydrogenase (LDH) equilibrium and in the neuronal tricarboxylic acid cycles. Finally, pyruvate derived from neuronal lactate oxidation, may return to the extracellular space and to the astrocyte, restoring the basal redox state and beginning a new loop of the lactate/pyruvate transcellular coupling cycle. Transcellular redox coupling operates through the plasma membrane transporters of monocarboxylates, similarly to the intracellular redox shuttles coupling the cytosolic and mitochondrial redox states through the transporters of the inner mitochondrial membrane. Finally, transcellular redox coupling mechanisms may couple glycolytic and oxidative zones in other heterogeneous tissues including muscle and tumors.

Astrocyte-derived GDNF is a potent inhibitor of microglial activation.

Neuroinflammation is recognized as a major factor in Parkinsons disease (PD) pathogenesis and increasing evidence propose that microglia is the main source of inflammation contributing to the dopaminergic degeneration observed in PD. Several studies suggest that astrocytes could act as physiological regulators preventing excessive microglia responses. However, little is known regarding how astrocytes modulate microglial activation. In the present study, using Zymosan A-stimulated midbrain microglia cultures, we showed that astrocytes secrete factors capable of modulating microglial activation, namely its phagocytic activity and the production of reactive oxygen species since both parameters were highly diminished in cells incubated with astrocytes conditioned media (ACM). Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF) and brain-derived neurotrophic factor (BDNF), known to have a neuroprotective role in the nigrostriatal system, are among the candidates to be astrocyte-secreted molecules involved in the modulation of microglial activation. The effect of ACM on Zymosan A-induced microglial activation was abolished when the GDNF present in the ACM was abrogated using a specific antibody, but not when ACM was neutralized with anti-CDNF, anti-BDNF or with a heat-inactivated GDNF antibody. In addition, media conditioned by astrocytes silenced for GDNF were not able to prevent microglial activation, whereas supplementation of non-conditioned media with GDNF prevented the activation of microglia evoked by Zymosan A. Taken together, these results indicate that astrocyte-derived GDNF plays a major contribution to the control of midbrain microglial activation, suggesting that GDNF can protect from neurodegeneration through the inhibition of neuroinflammation.

GDNF contributes to oestrogen-mediated protection of midbrain dopaminergic neurones.

Parkinson’s disease (PD) is characterised by the preferential loss of dopaminergic neurones from the substantia nigra (SN) that leads to the hallmark motor disturbances. Animal and human studies suggest a beneficial effect of oestrogen to the nigrostriatal system, and the regulation of neurotrophic factor expression by oestrogens has been suggested as a possible mechanism contributing to that neuroprotective effect. The present study was designed to investigate whether the neuroprotection exerted by 17β‐oestradiol on nigrostriatal dopaminergic neurones is mediated through the regulation of glial cell line‐derived neurotrophic factor (GDNF) expression. Using an in vivo rat model of PD, we were able to confirm the relevance of 17β‐oestradiol in defending dopaminergic neurones against 6‐hydroxydopamine (6‐OHDA) toxicity. 17β‐oestradiol, released by micro‐osmotic pumps, implanted 10 days before intrastriatal 6‐OHDA injection, prevented the loss of dopaminergic neurones induced by 6‐OHDA. 17β‐oestradiol treatment also promoted an increase in GDNF protein levels both in the SN and striatum. To explore the relevance of GDNF increases to 17β‐oestradiol neuroprotection, we analysed, in SN neurone‐glia cultures, the effect of GDNF antibody neutralisation and RNA interference‐mediated GDNF knockdown. The results showed that both GDNF neutralisation and GDNF silencing abolished the dopaminergic protection provided by 17β‐oestradiol against 6‐OHDA toxicity. Taken together, these results strongly identify GDNF as an important player in 17β‐oestradiol‐mediated dopaminergic neuroprotection.

Intracellular lithium and cyclic AMP levels are mutually regulated in neuronal cells.

In this work, we studied the effect of intracellular 3′,5′‐cyclic adenosine monophosphate (cAMP) on Li+ transport in SH‐SY5Y cells. The cells were stimulated with forskolin, an adenylate cyclase activator, or with the cAMP analogue, dibutyryl‐cAMP. It was observed that under forskolin stimulation both the Li+ influx rate constant and the Li+ accumulation in these cells were increased. Dibutyryl‐cAMP also increased Li+ uptake and identical results were obtained with cortical and hippocampal neurons. The inhibitor of the Na+/Ca2+ exchanger, KB‐R7943, reduced the influx of Li+ under resting conditions, and completely inhibited the effect of forskolin on the accumulation of the cation. Intracellular Ca2+ chelation, or inhibition of N‐type voltage‐sensitive Ca2+ channels, or inhibition of cAMP‐dependent protein kinase (PKA) also abolished the effect of forskolin on Li+ uptake. The involvement of Ca2+ on forskolin‐induced Li+ uptake was confirmed by intracellular free Ca2+ measurements using fluorescence spectroscopy. Exposure of SH‐SY5Y cells to 1 mm Li+ for 24 h increased basal cAMP levels, but preincubation with Li+, at the same concentration, decreased cAMP production in response to forskolin. To summarize, these results demonstrate that intracellular cAMP levels regulate the uptake of Li+ in a Ca2+‐dependent manner, and indicate that Li+ plays an important role in the homeostasis of this second messenger in neuronal cells.

Microglia of rat ventral midbrain recovers its resting state over time in vitro: Let microglia rest before work

Cortical or total brain cultures of microglia are commonly used as a model to study the inflammatory processes in Parkinsons disease. Here we characterize microglia cultures from rat ventral midbrain and evaluate their response to zymosan A. We used specific markers of microglia and evaluated the morphology, the phagocytic activity and reactive oxygen species (ROS) levels of the cells. During the first 10 days in vitro (DIV), cultures presented predominantly cells with a round morphology, expressing CD68 and with high phagocytic activity and ROS production. After 13 DIV, this tendency was reversed, with cultures showing higher number of ramified cells and fewer CD68+ cells along with lower phagocytic and ROS production capability, suggesting that microglia must be kept in vitro for at least 13 days to recover its resting state. The exposure of cultures with less than 10 DIV to zymosan A significantly decreased cell viability. Exposure of cultures with 13 DIV to zymosan A (0.05, 0.5, or 5 μg/ml) increased the total cell number, the percentage of CD68+ cells, and the phagocytic activity. Concentrations of zymosan A higher than 5 μg/ml were also effective in activating microglia but significantly decreased the number of viable cells. In summary, microglial cells remain in the activated state for several days after the isolation process and, thus, stimulation of microglia recently isolated can compromise interpretation of the results. However, upon 13 DIV, cells achieve properties of nonactivated microglia and present a characteristic response to a proinflammatory agent.

Tricarboxylic acid cycle inhibition by Li+ in the human neuroblastoma SH-SY5Y cell line: a 13C NMR isotopomer analysis.

Li+ effects on glucose metabolism and on the competitive metabolism of glucose and lactate were investigated in the human neuroblastoma SH-SY5Y cell line using 13C NMR spectroscopy. The metabolic model proposed for glucose and lactate metabolism in these cells, based on tcaCALC best fitting solutions, for both control and Li+ conditions, was consistent with: (i) a single pyruvate pool; (ii) anaplerotic flux from endogenous unlabelled substrates; (iii) no cycling between pyruvate and oxaloacetate. Li+ was shown to induce a 38 and 53% decrease, for 1 and 15 mM Li+, respectively, in the rate of glucose conversion into pyruvate, when [U-13C]glucose was present, while no effects on lactate production were observed. Pyruvate oxidation by the tricarboxylic acid cycle and citrate synthase flux were shown to be significantly reduced by 64 and 84% in the presence of 1 and 15 mM Li+, respectively, suggesting a direct inhibitory effect of Li+ on tricarboxylic acid cycle flux. This work also showed that when both glucose and lactate are present as energetic substrates, SH-SY5Y cells preferentially consumed exogenous lactate over glucose, as 62% of the acetyl-CoA was derived from [3-13C]lactate while only 26% was derived from [U-13C]glucose. Li+ did not significantly affect the relative utilisation of these two substrates by the cells or the residual contribution of unlabelled endogenous sources for the acetyl-CoA pool.

13C NMR tracers in neurochemistry: implications for molecular imaging.

Resumen del trabajo presentado a la 62nd Annual Conference on Magnetism and Magnetic Materials (MMM), celebrada en Pittsburgh (USA) del 6 al 10 de noviembre de 2017.Financial support 224 from Fundacao para a Ciencia e a Tecnologia (Lisboa, Portugal) grants 225 (PTDC/CVT/2006/66114 and UID/CVT/00276/2013)Tese de doutoramento em Ciencias da Saude, apresentada a Faculdade de Medicina da Universidade de CoimbraTrabajo presentado en el 8o Congreso de la Asociacion Iberica de Endocrinologia Comparada (AIEC), celebrado en Madrid del 5 al 7 de septiembre de 2011.Trabajo presentado en la International Conference and Exposition Aquaculture Europe 2017, celebrada en Dubrovnik del 17 al 20 de octubre de 2017.O presente estudo centra-se na analise das paisagens de poder que materializam as dinâmicas sociais e territoriais ocorridas nos finais da Idade do Ferro e inicios de epoca Romana no Noroeste Peninsular. Enquadra-se numa necessidade de se desenvolverem novas e inovadoras metodologias de trabalho, aliadas a uma robustez teorica e a um rigor empirico, cujas interpretacoes permitam a criacao de um novo conhecimento e que tenha aplicabilidade a outros contextos. Esta investigacao foi desenvolvida numa optica da Arqueologia da Paisagem. Assim, adoptou-se uma perspectiva diacronica e uma metodologia interdisciplinar, procurando-se ampliar as metodologias tradicionalmente utilizadas neste tipo de estudos, sobretudo com o recurso as tecnologias geoespaciais, na tentativa de se caracterizar a estruturacao do povoamento e territorio neste periodo e area geografica. O objectivo principal deste estudo reside na tentativa de caracterizacao sociopolitica das comunidades do Noroeste Peninsular, particularmente na sua area Meridional, nos finais da Idade do Ferro e inicios de epoca Romana. Tomaremos como caso de estudo a regiao do Alto Tâmega e Cavado. Trata-se de uma zona de fronteira e de hibridizacao cultural pelo menos desde a Idade do Ferro, localizando-se justamente na transicao entre a area dos oppida ocidentais e a dos pequenos castros orientais. Nesta zona registam-se processos de intensificacao economica, embora mais centrados na exploracao de recursos minerais, ao inves da exploracao e intensificacao agricola, dando lugar a uma estruturacao territorial bastante especifica e a formas particulares de expressao da desigualdade. Procuraremos analisar as dinâmicas territoriais e os processos de continuidade e de mudanca social, bem como as diferentes economias politicas e estrategias de poder, numa epoca onde tem lugar complexas politicas de interaccao cultural, particularmente com o mundo mediterrânico, bem como uma crescente negociacao social e identitaria. Procuraremos definir e clarificar os diferentes modelos de povoamento e as diferentes formas de estruturacao territorial em epoca pre-Romana e Romana. A base fundamental deste trabalho sera a objectivacao dos criterios locacionais e territoriais de cada povoado, com vista a se discriminarem as decisoes sociais que motivaram a eleicao de um determinado sitio, ja que distintos modelos locacionais e territoriais poderao associar-se a diferentes contextos culturais e a distintas formas de organizacao territorial e sociopolitica. Todavia, sera de ressaltar que este trabalho tera sempre um sentido comparativo, procurando-se analisar a variabilidade, mais do que uma reconstrucao positiva das condicoes que possam ter influenciado a localizacao dos sitios. Alem disso, partimos da diversidade regional e da heterogeneidade cultural, ja que mais que um todo homogeneo com uma evolucao unilinear, devemos antes, segundo uma perspectiva pos-colonial, contemplar uma multiplicidade de experiencias historicas particulares a diferentes escalas antes e depois da chegada de Roma. Apos os primeiros contactos com os Romanos, documenta-se uma estruturacao complexa do povoamento do Noroeste, que se manifesta no pleno desenvolvimento de grandes povoados tipo oppidum, que actuariam como verdadeiros lugares centrais do ponto de vista politico. Este fenomeno, que se desenvolve anteriormente a criacao generalizada de novos assentamentos romanos, e arqueologicamente mais visivel na parte Meridional da Galiza e no Norte de Portugal, onde os processos de ?oppidizacao? sao mais massivos e prematuros. Contudo, este processo de sinecismo e de hierarquizacao do povoamento podera ser consequencia de dinâmicas anteriores, uma vez que nao podemos negligenciar os complexos particularismos historicos das comunidades indigenas, tal como parece suceder em outros territorios europeus. Evidentemente que o contacto e a pressao Romana pode ter acelerado e precipitado todo este processo, embora talvez nao se tenha tratado de um processo unidireccional e monocausal. E necessario percepcionar os oppida em relacao estrutural a toda uma serie de fenomenos sociais, politicos e culturais que ocorrem no sul da Callaecia entre os seculos II a.C. e I d.C..This research has been developed on the behalf of a Doctoral (M3.1.2/F/025/2007) and a Post-Doctoral (M3.1.7/F/005/2011) Research Project, both supported by the Regional Fund for Science (FRC) of the Azorean Regional Government. This work was partially funded by Portuguese National Funds through FCT – Fundacao para a Ciencia e Tecnologia (Foundation for Science and Technology), under the project “PTDC/AAC-AMB/098786/2008”.Tese de Doutoramento em Ciencias da Saude, Universidade do Minho Escola de Ciencias da Saude.Trabajo presentado en la European Geosciences Union General Assembly, celebrada en Viena (Austria), del 8 al 13 de abril de 2018Este trabajo ha sido parcialmente financiado por la Fundacao para a Ciencia e Tecnologia, Ministerio da Educacao e Ciencia, Republica Portiguesa (SFRH/BD/44089/2008) y los proyectos: “Origins and Spread of Agriculture in the western Mediterranean region (ERC-2008-AdG 230561)” y “Stable isotopes in Mediterranean natural and agricultural ecosystems: from a mechanistic understanding of isotope fractionation processes in plants to the application in paleoenvironmental research (DGI CGL2009- 13079-C02-01)”.Trabajo presentado en el 18th International Symposium on Pollutant Responses in Marine Organisms (PRIMO 18), celebrado en Trondheim (Noruega) del 24 al 27 de mayo de 2015.VI Simposio Internacional de Ciencias del Mar - VI International Symposium of Marine Sciences (ISMS 2018), 20- 22 June 2018, Vigo.-- 1 pageResumen del poster presentado a la XXXV Reunion Bienal de la Real Sociedad Espanola de Fisica y al 25o Encuentro Iberico de Ensenanza de la Fisica, celebrados en Gijon (Espana) del 13 al 17 de julio de 2015.-- et al.Trabajo presentado en el I Congresso Luso-Extremadurense de Ciencias e Tecnologia, celebrado en Evora (Portugal), del 20 al 21 de octubre de 2017The 2nd International Symposium on Submarine Canyons (INCISE2014), 29th September-1st October 2014, Edinburgh.-- 1 page, 1 figureTrabajo presentado en la 10th International Hydrogenase Conference celebrada en Szeged (Hungria) del 8 al 12 de julio de 2013.An overview of 13C nuclear magnetic resonance (NMR) spectroscopy methods and their applications in the study of the metabolism of brain cells in vitro and in the in vivo brain is presented as well as their implications for modern molecular imaging techniques. Various topics will be discussed, such as general properties of the 13C NMR spectrum, 13C NMR spectroscopy acquisition protocols, determination of fractional 13C enrichment, 13C(2H) NMR methodologies, and the use of 13C hyperpolarized substrates for NMR spectroscopy and imaging. Some illustrative applications are described, both in vitro and in vivo.This study was financially supported by Fundacao Para a Ciencia e a Tecnologia (SFRH7 BPD/5560/2001) and HP BIODIBERIA program at the Real Jardin Botanico (Madrid).Conferencia invitada. -- 7th Conference on Elementary Processes in Atomic Systems,Průhonice, Prague, September 3-6, 2017.-- https://www.jh-inst.cas.cz/tchem/cepas2017/about-cepas-2017/The current international socioeconomic context has been emphasising the need of a new set of individual competencies in order to succeed in the professional world. A new concept of employability has also emerged, with a person-centred approach, which reflects the need to deal effectively with career-related changes (Fugate, Kinicki, & Ashforth, 2004). In a psychosocial perspective, it is assumed an individual ability to adapt to social expectations and to behave according to the changing conditions (Savickas & Porfeli, 2012). On the other hand, the last decade represented a period of profound transformations in the European space of higher education, driven by Bologna guidelines. Higher education institutions are expected to adapt new ways of work organization, promoting new core competencies in future professionals. In this context, the paper will describe a research project which aims to identify and analyse the impact factors on the employability of Portuguese graduates, namely, individual characteristics, curricular experiences during graduation courses and also employer’s characteristics. This project represents an attempt to a closer and necessary articulation between higher education practices and labour market requirements.Trabajo presentado en el MedCLIVAR Conference: Bridging the Mediterranean Climates, celebrado en Belgrado (Serbia) del 17 al 21 de septiembre de 2018Trabajo presentado por Mariana Reis Sobreiro para optar al grado de Doctor por la Universidad de Salamanca y realizado en el Instituto de Biologia Molecular y Celular del Cancer.13 paginas, 7 tablas, 1 figuras, 1 apendice. Special thanks go to Ana Mouro, Joao Luis Mouro, Miguel Porto, Nuno Pires and Sara Dias for assisting in the fieldwork, and Nuno Gomes and associated workers for the EDM loan and field aid.Trabajo presentado en en 16th International Symposium on Fish Nutrition and Feeding (ISFNF 2014), celebrado en Cairns (Australia) del 25 al 30 de mayo de 2014.Tese desenvolvida no quadro do Programa Doutoral em Ciencias e Engenharia do Ambiente, com o financiamento de uma bolsa de doutoramento (SFRH/BD/42168/2007) da Fundacao para a Ciencia e a Tecnologia (FCT) e o apoio dos projectos EROSFIRE II (PTDC/AGR-CFL/70968/2006), e ”FIREREG”(PTDC/AGR-CFL/099420/2008), ambos financiados pela Fundacao para a Ciencia e a Tecnologia (FCT) e o FSE no âmbito do III Quadro Comunitario de Apoio.Editors: A. Campar Almeida, Ana M. S. Bettencourt, D. Moura, Sergio Monteiro-Rodrigues and Maria Isabel Caetano Alves. 29 pp.Trabajo presentado en el 10o Congreso de la Asociacion Iberica de Endocrinologia Comparada (AIEC), celebrado en Castellon (Espana), del 23 al 25 de septiembre de 2015Trabajo presentado en Aquaculture Europe 2019, celebrado en Berlin (Alemania), del 7 al 10 de octubre de 2019Tese de Candidatura ao grau de Doutor em Ciencias Biomedicas submetida ao Instituto de Ciencias Biomedicas de Abel Salazar da Universidade do Porto por Ana Maria Bastos Barros Neto e realizado em el Centro Andaluz de Biologia del Desarrollo, centro mixto CSIC-UPO.Trabajo presentado en el EMS Annual Meeting: European Conference for Applied Meteorology and Climatology, celebrado en Dublin (Irlanda), de 4 al 8 de septiembre de 2017

H2O2- or l-DOPA-injured dopaminergic neurons trigger the release of soluble mediators that up-regulate striatal GDNF through different signalling pathways.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective molecule for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinsons disease. We have previously shown that H2O2- or l-3,4-dihydroxyphenylalanine (l-DOPA)-challenged dopaminergic neurons trigger the release of soluble factors that signal ventral midbrain astrocytes to increase GDNF expression. In the present work, we evaluated whether the factors released by ventral midbrain-challenged cells were able to alter GDNF expression in striatal cells, the targets of dopaminergic neurons projecting from the substantia nigra, and investigated the signalling pathways involved. Our data showed that soluble mediators released upon H2O2- or l-DOPA-induced dopaminergic injury up-regulated GDNF in striatal cells, with different temporal patterns depending on the oxidative agent used. Conditioned media from H2O2- or l-DOPA-challenged midbrain astrocyte cultures failed to up-regulate GDNF in striatal cultures. Likewise, there was no direct effect of H2O2 or l-DOPA on striatal GDNF levels suggesting that GDNF up-regulation was mediated by soluble factors released in the presence of failing dopaminergic neurons. Both phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways were involved in striatal GDNF up-regulation triggered by H2O2-induced dopaminergic injury, while diffusible factors released in the presence of l-DOPA-challenged dopaminergic neurons induced GDNF expression in striatal cells through the activation of the MAPK pathway. These soluble mediators may constitute, in the future, important targets for the control of endogenous GDNF expression enabling the development of new and, hopefully, more efficient neuroprotective/neurorestorative strategies for the treatment of Parkinsons disease.

Quantification and Localization of Intracellular Free Mg2+ in Bovine Chromaffin Cells

Magnesium is an essential element for all living systems. The quantification of free intracellular Mg2+ concentration ([Mg2+]i) is of utmost importance since changes in its basal value may be an indication of different pathologies due to abnormalities of Mg2+ metabolism. In this work we used 31P NMR and fluorescence spectroscopy to determine the resting [Mg2+]i in bovine chromaffin cells, a neuron-like cellular model, as well as confocal laser scanning microscopy to study the free Mg2+ spatial distribution in these cells. 31P NMR spectroscopy did not prove to be effective for the determination of [Mg2+]i in this particular case due to some special morphological and physiological properties of this cell type. A basal [Mg2+]i value of 0.551 ± 0.008 mM was found for these cells using fluorescence spectroscopy and the Mg2+-sensitive probe furaptra; this value falls in the concentration range reported in the literature for neurons from different sources. This technique proved to be an accurate and sensitive tool to determine the [Mg2+]i. lntraceilular free Mg2+ seems to be essentially localized in the nucleus and around it, as shown by confocal microscopy with the Mg2+-sensitive probe Magnesium Green. It was not possible to derive any conclusion about free Mg2+ localization inside the chromaffin granules and/or in the cytoplasm due to the lack of sufficient spatial resolution and to probe compartmentalization.

Role of Neurotrophic Factors in Parkinson´s Disease.

Parkinsons disease is an age-associated progressive neurodegenerative disorder that has gained crescent social and economic impact due to the aging of the western society. All current therapies are symptomatic and fail to reverse or halt the progression of dopaminergic neurons loss. The discovery of the capability of neurotrophic factors to protect these neurons lead numerous research groups to focus their efforts in developing therapies aiming at promoting the control of Parkinson´s disease through the delivery of neurotrophic factors to the brain or by boosting their endogenous levels. Both strategies were successful in inducing protection of dopaminergic neurons and motor recovery in preclinical models of the disease. Contrariwise, very limited success was obtained in clinical studies, where glial cell line-derived neurotrophic factor and neurturin were the neurotrophic factors of choice for Parkinsons disease therapy. These drawbacks motivate the development of novel forms of delivery or the modification of the injected molecules aiming at providing a more stable and effective administration with improved diffusion in the target tissue, and without the immune responses observed in the earliest clinical studies. Although promising results were obtained with some of these new approaches performed in experimental models of the disease, they were not yet tested in human studies. In this review, we present the current knowledge on neurotrophic factors and their role in Parkinsons disease, focusing on the strategies that have been developed to increase their levels in target areas of the brain to achieve protection of dopaminergic neurons and motor behaviour recovery.