Martinez-Pinilla, E. (Eva)
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- Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism(Springer, 2014) Sierra, S. (Salvador); Lanciego, J.L. (José Luis); Rico, A.J. (Alberto J.); Vazquez, A. (Alfonso); Roda, E. (Elvira); Franco, R. (Rafael); Dopeso-Reyes, I.G. (Iria G.); Luquin, N. (Natasha); Martinez-Pinilla, E. (Eva); Labandeira-Garcia, J.L. (José L.); Gomez-Bautista, V. (V.)Abstract Although type 1 cannabinoid receptors (CB1- Rs) are expressed abundantly throughout the brain, the presence of type 2 cannabinoid receptors (CB2Rs) in neurons is still somewhat controversial. Taking advantage of newly designed CB1R and CB2R mRNA riboprobes, we demonstrate by PCR and in situ hybridization that transcripts for both cannabinoid receptors are present within labeled pallidothalamic-projecting neurons of control and MPTP-treated macaques, whereas the expression is markedly reduced in dyskinetic animals. Moreover, an in situ proximity ligation assay was used to qualitatively assess the presence of CB1Rs and CB2Rs, as well as CB1R–CB2R heteromers within basal ganglia output neurons in all animal groups (control, parkinsonian and dyskinetic macaques). A marked reduction in the number of CB1Rs, CB2Rs and CB1R–CB2R heteromers was found in dyskinetic animals, mimicking the observed reduction in CB1R and CB2R mRNA expression levels. The fact that chronic levodopa treatment disrupted CB1R–CB2R heteromeric complexes should be taken into consideration when designing new drugs acting on cannabinoid receptor heteromers.
- The relevance of theobromine for the beneficial effects of cocoa consumption(Frontiers, 2015) Oñatibia, A. (Ainhoa); Franco, R. (Rafael); Martinez-Pinilla, E. (Eva)Cocoa consumption began in America and in the mid sixteenth Century it quickly spread to Europe. Beyond being considered a pleasant habit due to its rich sweet lingering taste, chocolate was considered a good nutrient and even a medicine. Traditionally, health benefits of cocoa have been related with the high content of antioxidants of Theobroma cocoa beans. However, the direct psychoactive effect due to methylxanthines in cocoa is notable. Theobromine and caffeine, in the proportions found in cocoa, are responsible for the liking of the food/beverage. These compounds influence in a positive way our moods and our state of alertness. Theobromine, which is found in higher amounts than caffeine, seems to be behind several effects attributed to cocoa intake. The main mechanisms of action are inhibition of phosphodiesterases and blockade of adenosine receptors. Further mechanisms are being explored to better understand the health benefits associated to theobromine consumption. Unlike what happens in other mammals -pets- included, theobromine is safe for humans and has fewer unwanted effects than caffeine. Therefore, theobromine deserves attention as one of the most attractive molecules in cocoa.
- Maternal imprinting on cognition markers of wild type and transgenic Alzheimer's disease model mice(Nature Research, 2018) Perez-Mediavilla, L.A. (Luis Alberto); Zamarbide-González, M. (Marta); Franco, R. (Rafael); Gil-Bea, F.J. (Francisco J.); Martinez-Pinilla, E. (Eva); Bannenberg, P. (Paul); Sandoval, J. (Juan)The risk of suffering from Alzheimer’s disease (AD) is higher in individuals from AD-affected mothers. The purpose of this investigation was to study whether maternal transmission might produce AD-related alterations in progenies of mice that do not have any genotypic alteration. We used cognitively-intact mothers harbouring in heterozygosity the transgene for overexpressing the Swedish double mutant version of the human amyloid precursor protein (hAβPPswe). The phenotype of the offspring with or without the transgene resulting from crossing young Tg2576 females with wild-type males were compared with those of the offspring resulting from crossing wild-type females with Tg2576 males. The hAβPPswe-bearing offspring from Tg2576 mothers showed an aggravated AD-like phenotype. Remarkably, cognitive, immunohistochemical and some biochemical features displayed by Tg2576 heterozygous mice were also found in wild-type animals generated from Tg2576 females. This suggests the existence of a maternal imprinting in the wild-type offspring that confers a greater facility to launch an AD-like neurodegenerative cascade. Such progeny, lacking any mutant amyloid precursor protein, constitutes a novel model to study maternal transmission of AD and, even more important, to discover early risk markers that predispose to the development of AD.
- Phenyl acyl acids attenuate the unfolded protein response in tunicamycin-treated neuroblastoma cells(2013) Perez-Mediavilla, L.A. (Luis Alberto); Ricobaraza, A. (Ana); Zamarbide-González, M. (Marta); Aragón-Amonárriz, T. (Tomás); Franco, R. (Rafael); Martinez-Pinilla, E. (Eva)
- Differential neuroprotective effects of 5'-Deoxy-5'-Methylthioadenosine(Public Library of Science, 2014) Sanchez-Gomez, M.V. (María Victoria); Domercq, M. (María); Parent, J.M. (Jack M.); Fernandez-Diez, B. (B.); Gottlieb, M. (Miroslav); Matute, C. (Carlos); Ceña, V. (Valentín); Moreno, B. (Beatriz); Giralt, A. (Albert); Posadas, I. (Inmaculada); Giralt, E. (Ernest); Villoslada, P. (Pablo); Lopez, I.P. (Iciar P.); Franco, R. (Rafael); Collon, K.W. (Kevin W.); Martinez-Pinilla, E. (Eva); Teixido, M. (Meritxell); Alberch, J. (Jordi); Zhang, H. (Helen)Background: 59-deoxy-59-methylthioadenosine (MTA) is an endogenous compound produced through the metabolism of polyamines. The therapeutic potential of MTA has been assayed mainly in liver diseases and, more recently, in animal models of multiple sclerosis. The aim of this study was to determine the neuroprotective effect of this molecule in vitro and to assess whether MTA can cross the blood brain barrier (BBB) in order to also analyze its potential neuroprotective efficacy in vivo. Methods: Neuroprotection was assessed in vitro using models of excitotoxicity in primary neurons, mixed astrocyte-neuron and primary oligodendrocyte cultures. The capacity of MTA to cross the BBB was measured in an artificial membrane assay and using an in vitro cell model. Finally, in vivo tests were performed in models of hypoxic brain damage, Parkinson’s disease and epilepsy. Results: MTA displays a wide array of neuroprotective activities against different insults in vitro. While the data from the two complementary approaches adopted indicate that MTA is likely to cross the BBB, the in vivo data showed that MTA may provide therapeutic benefits in specific circumstances. Whereas MTA reduced the neuronal cell death in pilocarpine-induced status epilepticus and the size of the lesion in global but not focal ischemic brain damage, it was ineffective in preserving dopaminergic neurons of the substantia nigra in the 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-mice model. However, in this model of Parkinson’s disease the combined administration of MTA and an A2A adenosine receptor antagonist did produce significant neuroprotection in this brain region. Conclusion: MTA may potentially offer therapeutic neuroprotection.
- Lifelong expression of apolipoprotein D in the human brainstem: correlation with reduced age-related neurodegeneration(Public Library of Science, 2013) Navarro, A. (Ana); Diaz, C. (Celso); Ordoñez, C. (Cristina); Mendez, E. (Elena); Martinez-Pinilla, E. (Eva); Valle, E. (Eva) del; Tolivia, J. (Jorge)The lipocalin apolipoprotein D (Apo D) is upregulated in peripheral nerves following injury and in regions of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, during aging and progression of certain neurological diseases. In contrast, few studies have examined Apo D expression in the brainstem, a region necessary for survival and generally less prone to age-related degeneration. We measured Apo D expression in whole human brainstem lysates by slot-blot and at higher spatial resolution by quantitative immunohistochemistry in eleven brainstem nuclei (the 4 nuclei of the vestibular nuclear complex, inferior olive, hypoglossal nucleus, oculomotor nucleus, facial motor nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus nerve, and Roller`s nucleus). In contrast to cortex, hippocampus, and cerebellum, apolipoprotein D was highly expressed in brainstem tissue from subjects (N = 26, 32−96 years of age) with no history of neurological disease, and expression showed little variation with age. Expression was significantly stronger in somatomotor nuclei (hypoglossal, oculomotor, facial) than visceromotor or sensory nuclei. Both neurons and glia expressed Apo D, particularly neurons with larger somata and glia in the periphery of these brainstem centers. Immunostaining was strongest in the neuronal perinuclear region and absent in the nucleus. We propose that strong brainstem expression of Apo D throughout adult life contributes to resistance against neurodegenerative disease and age-related degeneration, possibly by preventing oxidative stress and ensuing lipid peroxidation.
- Health benefits of methylxanthines in cacao and chocolate(MDPI, 2013) Oñatibia, A. (Ainhoa); Franco, R. (Rafael); Martinez-Pinilla, E. (Eva)One may wonder why methylxanthines are so abundant in beverages used by humans for centuries, or in cola-drinks that have been heavily consumed since their appearance. It is likely that humans have stuck to any brew containing compounds with psychoactive properties, resulting in a better daily life, i.e., more efficient thinking, exploring, hunting, etc., however, without the serious side effects of drugs of abuse. The physiological effects of methylxanthines have been known for a long time and they are mainly mediated by the so-called adenosine receptors. Caffeine and theobromine are the most abundant methylxanthines in cacao and their physiological effects are notable. Their health-promoting benefits are so remarkable that chocolate is explored as a functional food. The consequences of adenosine receptor blockade by natural compounds present in cacao/chocolate are here reviewed. Palatability and health benefits of methylxanthines, in general, and theobromine, in particular, have further contributed to sustain one of the most innocuous and pleasant habits: chocolate consumption.