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News Article | May 19, 2017
Site: www.sciencedaily.com

The annual mortality rate in childhood cancer of the sympathetic nervous system, or neuroblastoma, is 10 per million between the ages of 0 and 4. The collaborative work between Basque and Valencian researchers has served to identify some genetic mutations that will help to improve the treatment of this disease. Researchers at the Instituto de Investigación Sanitaria La Fe (Institute of Healthcare Research La Fe) in Valencia led by Jaime Font de Mora, in collaboration with José Luis Zugaza, an Ikerbasque researcher at the UPV/EHU-University of the Basque Country and the "Achucarro Basque Center for Neuroscience," have by means of NGS (Next Generation Sequencing) identified mutations in the Tiam1 gene that predict a better prognosis for neuroblastoma patients. A neuroblastoma is a solid, extracranial tumor more frequent in childhood. It accounts for 7% of all paediatric cancers and is the cause of 15% of the total number of deaths resulting from oncological processes in childhood. The incidence of it ranges between 8 and 10 cases per million children. Family cases of neuroblastoma have been described but they are extremely rare. Right now, it is not known how this rare type of cancer originates. The study reveals that these mutations that anticipate the progression of this disease are located in various Tiam1 domains related to the Ras and Rac GTPases and also with Myc; all these proteins are involved in the aetiology and progression of this type of cancer. The results have been published in the journal Oncotarget, which specialises in works dealing with targets for different types of cancers. These results suggest that the signalosome controlled by Tiam1 may be essential in the development of the neuroblastoma and, therefore, Tiam1 is positioned as a target that could help to improve the effectiveness of neuroblastoma treatment. The next step is to incorporate these studies into clinical practice to improve the tools and procedures in the diagnosis with a view to implementing earlier treatments for the children affected.


Mato S.,University of the Basque Country | Mato S.,Achucarro Basque Center for Neuroscience | Sanchez-Gbmez M.V.,University of the Basque Country | Sanchez-Gbmez M.V.,Achucarro Basque Center for Neuroscience | And 4 more authors.
GLIA | Year: 2013

Dyshomeostasis of cytosolic Zn2+ is a critical mediator of neuronal damage during excitotoxicity. However, the role of this cation in oligodendrocyte pathophysiology is not well understood. The current study examined the contribution of Zn2+ deregulation to oligodendrocyte injury mediated by AMPA receptors. Oligodendrocytes loaded with the Zn2+-selective indicator FluoZin-3 responded to mild stimulation of AMPA receptors with fast cytosolic Zn2+ rises that resulted from intracellular release, as they were not blocked by the extracellular Zn2+ chelator Ca-EDTA. Pharmacological experiments suggested that AMPA-induced Zn2+ mobilization depends on cytosolic Ca2+ accumulation, arises from mitochondria and protein-bound pools, and is triggered by mechanisms that do not involve the generation of reactive oxygen species. Moreover, intracellular Zn2+ rises resulting from AMPA receptor activation seem to be promoted by Ca2+-dependent cytosolic acidification. Addition of the cell-permeable Zn2+ chelator TPEN significantly reduced mitochondrial membrane depolarization, reactive oxygen species production, and cell death by sub-maximal activation of AMPA receptors both in vitro and in situ, suggesting that Zn2+ deregulation is an important mediator of oligodendrocyte excitotoxicity. These data provide evidence that strategies aimed at maintaining Zn2+ homeostasis may be useful for the treatment of disorders in which excitotoxicity is an important trigger of oligodendroglial death. © 2013 Wiley Periodicals, Inc.


Tremblay M.-E.,Laval University | Lecours C.,Laval University | Samson L.,Laval University | Sanchez-Zafra V.,Achucarro Basque Center for Neuroscience | And 4 more authors.
Frontiers in Neuroanatomy | Year: 2015

Under the guidance of Ramón y Cajal, a plethora of students flourished and began to apply his silver impregnation methods to study brain cells other than neurons: the neuroglia. In the first decades of the twentieth century, Nicolás Achúcarro was one of the first researchers to visualize the brain cells with phagocytic capacity that we know today as microglia. Later, his pupil Pío del Río-Hortega developed modifications of Achúcarro’s methods and was able to specifically observe the fine morphological intricacies of microglia. These findings contradicted Cajal’s own views on cells that he thought belonged to the same class as oligodendroglia (the so called “third element” of the nervous system), leading to a long-standing discussion. It was only in 1924 that Río-Hortega’s observations prevailed worldwide, thus recognizing microglia as a unique cell type. This late landing in the Neuroscience arena still has repercussions in the twenty first century, as microglia remain one of the least understood cell populations of the healthy brain. For decades, microglia in normal, physiological conditions in the adult brain were considered to be merely “resting,” and their contribution as “activated” cells to the neuroinflammatory response in pathological conditions mostly detrimental. It was not until microglia were imaged in real time in the intact brain using two-photon in vivo imaging that the extreme motility of their fine processes was revealed. These findings led to a conceptual revolution in the field: “resting” microglia are constantly surveying the brain parenchyma in normal physiological conditions. Today, following Cajal’s school of thought, structural and functional investigations of microglial morphology, dynamics, and relationships with neurons and other glial cells are experiencing a renaissance and we stand at the brink of discovering new roles for these unique immune cells in the healthy brain, an essential step to understand their causal relationship to diseases. © 2015 Tremblay, Lecours, Samson, Sánchez-Zafra and Sierra.


Sierra A.,Ikerbasque | Sierra A.,Achucarro Basque Center for Neuroscience | Sierra A.,University of the Basque Country | Beccari S.,Achucarro Basque Center for Neuroscience | And 8 more authors.
Neural Plasticity | Year: 2014

Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory. © 2014 Amanda Sierra et al.


News Article | November 10, 2016
Site: www.eurekalert.org

It has been known for some time that the extracts of the Cannabis plant, just like synthetic cannabinoids and those produced by the brain itself, join up with type 1 (CB1) cannabinoid receptors located in the nerve endings of the neurons, and inhibit the release of chemical messengers (neurotransmitters) in the communication areas between the nerve cells. The knowledge about the way cannabinoids work has been expanded in recent years when it was shown that the CB1 receptor is also located in and functions in the mitochondria of the neurons; mitochondria are the organelles responsible for producing cell energy. A new piece of research, which has been published in the online version of the journal Nature, has now gone a step further on discovering that the amnesia caused by cannabinoids needs the activation of the CB1 cannabinoid receptors located in the mitochondria of the hippocampus, the brain structure involved in memory formation. To obtain the results of this research, led by Dr Giovanni Marsicano of the University of Bordeaux, the contribution of the following doctors was crucial: Nagore Puente, Leire Reguero, Izaskun Elezgarai and Pedro Grandes; they are neuroscientists in the Department of Neurosciences of the UPV/EHU's Faculty of Medicine and Nursing and of the Achucarro Basque Center for Neuroscience and they also participated in a previous discovery about the location and functioning of the CB1 receptor in the mitochondria. In this new piece of research, the researchers used a broad range of cutting-edge experimental techniques and saw that the genetic elimination of the CB1 receptor from the mitochondria of the hippocampus prevents memory loss, the reduction in mitochondrial movement and the decrease in neural communication induced by the cannabinoids. This research also revealed that the amnesia caused by cannabinoids and the related cell processes are linked to an acute alteration in bioenergetic mitochondrial activity owing to the direct activation of the CB1 receptors in the mitrochondria. This activation leads to the inhibiting of the cannabinoid signalling cascade inside the mitochondria and cell respiration diminishes as a result. This reduction in cell respiration through cannabinoids is not restricted to the brain as a similar phenomenon occurs in skeletal and cardiac muscle, as has recently been published in another piece of research by the group of Dr Grandes. "Mitochondrial malfunctioning could have serious consequences for the brain. For example, chronic mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, strokes or disorders associated with ageing. However, the involvement of the acute variation in mitochondrial activity in higher brain functions, such as memory, was unknown," pointed out Dr Grandes. So this research has revealed that the CB1 cannabinoid receptors in the mitochondria regulate the memory processes by modulating mitochondrial energy metabolism. Furthermore, although cannabinoid by-products have a well-known therapeutic potential, their use is limited by the significant adverse effects that emerge when acting on CB1 receptors, including memory loss. The results of this research suggest that "a selective intervention on specific CB1 cannabinoid receptors located in the brain in certain specific neurone compartments could be of interest with a view to developing new therapeutic tools based on the most effective and safest cannabinoids in the treatment of certain brain diseases," explained Dr Grandes. "This research is the result of 6 years' work in which 28 researchers have participated. In our case it would not have been possible without the funding received from the UPV/EHU, the Basque Government and Spanish institutions, which have placed their trust in us even during these years of tremendous cutbacks for research; this is something I recognise and which I am grateful for," concluded Pedro Grandes. Pedro Grandes has recently been Visiting Professor at the University of Victoria, British Columbia, Canada, where he has been doing research work and teaching students of medicine and post-graduate students.


Martin A.,CIC Biomagune | Szczupak B.,CIC Biomagune | Gomez-Vallejo V.,CIC Biomagune | Domercq M.,University of the Basque Country | And 10 more authors.
Journal of Neuroscience | Year: 2015

PET imaging of nicotinic acetylcholine receptors (nAChRs) could become an effective tool for the diagnosis and therapy evaluation of neurologic diseases. Despite this, the role of nAChRs α4β2 receptors after brain diseases such as cerebral ischemia and its involvement in inflammatory reaction is still largely unknown. To investigate this, we performed in parallel in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) with 2[18F]-fluoro-A85380 and [11C]PK11195 at 1, 3, 7, 14, 21, and 28 d after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with 2[18F]-fluoro-A85380 and [11C]PK11195 showed a progressive binding increase from days 3–7, followed by a progressive decrease from days 14–28 after cerebral ischemia onset. Ex vivo immunohistochemistry for the nicotinic α4β2 receptor and the mitochondrial translocator protein (18 kDa) (TSPO) confirmed the PET findings and demonstrated the overexpression of α4β2 receptors in both microglia/macrophages and astrocytes from days 7–28 after experimental ischemic stroke. Likewise, the role played by α4β2 receptors on neuroinflammation was supported by the increase of [11C]PK11195 binding in ischemic rats treated with the α4β2 antagonist dihydro-β-erythroidine hydrobromide (DHBE) at day 7 after MCAO. Finally, both functional and behavioral testing showed major impaired outcome at day 1 after ischemia onset, followed by a recovery of the sensorimotor function and dexterity from days 21–28 after experimental stroke. Together, these results suggest that the nicotinic α4β2 receptor could have a key role in the inflammatory reaction underlying cerebral ischemia in rats. © 2015 the authors.


Ruiz A.,University of the Basque Country | Ruiz A.,Achucarro Basque Center for Neuroscience | Ruiz A.,Institute Salud Carlos III | Alberdi E.,University of the Basque Country | And 5 more authors.
Cell Death and Disease | Year: 2014

Inhibition of the mitochondrial Na+/Ca2+ exchanger (NCLX) by CGP37157 is protective in models of neuronal injury that involve disruption of intracellular Ca2+ homeostasis. However, the Ca 2+ signaling pathways and stores underlying neuroprotection by that inhibitor are not well defined. In the present study, we analyzed how intracellular Ca2+ levels are modulated by CGP37157 (10 μM) during NMDA insults in primary cultures of rat cortical neurons. We initially assessed the presence of NCLX in mitochondria of cultured neurons by immunolabeling, and subsequently, we analyzed the effects of CGP37157 on neuronal Ca2+ homeostasis using cameleon-based mitochondrial Ca2+ and cytosolic Ca2+ ([Ca2+]i) live imaging. We observed that NCLX-driven mitochondrial Ca2+ exchange occurs in cortical neurons under basal conditions as CGP37157 induced a decrease in [Ca2] i concomitant with a Ca2+ accumulation inside the mitochondria. In turn, CGP37157 also inhibited mitochondrial Ca2+ efflux after the stimulation of acetylcholine receptors. In contrast, CGP37157 strongly prevented depolarization-induced [Ca2+]i increase by blocking voltage-gated Ca2+ channels (VGCCs), whereas it did not induce depletion of ER Ca2+ stores. Moreover, mitochondrial Ca 2+ overload was reduced as a consequence of diminished Ca 2+ entry through VGCCs. The decrease in cytosolic and mitochondrial Ca2+ overload by CGP37157 resulted in a reduction of excitotoxic mitochondrial damage, characterized here by a reduction in mitochondrial membrane depolarization, oxidative stress and calpain activation. In summary, our results provide evidence that during excitotoxicity CGP37157 modulates cytosolic and mitochondrial Ca2+ dynamics that leads to attenuation of NMDA-induced mitochondrial dysfunction and neuronal cell death by blocking VGCCs. © 2014 Macmillan Publishers Limited All rights reserved.


Pascual-Brazo J.,Catholic University of Leuven | Baekelandt V.,Catholic University of Leuven | Encinas J.M.,Achucarro Basque Center for Neuroscience | Encinas J.M.,Ikerbasque | Encinas J.M.,University of the Basque Country
Current Pharmaceutical Design | Year: 2014

Thirteen years have passed since the neurogenic hypothesis of depression was postulated. One of its aspects, that decreased neurogenesis could be causative of the onset of depression has been difficult to prove. Another aspect, the prediction that increasing neurogenesis would not only be supportive but also required to produce clinical results by antidepressants has gathered experimental validation. Thus a question arises: should new antidepressant strategies based solely on increasing neurogenesis be pursued? At the risk of disappointing the audience, we will not provide a straight answer to this question in this review, but we do hope to enlighten the reader regarding what is known about adult hippocampal neurogenesis, the indications and evidence of its involvement in the onset and treatment of depression, and the advances that have been made in the field in recent years. As we will recount here, the main body of support in favor of the neurogenic hypothesis of depression is based more on intimation than actual proof. However the rare examples that provide support are sufficiently robust to justify investment of resources and effort to clarify the issue, even if the involvement of neurogenesis, both in the etiology and the treatment of depression, is only partial and comprises only subtle components of this complex mental disorder. © 2014 Bentham Science Publishers.


Busquets-Garcia A.,University Pompeu Fabra | Gomis-Gonzalez M.,University Pompeu Fabra | Guegan T.,University Pompeu Fabra | Agustin-Pavon C.,Center for Genomic Regulation | And 21 more authors.
Nature Medicine | Year: 2013

Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in the pathology of this disease. The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 activation, is altered in several brain areas of Fmr1 knockout mice. We found that CB1R blockade in male Fmr1 knockout (Fmr1 -/y) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5. Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS. © 2013 Nature America, Inc. All rights reserved.


News Article | November 10, 2016
Site: www.chromatographytechniques.com

It has been known for some time that the extracts of the Cannabis plant, just like synthetic cannabinoids and those produced by the brain itself, join up with type 1 (CB1) cannabinoid receptors located in the nerve endings of the neurons, and inhibit the release of chemical messengers (neurotransmitters) in the communication areas between the nerve cells. The knowledge about the way cannabinoids work has been expanded in recent years when it was shown that the CB1 receptor is also located in and functions in the mitochondria of the neurons. A new piece of research, which has been published in the online version of the journal Nature, has now gone a step further on discovering that the amnesia caused by cannabinoids needs the activation of the CB1 cannabinoid receptors located in the mitochondria of the hippocampus, the brain structure involved in memory formation. To obtain the results of this research, led by Giovanni Marsicano of the University of Bordeaux, the contribution of the following doctors was crucial--Nagore Puente, Leire Reguero, Izaskun Elezgarai and Pedro Grandes -- neuroscientists in the Department of Neurosciences of the UPV/EHU's Faculty of Medicine and Nursing and of the Achucarro Basque Center for Neuroscience. They also participated in a previous discovery about the location and functioning of the CB1 receptor in the mitochondria. In this new piece of research, the researchers used a broad range of cutting-edge experimental techniques and saw that the genetic elimination of the CB1 receptor from the mitochondria of the hippocampus prevents memory loss, the reduction in mitochondrial movement and the decrease in neural communication induced by the cannabinoids. This research also revealed that the amnesia caused by cannabinoids and the related cell processes are linked to an acute alteration in bioenergetic mitochondrial activity owing to the direct activation of the CB1 receptors in the mitrochondria. This activation leads to the inhibiting of the cannabinoid signaling cascade inside the mitochondria and cell respiration diminishes as a result. This reduction in cell respiration through cannabinoids is not restricted to the brain as a similar phenomenon occurs in skeletal and cardiac muscle, as has recently been published in another piece of research by the group of Grandes. "Mitochondrial malfunctioning could have serious consequences for the brain. For example, chronic mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, strokes or disorders associated with ageing. However, the involvement of the acute variation in mitochondrial activity in higher brain functions, such as memory, was unknown," explained Grandes. So this research has revealed that the CB1 cannabinoid receptors in the mitochondria regulate the memory processes by modulating mitochondrial energy metabolism. Furthermore, although cannabinoid by-products have a well-known therapeutic potential, their use is limited by the significant adverse effects that emerge when acting on CB1 receptors, including memory loss. The results of this research suggest that "a selective intervention on specific CB1 cannabinoid receptors located in the brain in certain specific neurone compartments could be of interest with a view to developing new therapeutic tools based on the most effective and safest cannabinoids in the treatment of certain brain diseases," said Grandes. "This research is the result of six years' work, in which 28 researchers have participated. In our case it would not have been possible without the funding received from the UPV/EHU, the Basque Government and Spanish institutions, which have placed their trust in us even during these years of tremendous cutbacks for research; this is something I recognize and which I am grateful for," concluded Grandes.

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