Striatal pre- and postsynaptic profile of adenosine A2A receptor antagonists

Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively.

Extracellular Subunit Interactions Control Transitions between Functional States of Acid-sensing Ion Channel 1a.

Acid-sensing ion channels (ASICs) are neuronal, voltage-independent Na(+) channels that are transiently activated by extracellular acidification. They are involved in pain sensation, the expression of fear, and in neurodegeneration after ischemic stroke. Our study investigates the role of extracellular subunit interactions in ASIC1a function. We identified two regions involved in critical intersubunit interactions. First, formation of an engineered disulfide bond between the palm and thumb domains leads to partial channel closure. Second, linking Glu-235 of a finger loop to either one of two different residues of the knuckle of a neighboring subunit opens the channel at physiological pH or disrupts its activity. This suggests that one finger-knuckle disulfide bond (E235C/K393C) sets the channel in an open state, whereas the other (E235C/Y389C) switches the channel to a non-conducting state. Voltage-clamp fluorometry experiments indicate that both the finger loop and the knuckle move away from the β-ball residue Trp-233 during acidification and subsequent desensitization. Together, these observations reveal that ASIC1a opening is accompanied by a distance increase between adjacent thumb and palm domains as well as a movement of Glu-235 relative to the knuckle helix. Our study identifies subunit interactions in the extracellular loop and shows that dynamic changes of these interactions are critical for normal ASIC function.

Trastornos neurológicos: repasemos nuestros conocimientos

Según el informe"Trastornos neurológicos: un desafío para la salud pública", elaborado por la OMS, unos mil millones de personas en todo el mundo padecen alteraciones neurológicas. Estos trastornos son una causa importante de mortalidad y representan el 12% del total de muertes a escala mundial. Entre otras, destacan las enfermedades vasculares cerebrales (85%), la enfermedad de Alzheimer (6,28%), la epilepsia (1,86%) y la enfermedad de Parkinson (1,55%). En España, los últimos datos publicados por...

Continuing Medical Education Self-Assessment Questions Vol. 50, No. 2 - April 2014. Focal vibration in neurorehabilitation.

During the last decade, many studies have been carried out to understand the effects of focal vibratory stimuli at various levels of the central nervous system and to study pathophysiological mechanisms of neurological disorders as well as the therapeutic effects of focal vibration in neurorehabilitation. This review aimed to describe the effects of focal vibratory stimuli in neurorehabilitation including the neurological diseases or disorders like stroke, spinal cord injury, multiple sclerosis, Parkinson's' disease and dystonia. In conclusion, focal vibration stimulation is well tolerated, effective and easy to use, and it could be used to reduce spasticity, to promote motor activity and motor learning within a functional activity, even in gait training, independent from etiology of neurological pathology. Further studies are needed in the future well- designed trials with bigger sample size to determine the most effective frequency, amplitude and duration of vibration application in the neurorehabilitation.

Synaptic dysfunction, memory deficits and hippocampal atrophy due to ablation of mitochondrial fission in adult forebrain neurons.

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

Étude retrospective observationnelle sur l'usage des biomarqueurs du liquide céphalo-rachidien de la maladie d'Alzheimer [Prospective and observational study of use of cerebrospinal fluid biomarkers of Alzheimer's disease]

Objectifs: Le dosage des biomarqueurs du liquide céphalorachidien (LCR) ne fait pas partie des recommandations de la démarche diagnostique de la maladie d'Alzheimer (MA) en France. Nous voulions analyser l'apport de leur dosage en pratique clinique quotidienne. Matériel et méthode: Étude rétrospective observationnelle, portant sur l'ensemble des dosages de biomarqueurs du LCR de la MA effectués entre le 1er novembre 2010 et le 30 septembre 2012 dans l'hôpital de jour (HDJ) et le service de médecine interne gériatrique (SMIG) du centre mémoire de ressources et de recherche (CMRR) des hôpitaux universitaires de Strasbourg (Alsace, France). Résultats: Quatre-vingt-dix-sept patients (femmes : 60,8 % ; âge moyen : 80 ± 6,5 ans) ont été considérés. En HDJ (n = 50), les biomarqueurs étaient utilisés pour le diagnostic positif de MA (64,0 %) ou le diagnostic différentiel entre les démences (36,0 %). Au SMIG (n = 47), leur dosage était effectué afin de confirmer une MA (19,1 %), de rechercher une pathologie cognitive sous-jacente à un syndrome confusionnel (17,0 %) ou pour diagnostiquer une démence chez des patients atteints de pathologies psychiatriques (29,8 %). Si 49,5 % des patients ont eu un diagnostic de MA confirmée, les biomarqueurs ont contribué à infirmer cette étiologie dans 9,2 % des cas. Le doute entre une MA et une autre étiologie persistait cependant encore chez 10 patients. Les analyses comparatives des taux des différents biomarqueurs ont montré que la protéine tau est observée avec un taux significativement plus élevé dans la MA que dans la démence vasculaire (p = 0,003) et à la limite de la significativité pour la maladie de Parkinson (p = 0,06). Le profil observé avec la Ptau est similaire mais avec une significativité atteinte vis-à-vis de la démence de la maladie de Parkinson (p = 0,01). En ce qui concerne l'Aβ1-42, si les taux moyens étaient les plus élevés dans les démences vasculaire et à corps de Lewy, (p < 0,0001 et p < 0,01), ils étaient plus faibles en cas de démence de la maladie de Parkinson mais sans atteindre le seuil de signification (p = 0,12). Conclusion: Cette étude a analysé l'utilisation des biomarqueurs de la MA en pratique courante. Si leur intérêt se positionne actuellement dans le diagnostic de la MA à un stade léger, ces biomarqueurs montrent leur utilité dans les situations où le diagnostic clinique est rendu difficile par un trouble psychiatrique et/ou une confusion, une clinique atypique où lorsque les tests cognitifs sont irréalisables.

Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.

BACKGROUND: Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing. RESULTS: The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. CONCLUSIONS: Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.

Tools and data services registry: a community effort to document bioinformatics resources.

Life sciences are yielding huge data sets that underpin scientific discoveries fundamental to improvement in human health, agriculture and the environment. In support of these discoveries, a plethora of databases and tools are deployed, in technically complex and diverse implementations, across a spectrum of scientific disciplines. The corpus of documentation of these resources is fragmented across the Web, with much redundancy, and has lacked a common standard of information. The outcome is that scientists must often struggle to find, understand, compare and use the best resources for the task at hand.Here we present a community-driven curation effort, supported by ELIXIR-the European infrastructure for biological information-that aspires to a comprehensive and consistent registry of information about bioinformatics resources. The sustainable upkeep of this Tools and Data Services Registry is assured by a curation effort driven by and tailored to local needs, and shared amongst a network of engaged partners.As of November 2015, the registry includes 1785 resources, with depositions from 126 individual registrations including 52 institutional providers and 74 individuals. With community support, the registry can become a standard for dissemination of information about bioinformatics resources: we welcome everyone to join us in this common endeavour. The registry is freely available at https://bio.tools.

Neurologie [Neurology].

In 2015, cerebral stimulation becomes increasingly established in the treatment of pharmacoresistant epilepsy. Efficacy of endovascular treatment has been demonstrated for acute ischemic stroke. Deep brain stimulation at low frequency improves dysphagia and freezing of gait in Parkinson patients. Bimagrumab seems to increase muscular volume and force in patients with inclusion body myositis. In cluster-type headache, a transcutaneous vagal nerve stimulator is efficient in stopping acute attacks and also reducing their frequency. Initial steps have been undertaken towards modulating memory by stimulation of the proximal fornix. Teriflunomide is the first oral immunomodulatory drug for which efficacy has been shown in preventing conversion from clinical isolated syndrome to multiple sclerosis.

Therapeutic benefits of body percussion using the BAPNE method

Body percussion using to the BAPNE method is a means of cognitive stimulation with multiple applications. The aim of this research is to assess their full potential as a source of therapy. The methodology used is theoretical in nature and makes use of a wide bibliography to find evidence for its therapeutic effect. In essence, body percussion can be seen to lead to improvements in three areas. the Physical, as it stimulates awareness of the body, control of movement and muscular strength, coordination and balance; the Mental, as it improves concentration, memory and perception; and finally Socio-affective, as it helps to build egalitarian relationships and leads to a decrease in anxiety in social interactions. This means of therapy has several different uses and it is targeted at different groups. In the present investigation we categorise them into five main groups: individuals with neurodegenerative diseases like Alzheimer's or Parkinson's disease; individuals with learning disorders such as dyslexia or ADHD; patients affected by diseases of the spinal cord, cranial neuropathies and trauma (Neurorehabilitation); and for the treatment of addictive behavior (addiction); and depressive disorders or anxiety disorders.After thorough analysis, we have found scientific evidence that the therapeutic body percussion using the BAPNE method improves the quality of life of patients and it is an important factor in stabilizing the development of different diseases.In addition, evidence involving certain biological indicators (in control and experimental groups, and through a pre-test and post-test) show its effect on levels of stress and anxiety (reduction of cortisol), as well as improvement of social relations as a result of working as a group (increased levels of oxytocin), and improvements seen in self-esteem and in a variety of personal aspects through the Aspects of Identity questionnaire.

Mechanisms of protein homeostasis in health, aging and disease.

When emerging from the ribosomes, new polypeptides need to fold properly, eventually translocate, and then assemble into stable, yet functionally flexible complexes. During their lifetime, native proteins are often exposed to stresses that can partially unfold and convert them into stably misfolded and aggregated species, which can in turn cause cellular damage and propagate to other cells. In animal cells, especially in aged neurons, toxic aggregates may accumulate, induce cell death and lead to tissue degeneration via different mechanisms, such as apoptosis as in Parkinson's and Alzheimer's diseases and aging in general. The main cellular mechanisms effectively controlling protein homeostasis in youth and healthy adulthood are: (1) the molecular chaperones, acting as aggregate unfolding and refolding enzymes, (2) the chaperone-gated proteases, acting as aggregate unfolding and degrading enzymes, (3) the aggresomes, acting as aggregate compacting machineries, and (4) the autophagosomes, acting as aggregate degrading organelles. For unclear reasons, these cellular defences become gradually incapacitated with age, leading to the onset of degenerative diseases. Understanding these mechanisms and the reasons for their incapacitation in late adulthood is key to the design of new therapies against the progression of aging, degenerative diseases and cancers.

Long-term controlled GDNF over-expression reduces dopamine transporter activity without affecting tyrosine hydroxylase expression in the rat mesostriatal system.

The dopamine (DA) transporter (DAT) is a plasma membrane glycoprotein expressed in dopaminergic (DA-) cells that takes back DA into presynaptic neurons after its release. DAT dysfunction has been involved in different neuro-psychiatric disorders including Parkinson's disease (PD). On the other hand, numerous studies support that the glial cell line-derived neurotrophic factor (GDNF) has a protective effect on DA-cells. However, studies in rodents show that prolonged GDNF over-expression may cause a tyrosine hydroxylase (TH, the limiting enzyme in DA synthesis) decline. The evidence of TH down-regulation suggests that another player in DA handling, DAT, may also be regulated by prolonged GDNF over-expression, and the possibility that this effect is induced at GDNF expression levels lower than those inducing TH down-regulation. This issue was investigated here using intrastriatal injections of a tetracycline-inducible adeno-associated viral vector expressing human GDNF cDNA (AAV-tetON-GDNF) in rats, and doxycycline (DOX; 0.01, 0.03, 0.5 and 3mg/ml) in the drinking water during 5weeks. We found that 3mg/ml DOX promotes an increase in striatal GDNF expression of 12× basal GDNF levels and both DA uptake decrease and TH down-regulation in its native and Ser40 phosphorylated forms. However, 0.5mg/ml DOX promotes a GDNF expression increase of 3× basal GDNF levels with DA uptake decrease but not TH down-regulation. The use of western-blot under non-reducing conditions, co-immunoprecipitation and in situ proximity ligation assay revealed that the DA uptake decrease is associated with the formation of DAT dimers and an increase in DAT-α-synuclein interactions, without changes in total DAT levels or its compartmental distribution. In conclusion, at appropriate GDNF transduction levels, DA uptake is regulated through DAT protein-protein interactions without interfering with DA synthesis.

Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise.

The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging.

Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise.

The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging.