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Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The vertebrate brain has an exceptionally high energy need. During ischemia, intracellular ATP concentrations decline rapidly, resulting in the breakdown of ion gradients and cellular damage. Here, we employed the nanosensor ATeam1.03YEMK to analyse the pathways driving the loss of ATP upon transient metabolic inhibition in neurons and astrocytes of the mouse neocortex. We demonstrate that brief chemical ischemia, induced by combined inhibition of glycolysis and oxidative phosphorylation, results in a transient decrease in intracellular ATP. Neurons experienced a larger relative decline and showed less ability to recover from prolonged (>5 min) metabolic inhibition than astrocytes. Blocking voltage‐gated Na+ channels or NMDA receptors ameliorated the ATP decline in neurons and astrocytes, while blocking glutamate uptake aggravated the overall reduction in neuronal ATP, confirming the central role of excitatory neuronal activity in the cellular energy loss. Unexpectedly, pharmacological inhibition of transient receptor potential vanilloid 4 (TRPV4) channels significantly reduced the ischemia‐induced decline in ATP in both cell types. Imaging with Na+‐sensitive indicator dye ING‐2 furthermore showed that TRPV4 inhibition also reduced ischemia‐induced increases in intracellular Na+. Altogether, our results demonstrate that neurons exhibit a higher vulnerability to brief metabolic inhibition than astrocytes. Moreover, they reveal an unexpected strong contribution of TRPV4 channels to the loss of cellular ATP and suggest that the demonstrated TRPV4‐related ATP consumption is most likely a direct consequence of Na+ influx. Activation of TRPV4 channels thus provides a hitherto unacknowledged contribution to the cellular energy loss during energy failure, generating a significant metabolic cost in ischemic conditions. Key points: In the ischemic brain, cellular ATP concentrations decline rapidly, which results in the collapse of ion gradients and promotes cellular damage and death.We analysed the pathways driving the loss of ATP upon transient metabolic inhibition in neurons and astrocytes of the mouse neocortex.Our results confirm the central role of excitatory neuronal activity in the cellular energy loss and demonstrate that neurons experience a larger decline in ATP and are more vulnerable to brief metabolic stress than astrocytes.Our study also reveals a new, previously unknown involvement of osmotically activated transient receptor potential vanilloid 4 (TRPV4) channels to the reduction in cellular ATP in both cell types and indicates that this is a consequence of TRPV4‐mediated Na+ influx.We conclude that activation of TRPV4 channels provides a considerable contribution to the cellular energy loss, thereby generating a significant metabolic cost in ischemic conditions. [ABSTRACT FROM AUTHOR]

Over a hundred years of study on the favourable effect of ketogenic diets in the treatment of epilepsy have contributed to a long-lasting discussion on its potential influence on other neurological diseases. A significant increase in the number of scientific studies in that field has been currently observed. The aim of this paper is a widespread, thorough analysis of the available scientific evidence in respect of the role of the ketogenic diet in the therapy of neurological diseases such as: epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and migraine. A wide range of the mechanisms of action of the ketogenic diet has been demonstrated in neurological diseases, including, among other effects, its influence on the reduction in inflammatory conditions and the amount of reactive oxygen species (ROS), the restoration of the myelin sheath of the neurons, the formation and regeneration of mitochondria, neuronal metabolism, the provision of an alternative source of energy for neurons (ketone bodies), the reduction in glucose and insulin concentrations, the reduction in amyloid plaques, the induction of autophagy, the alleviation of microglia activation, the reduction in excessive neuronal activation, the modulation of intestinal microbiota, the expression of genes, dopamine production and the increase in glutamine conversion into GABA. The studies discussed (including randomised controlled studies), conducted in neurological patients, have stressed the effectiveness of the ketogenic diet in the treatment of epilepsy and have demonstrated its promising therapeutic potential in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and migraine. A frequent advantage of the diet was demonstrated over non-ketogenic diets (in the control groups) in the therapy of neurological diseases, with simultaneous safety and feasibility when conducting the nutritional model. [ABSTRACT FROM AUTHOR]

Dans les années 1980, Benjamin Libet apporte la preuve que nous prenons conscience de nos actes quelques centièmes de secondes après que ceux-ci sont déjà engagés sur le plan de l'activité cérébrale, semblant démontrer ainsi que nos décisions échappent à notre volonté consciente. Cette expérience ayant été répliquée par différentes équipes avec des résultats identiques, bien que différemment interprétés, le libre arbitre se voit ainsi questionné scientifiquement et l'intentionnalité criminelle des individus psychopathes possiblement réinterrogée. À partir de la théorie de la sélection des groupes neuronaux d'Edelman, illustrée par l'analyse de cas cliniques, cet article propose une hypothèse selon laquelle le libre arbitre se matérialiserait dans des réseaux neuronaux qui se seraient développés et pérennisés au cours du développement de l'enfant, via ses expériences sensorielles indexées de valeurs émotionnelles. Ces réseaux neuronaux, mis en mémoire, constitueraient des répertoires singuliers à chacun de nous, servant de modèles pour toutes nos décisions à venir. Ainsi, l'homme en général et le criminel psychopathe en particulier auraient d'autant moins de latitude pour agir librement que leurs répertoires se seront développés au cours de leur enfance, dans l'uniformité et la rigidité. In the Eighties, Benjamin Libet demonstrated that we become aware of an action that happens several hundred milliseconds after the onset of the brain activity, suggesting that our voluntary decisions escape to our consciousness. This original experimental study has been replicated several times with the same results-even if their interpretations differ, which challenges scientifically the issue of free will. Thus, criminal Intentionality of psychopathic individuals could be re-examined. Using Edelman's Neural Darwinism, we developed the hypothesis that free will materializes in neural networks and we illustrate this by clinical case analysis. These have developed and perpetuated during the child development via their sensory experiences indexed with emotional values. These networks are stored in memory, and constitute a collection of our own individual habits which serve as a model for all our future decisions. General human and particularly psychopathic criminals would have even less latitude to act freely since their complexes have developed uniformly and rigidly during their childhood. [ABSTRACT FROM AUTHOR]

L’objectif du modèle PRESENCE est de mettre en lumière les connaissances sur le développement du cerveau au service des neurosciences de l’éducation. PRESENCE combine une exploration approfondie de l'organisation du cerveau avec une revue de la littérature et perspective théorico-pratique sur la façon dont il permet l'émergence d'états mentaux complexes. Habilement tissé ensemble, le résultat est une image unique du cerveau qui est enracinée dans la morphologie et le fonctionnement cellulaire par la prédisposition génétique/épigénétique, l’élagage synaptique, la neuroplasticité et la neurogenèse puis mise en mouvement par la dynamique des réseaux de neurones et leur synchronisation en passant par la conscience et le libre arbitre. PRESENCE est un modèle sur lequel le CAS en neuroscience de l’éducation s’est basé. Le premier épisode de cette série de huit épisodes nous fait voyager au cœur de la prédisposition génétique et épigénétique. Les connexions sont établies selon un plan génétiquement programmé mais leur maintien et leur qualité peuvent être largement régulés par l’activité neuronale et donc l’expérience. En intervenant auprès du jeune il faut garder à l’esprit le fait qu’on intervient auprès d’une structure cérébrale génétiquement et épigénétiquement complexe et imprévisible ; que nos interventions ont les capacités d’interagir avec cette structure et la modifier pour le meilleur ou pour le pire. Les études dans le domaine ainsi que les réflexions de l’auteure présentées dans cette mini-revue de la littérature mettent en lumière le rôle de l’environnent dans le tissage des réseaux de neurones de l’enfant. Tout particulièrement, les recherches en neurosciences soulignent l’impact de l’environnement dans le développement de l’Être en construction.

• Excessive arsenic intake has neurotoxic effects. • Arsenic induces neuronal apoptosis and ultrastructural damage. • Arsenic activates Fas/FasL signaling pathway of nerve cells. • ZB4 reverses arsenic-induced apoptosis of SHSY5Y cells. The molecular mechanisms underlying arsenic-induced neurotoxicity have not been completely elucidated. Our study aimed to determine the role of the Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis. Pathological and molecular biological tests were performed on the cerebral cortex of arsenic-exposed rats and SH-SY5Y neuroblastoma cells. Arsenic induced apoptosis in the cortical neurons, which corresponded to abnormal ultrastructural changes. Mechanistically, arsenic activated the Fas-FasL-FADD signaling pathway and the downstream caspases both in vivo and in vitro. ZB4 treatment reversed the apoptotic effects of arsenic on the SHSY5Y cells. Taken together, arsenic induces neurotoxicity by activating the Fas-FasL-FADD signaling pathway. [ABSTRACT FROM AUTHOR]

Nerve cells (neurones) are 'excitable' cells that can transduce a variety of stimuli into electrical signals, continuously sending information about the external and internal environment (in the form of sequences of action potentials) to the central nervous system (CNS). Interneurones in the CNS integrate this information and send signals along output (efferent) neurones to various parts of the body for the appropriate actions to be taken in response to environmental changes. Networks of neurones have been arbitrarily classified into various nervous systems that gather and transmit sensory information and control skeletal muscle function and autonomic function, etc. The junctions between neurones (synapses) are either electrical or chemical. The former permit the direct transfer of electrical current between cells, whereas the latter utilize chemical signalling molecules (neurotransmitters) to transfer information between cells. Neurotransmitters are mainly amino acids, amines or peptides (although other molecules such as purines and nitric oxide are utilized by some cells), and can be excitatory or inhibitory. Individual neurones within the CNS may receive synaptic inputs from thousands of other neurones. Therefore, each neurone 'integrates' this vast complexity of inputs and responds accordingly (either by remaining silent or firing action potentials to other neurones). Adaptations in the function and structure of chemical synapses in particular (synaptic plasticity) are thought to underlie the mechanisms mediating cognitive functions (learning and memory). [ABSTRACT FROM AUTHOR]

Irisin is a novel hormone‐like myokine that plays an important role in central nervous system (CNS) diseases, such as cerebral ischaemia and Alzheimer's disease. However, irisin is rarely investigated in multiple sclerosis (MS), a typical inflammatory demyelinating disease of the CNS, and in experimental autoimmune encephalomyelitis (EAE), a typical model of MS. We determined the levels of irisin in the serum and cerebrospinal fluid in patients with MS. The expression and histological distribution of irisin were determined in EAE. Serum irisin levels in patients with MS and in EAE mice were increased, and the levels of FNDC5/irisin mRNA were decreased in the spinal cord and brain regardless of the onset, peak or chronic phase of EAE. Immunofluorescence staining showed co‐localization of irisin and neurones. The levels of irisin fluctuated with disease progression in MS and EAE. Irisin may be involved in the pathological process of MS/EAE. [ABSTRACT FROM AUTHOR]

More than a century of dedicated research has resulted in what we now know, and what we think we know, about synapses and neural circuits. This piece asks to what extent some of the major advances – both theoretical and practical – have resulted from carefully considered theory, or experimental design: endeavors that aim to address a question, or to refute an existing hypothesis. It also, however, addresses the important part that serendipity and chance have played. There are cases where hypothesis driven research has resulted in important progress. There are also examples where a hypothesis, a model, or even an experimental approach – particularly one that seems to provide welcome simplification – has become so popular that it becomes dogma and stifles advance in other directions. The nervous system rejoices in complexity, which should neither be ignored, nor run from. The emergence of testable “rules” that can simplify our understanding of neuronal circuits has required the collection of large amounts of data that were difficult to obtain. And although those collecting these data have been criticized for not advancing hypotheses while they were “collecting butterflies,” the beauty of the butterflies always enticed us toward further exploration.

More than a century of dedicated research has resulted in what we now know, and what we think we know, about synapses and neural circuits. This piece asks to what extent some of the major advances – both theoretical and practical – have resulted from carefully considered theory, or experimental design: endeavors that aim to address a question, or to refute an existing hypothesis. It also, however, addresses the important part that serendipity and chance have played. There are cases where hypothesis driven research has resulted in important progress. There are also examples where a hypothesis, a model, or even an experimental approach – particularly one that seems to provide welcome simplification – has become so popular that it becomes dogma and stifles advance in other directions. The nervous system rejoices in complexity, which should neither be ignored, nor run from. The emergence of testable "rules" that can simplify our understanding of neuronal circuits has required the collection of large amounts of data that were difficult to obtain. And although those collecting these data have been criticized for not advancing hypotheses while they were "collecting butterflies," the beauty of the butterflies always enticed us toward further exploration. [ABSTRACT FROM AUTHOR]

Objective To study the method of inducing astrocytes into neurons by reprogramming in vitro. Methods Astrocytes were cultured in vitro from the cerebral cortex of rats 1 to 4 days old. The purified and identified third generation astrocytes were cultured on poly-D-lysine coated cover slips in 24 well plates and divided into induction group and control group. Induction group: Y-27632(0. 5 µmoVL), VPA(O. 5 µmoVL), SB431542(94 nmoVL) and RepSox ( 25 µmoVL) were dissolved in DMSO, and the mixture of these four small molecules was added into 24 well plate. Control group: the same volume of DMSO was added. After 7 days of continuous stimulation with small molecular substances, the cells in the induction group were cultured in the medium containing BDNF and NT-3 for 14 days to make immature neurons transform into mature neurons. After 7 days, the cells in the control group were cultured in the medium containing BDNF and NT-3 for 14 days. After 14 days, the morphological changes of cells were observed under light microscope. The expression of TUJl, MAP2 and NeuN were detected by immunofluorescence. Results In the induction group, the astrocytes were reprogrammed with small molecular substances for 7 days and then added to the neuron culture medium for 14 days. Under light microscope, most of the astrocytes changed in morphology, the full cytoplasm became slender, and many processes extended and the processes were longer. Immunofluorescence detection showed that the proportion of positive cells of neuron markers TUJl, MAP2 and NeuN( 15. 6% ± 0. 7%) was significantly higher than that of the control group ( 15. 6% ± 0. 7%) ( P < 0. 05). Conclusion Small molecule Y27632, VPA,SB431542 andRepSox compounds can directly reprogram astrocytes into neurons. [ABSTRACT FROM AUTHOR]

Pruritus (itch) is defined as an unpleasant sensation leading to the need to scratch. It is therefore a sensation that is distinct from pain but whose repercussions are quite equivalent. Pruritus and pain are differentiated not only by the induction of different reactions (scratching, withdrawal) but also by rather opposite effects of heat and cold or completely opposite effects of opiates. The treatments are very different. In the skin and some mucosa, there are specific pruritus receptors (pruriceptors) and then there are specific pathways leading the "pruritus" signal to different areas of the brain. These pathways are shared with the pain pathways or not. The mechanisms of peripheral and central sensitization to pruritus are increasingly well understood, with the clinical consequences of chronic pruritus, alloknesia and hyperknesia. Pain can inhibit pruritus by activating interneurons. It can sometimes coexist with pruritus, particularly in the case of neuropathic pruritus. The causes of pruritus are most often dermatological but other causes are also possible: renal, hepatic, endocrine, metabolic, hematological, paraneoplastic, neurological, psychic, iatrogenic or mixed. Until now, the management of pruritus has been disappointing. Antihistamines are rarely effective. Gabapentinoids may be used. Recent progress in research is opening up new avenues: κ-agonists, µ-antagonists, anti-IL31, anti-IL4/13, NK1 inhibitors, anti-Jak, etc. A network of antipruritus centers inspired by the organization of pain management centers would probably be very useful. [ABSTRACT FROM AUTHOR]

Background: Bio-electrospray (BES) is a jet-based delivery system driven by an electric field that has the ability to form micro to nano-sized droplets. It holds great potential as a tissue engineering tool as it can be used to place cells into specific patterns. As the human central nervous system (CNS) cannot be studied in vivo at the cellular and molecular level, in vitro CNS models are needed. Human neural stem cells (hNSCs) are the CNS building block as they can generate both neurones and glial cells. Methods: Here we assessed for the first time how hNSCs respond to BES. To this purpose, different hNSC lines were sprayed at 10 kV and their ability to survive, grow and differentiate was assessed at different time points. Results: BES induced only a small and transient decrease in hNSC metabolic activity, from which the cells recovered by day 6, and no significant increase in cell death was observed, as assessed by flow cytometry. Furthermore, bio-electrosprayed hNSCs differentiated as efficiently as controls into neurones, astrocytes and oligodendrocytes, as shown by morphological, protein and gene expression analysis. Conclusions: This study highlights the robustness of hNSCs and identifies BES as a suitable technology that could be developed for the direct deposition of these cells in specific locations and configurations.

Background: Bio-electrospray (BES) is a jet-based delivery system driven by an electric field that has the ability to form micro to nano-sized droplets. It holds great potential as a tissue engineering tool as it can be used to place cells into specific patterns. As the human central nervous system (CNS) cannot be studied in vivo at the cellular and molecular level, in vitro CNS models are needed. Human neural stem cells (hNSCs) are the CNS building block as they can generate both neurones and glial cells. Methods: Here we assessed for the first time how hNSCs respond to BES. To this purpose, different hNSC lines were sprayed at 10 kV and their ability to survive, grow and differentiate was assessed at different time points. Results: BES induced only a small and transient decrease in hNSC metabolic activity, from which cells recovered by day 6, and no significant increase in cell death was observed, as assessed by flow cytometry. Furthermore, bio-electrosprayed hNSCs differentiated as efficiently as controls into neurones, astrocytes and oligodendrocytes as shown by morphological, protein and gene expression analysis. Conclusions: This study highlights the robustness of hNSCs and identifies BES as a suitable technology that could be developed for the direct deposition of these cells in specific locations and configurations.

Over the last two decades, it has become clear that classical molecules that regulate neurodevelopment also play an important role in directly regulating the development of the vascular system and vice versa. The prototypical angiogenic ligand vascular endothelial growth factor (VEGF) is by now also regarded as a molecular regulator of different neurodevelopmental processes, such as neuronal progenitor proliferation, migration and differentiation, dendritic and axonal branching and synaptogenesis. The direct effect of other classical angiogenic factors, such as angiopoietins and its receptor Tie2, on neurodevelopmental processes remains less defined. Recent work from our group indicates that the angiopoietin-Tie2 pathway does not only regulate blood vessel formation and stabilization but also simultaneously affect neuronal dendritogenesis in a cell-autonomous manner. In this mini-review, we will integrate our findings within the current understanding of the neurovascular link and within the previous knowledge of the potential effects of angiopoietins in the neuronal context. [ABSTRACT FROM AUTHOR]

As shown in our previous paper ('Regression I. Experimental approaches to regression', JAP, 65, 2, 345-65), the common mechanism of regression can be described as reversible dedifferentiation, which is understood as a relative increase of the proportion of low-differentiated (older) systems in actualized experience. Experimental data show that regression following disease (chronic tension headache) is followed by adaptation and an increase in system differentiation in that experience domain which contains systems responsible for that adaptation. The results of mathematical modelling support the idea that reversible dedifferentiation can be one of the mechanisms for increasing the effectiveness of adaptation through learning. Reversible dedifferentiation, which is phenomenologically described as regression, is a general mechanism for restructuring the organism-environment interactions in situations where behaviours that were effective in the past become ineffective. Reversible dedifferentiation has evolved as a component of adaptation when new behaviours are formed and large-scale modifications in the existing behaviours are required in the face of changes in the external and/or internal environment. Thus, the authors believe that this article provides evidence for Jung's view that regression is not only a 'return' to past forms of thinking, affects and behaviour, but that regressive processes provide a significant impetus for psychological growth and development. [ABSTRACT FROM AUTHOR]

The concept of regression is considered with an emphasis on the differences between the positions of Freud and Jung regarding its significance. The paper discusses the results of experimental analyses of individual experience dynamics (from gene expression changes and impulse neuronal activity in animals to prosocial behaviour in healthy humans at different ages, and humans in chronic pain) in those situations where regression occurs: stress, disease, learning, highly emotional states and alcohol intoxication. Common mechanisms of regression in all these situations are proposed. The mechanisms of regression can be described as reversible dedifferentiation, which is understood as a relative increase of the representation of low-differentiated (older) systems in the actualized experience. In all of the cases of dedifferentiation mentioned above, the complexity of the systemic organization of behaviour significantly decreases. [ABSTRACT FROM AUTHOR]

Heavy alcohol consumption leads to neuropathological damage and alcohol use disorder, which affects the health of people and results in a cost burden. However, the genes modulating sensitivity to ethanol remain largely unknown. Here, we identified a novel gene, Drosophilaglutathione transferase omega 1 (GstO1), which plays a critical role in regulating sensitivity to ethanol sedation. GstO1 mutant flies showed highly increased ethanol sensitivity. Furthermore, the expression level of GstO1 regulates the behavioural response to ethanol, because decreasing and increasing GstO1 affects sedation sensitivity in a contrasting manner. In addition, the RNA interference‐mediated knockdown of GstO1 expression reveals that GstO1 mediates sensitivity to ethanol sedation in neurones, including dopaminergic and serotonergic neurones. Altogether, our findings provide the first evidence for the involvement of glutathione transferase in the response to alcohol in Drosophila and provide a novel mechanistic insight into the toxicity and sensitivity of ethanol exposure. [ABSTRACT FROM AUTHOR]

Abstract Nerve cells (neurones) are 'excitable' cells that can transduce a variety of stimuli into electrical signals, continuously sending information about the external and internal environment (in the form of sequences of action potentials) to the central nervous system (CNS). Interneurones in the CNS integrate this information and send signals along output (efferent) neurones to various parts of the body for the appropriate actions to be taken in response to environmental changes. Networks of neurones have been arbitrarily classified into various nervous systems that gather and transmit sensory information and control skeletal muscle function and autonomic function, etc. The junctions between neurones (synapses) are either electrical or chemical. The former permit the direct transfer of electrical current between cells, whereas the latter utilize chemical signalling molecules (neurotransmitters) to transfer information between cells. Neurotransmitters are mainly amino acids, amines or peptides (although other molecules such as purines and nitric oxide are utilized by some cells), and can be excitatory or inhibitory. Individual neurones within the CNS may receive synaptic inputs from thousands of other neurones. Therefore, each neurone 'integrates' this vast complexity of inputs and responds accordingly (either by remaining silent or firing action potentials to other neurones). Adaptations in the function and structure of chemical synapses in particular (synaptic plasticity) are thought to underlie the mechanisms mediating cognitive functions (learning and memory). [ABSTRACT FROM AUTHOR]

Whilst it is universally accepted that the energy support of the brain is glucose, the form in which the glucose is taken up by neurones is the topic of intense debate. In the last few decades, the concept of lactate shuttling between glial elements and neural elements has emerged in which the glial cells glycolytically metabolise glucose/glycogen to lactate, which is shuttled to the neural elements via the extracellular fluid. The process occurs during periods of compromised glucose availability where glycogen stored in astrocytes provides lactate to the neurones, and is an integral part of the formation of learning and memory where the energy intensive process of learning requires neuronal lactate uptake provided by astrocytes. More recently sleep, myelination and motor end plate integrity have been shown to involve lactate shuttling. The sequential aspect of lactate production in the astrocyte followed by transport to the neurones is vulnerable to interruption and it is reported that such disparate pathological conditions as Alzheimer’s disease, amyotrophic lateral sclerosis, depression and schizophrenia show disrupted lactate signalling between glial cells and neurones.

Although originally restricted to their structural role as major constituents of membranes, lipids are now well-defined actors to integrate intracellular or extracellular signals. Accordingly, it has been known for decades that lipids, especially those coming from diet, are important to maintain normal physiological functions and good health. This is especially the case to maintain proper cognitive functions and avoid neuronal degeneration. But besides this empiric knowledge, the exact molecular nature of lipids in cellular signaling, as well as their precise mode of action are only starting to emerge. The recent development of novel pharmacological, molecular, cellular and genetic tools to study lipids in vitro and in vivo has contributed to this improvement in our knowledge. Among these important lipids, phosphatidic acid (PA) plays a unique and central role in a great variety of cellular functions. This article will review the different findings illustrating the involvement of PA generated by phospholipase D (PLD) and diacylglycerol kinases (DGK) in the different steps of neuronal development and neurosecretion. We will also present lipidomic evidences indicating that different species of PA are synthesized during these two key neuronal phenomena. [ABSTRACT FROM AUTHOR]

The aim of the present article is to analyse the evolutionary links between protozoa and neuronal and neurosecretory cells. To this effect we employ functional and topological data available for ciliates, in particular for Paramecium . Of note, much less data are available for choanoflagellates, the progenitors of metazoans, which currently are in the focus of metazoan genomic data mining. Key molecular players are found from the base to the highest levels of eukaryote evolution, including neurones and neurosecretory cells. Several common fundamental mechanisms, such as SNARE proteins and assembly of exocytosis sites, GTPases, Ca 2+ -sensors, voltage-gated Ca 2+ -influx channels and their inhibition by the forming Ca 2+ /calmodulin complex are conserved, albeit with different subcellular channel localisation, from protozoans to man. Similarly, Ca 2+ -release channels represented by InsP 3 receptors and putative precursors of ryanodine receptors, which all emerged in protozoa, serve for focal intracellular Ca 2+ signalling from ciliates to mammalian neuronal cells, eventually in conjunction with store-operated Ca 2+ -influx. Restriction of Ca 2+ signals by high capacity/low affinity Ca 2+ -binding proteins is maintained throughout the evolutionary tree although the proteins involved differ between the taxa. Phosphatase 2B/calcineurin appears to be involved in signalling and in membrane recycling throughout evolution. Most impressive example of evolutionary conservation is the sub-second dynamics of exocytosis-endocytosis coupling in Paramecium cells, with similar kinetics in neuronal and neurosecretory systems. Numerous cell surface receptors and channels that emerge in protozoa operate in the human nervous system, whereas a variety of cell adhesion molecules are newly “invented” during evolution, enabled by an increase in gene numbers, alternative splice forms and transcription factors. Thereby, important regulatory and signalling molecules are retained as a protozoan heritage. [ABSTRACT FROM AUTHOR]

An oxygen-glucose deprivation and reoxygenation model in primary cultured rat cortical neurons was developed for this study to investigate the effects of ellagic acid (EA), a low-molecular-weight polyphenol, on neuron cells and their function, and to evaluate whether EA can be safely utilized by humans as a functional food or therapeutic agent. Administration of EA significantly decreased the volume of cerebrum infarction and the neurological deficit scores of the rats; EA treatment also increased the number of Bcl-2-positive cells and the ratio of Bcl-2-positive to Bax-positive neurons in the semidarkness zone near the brain ischemic focus in the photothrombotic cerebral ischemia model. Treatment of EA resulted in increased neuron viability, cell nuclear integrity, and the ratio of Bcl-2/Bax expression in the primary cultured neuron model; EA treatment also lead to a decrease in the number of apoptotic cells. Our results therefore suggest a specific mechanism for the beneficial effects of EA, providing new insights into how it provides neuroprotection. To the best of our knowledge, these results represent new insights on the mechanisms of the brain cell protective activity of EA. Thus, EA may be used in functional foods or medicines to help treat nerve dysfunction, neurodegenerative disease, and aging. [ABSTRACT FROM AUTHOR]

In the brain, TRPC1 channels are abundantly expressed in neurones virtually in all regions; these proteins function as receptor-activated ion channels and are implicated in numerous processes, being specifically important for neurogenesis. Primary cultures of mouse cerebellar granule cell, cerebral cortical neurones, and freshly isolated neurones from in vivo brains were used to study effects of chronic treatment with anti-bipolar drugs [carbamazepine (CBZ), lithium salts and valproic acid] on gene expression of TRPC1. Expression of TRPC1 mRNA was identified with reverse transcription-polymerase chain reaction, whereas protein content was determined by Western blotting. Store-operated plasmalemmal Ca2+ entry (SOCE) was measured with fura-2 based microfluorimetry. Chronic treatment with each of the three drugs down-regulated mRNA and protein expression in cultured cerebellar granule cells in a time- and concentration-dependent manner. Similar effect was also observed in cultured cerebral cortical neurones treated with CBZ, lithium salts and valproic acid and in freshly isolated neurones from the brains of CBZ-treated animals. The amplitude of SOCE was substantially decreased in cerebellar granule cells chronically treated with each of the three drugs. Our findings indicate that down-regulation of TRPC1 gene expression and function in neurones may be one of the mechanisms of anti-bipolar drugs action. [ABSTRACT FROM AUTHOR]

Prevention and treatment of Alzheimer disease are urgent problems for elderly people in developed countries. We previously reported that nobiletin, a poly-methoxylated flavone from the citrus peel, improved the symptoms in various types of animal models of memory loss and activated the cAMP responsive element (CRE)-dependent transcription in PC12 cells. Nobiletin activated the cAMP/PKA/MEK/Erk/MAPK signaling pathway without using the TrkA signaling activated by nerve growth factor (NGF). Here, we examined the effect of combination of nobiletin and NGF on the CRE-dependent transcription in PC12 cells. Although NGF alone had little effect on the CRE-dependent transcription, NGF markedly enhanced the CRE-dependent transcription induced by nobiletin. The NGF-induced enhancement was neutralized by a TrkA antagonist, K252a. This effect of NGF was effective on the early signaling event elicited by nobiletin. These results suggested that there was crosstalk between NGF and nobiletin signaling in activating the CRE-dependent transcription in PC12 cells. [ABSTRACT FROM AUTHOR]

Nerve cells (neurones) are ‘excitable’ cells that can transduce a variety of stimuli into electrical signals, continuously sending information about the external and internal environment (in the form of sequences of action potentials) to the central nervous system (CNS). Interneurones in the CNS integrate this information and send signals along output (efferent) neurones to various parts of the body for the appropriate actions to be taken in response to environmental changes. Networks of neurones have been arbitrarily classified into various nervous systems that gather and transmit sensory information and control skeletal muscle function and autonomic function, etc. The junctions between neurones (synapses) are either electrical or chemical. The former permit the direct transfer of electrical current between cells, whereas the latter utilize chemical signalling molecules (neurotransmitters) to transfer information between cells. Neurotransmitters are mainly amino acids, amines or peptides (although other molecules such as purines and nitric oxide are utilized by some cells), and can be excitatory or inhibitory. Individual neurones within the CNS may receive synaptic inputs from thousands of other neurones. Therefore, each neurone ‘integrates’ this vast complexity of inputs and responds accordingly (either by remaining silent or firing action potentials to other neurones). Adaptations in the function and structure of chemical synapses in particular (synaptic plasticity) are thought to underlie the mechanisms mediating cognitive functions (learning and memory). [ABSTRACT FROM AUTHOR]

The response of neurones in the Red Nucleus pars magnocellularis (RNm) to both tone bursts and electrical stimulation were observed in three cynomolgus monkeys (Macaca fascicularis), in a series of studies primarily designed to characterise the influence of the dopaminergic ventral midbrain on auditory processing. Compared to its role in motor behaviour, little is known about the sensory response properties of neurons in the red nucleus; particularly those concerning the auditory modality. Sites in the RN were recognised by observing electrically evoked body movements characteristic for this deep brain structure. In this study we applied brief monopolar electrical stimulation to 118 deep brain sites at a maximum intensity of 200 µA, thus evoking minimal body movements. Auditory sensitivity of RN neurons was analysed more thoroughly at 15 sites, with the majority exhibiting broad tuning curves and phase locking up to 1.03 kHz. Since the RN appears to receive inputs from a very early stage of the ascending auditory system, our results suggest that sounds can modify the motor control exerted by this brain nucleus. At selected locations, we also tested for the presence of functional connections between the RN and the auditory cortex by inserting additional microelectrodes into the auditory cortex and investigating how action potentials and local field potentials were affected by electrical stimulation of the RN.

The accumulation of reactive oxygen species leading to oxidative damage and cell death plays an important role in a number of neurodegenerative disorders. FOXO3a, the main isoform of FOXO transcription factors, mediates the cellular response to oxidative stress by regulating the expression of genes involved in DNA repair and glutamine metabolism, including glutamine synthetase (GS). Immunohistochemical investigation of the population-based neuropathology cohort of the Medical Research Council’s Cognitive Function and Ageing Study (MRC CFAS) demonstrates that nuclear retention of FOXO3a significantly correlates with a DNA damage response and with GS expression by astrocytes. Furthermore, we show that GS expression correlates with increasing Alzheimer-type pathology in this ageing cohort. Our findings suggest that in response to oxidative stress, the nuclear retention of FOXO3a in astrocytes upregulates expression of GS as a neuroprotective mechanism. However, the activity of GS may be compromised by increasing levels of oxidative stress in the ageing brain resulting in dysfunctional enzyme activity, neuronal excitotoxic damage and cognitive impairment. [ABSTRACT FROM AUTHOR]

This work presents the empirical study of a reciprocating compressor using Artificial Intelligence to model it. Several artificial neural networks were used to model three energy parameters of the compressor with high precision. The number of neurons in each ANN was optimized to use the minimum number of neurons without compromising accuracy; very few neurons were used when comparing with other works. Computer simulations show that the ANN model for the mass flow rate has the highest accuracy when compared with the models for the discharge temperature and power consumption. These simulations also illustrate that the ANN model for the discharge temperature presented the lowest accuracy. Using the ANN model, 3D plots were built to analyze the energy behavior of the compressor. [ABSTRACT FROM AUTHOR]

Noble gases are chemically inert elements, some of which exert biological activity. Experimental neuroprotection in particular has been widely shown for xenon, argon and helium. The underlying mechanisms of action are not yet fully understood. Besides an interference with neuronal ion-gated channels and cellular signaling pathways as well as anti-apoptotic effects, the modulation of neuroinflammation seems to play a crucial role. This review presents the current knowledge on neuroprotection by noble gases with a focus on interactions with the neuronal-glial network and neuroinflammation and the perspectives on clinical applications. [ABSTRACT FROM AUTHOR]

The Raman spectra of liposomes were measured under xenon pressures and low temperatures to observe the spectra changes accompanying the gel to liquid crystalline phase transition of the liposomes. C-H stretching bonds of the lipids in the liposome were slightly red shifted at approximately 285 K and atmospheric pressure, which coincided well with the phase transition condition. This Raman peak shift was observed at lower temperatures and related linearly to the xenon pressures. The xenon pressure dependence on the phase transition temperature was in good agreement with the DSC measurements, and the red shifts of Raman peaks supported the molecular mechanism of interaction between xenon and phospholipid bilayers suggested by the MD simulations. The phase transition measurements under xenon pressure with the microscopic Raman spectroscopy were applied to cultured neuronal networks to observe the interaction of dissolved xenon with the cell membrane and the surrounding water. [ABSTRACT FROM AUTHOR]

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Aims Population-based studies have shown that approximately 20% of the ageing population (aged 65 years and over) with dementia have little or no classical Alzheimer-type neuropathology. Cumulative DNA damage and a reduced capacity of DNA repair may result in neuronal dysfunction and contribute to cognitive impairment independent of Alzheimer-type pathology in the ageing brain. Methods We investigated expression of the DNA damage response ( DDR)-associated molecules γH2AX and DNA- PKcs using immunohistochemistry and western blotting, and senescence-associated β-galactosidase in the frontal association neocortex of cases with low levels of Alzheimer-type pathology ( Braak & Braak stage 0- II), and explored their relationship to cognitive impairment in a population-representative sample from the Medical Research Council's Cognitive Function and Ageing Study cohort. Results Increases in both γH2AX+ ( rs = −0.36, P = 0.025) and DNA- PKcs+ ( rs = −0.39, P = 0.01) neuronal counts were associated with a lower Mini- Mental State Examination score. Increasing levels of senescence associated-β-gal+ pyramidal neurones were weakly associated with the total number of DNA-PKcs+ neurones ( P = 0.08), but not with traditional senescence-associated signalling molecules, including p53 and p16. Conclusion The association between the neuronal DDR and cognitive impairment, independent of AD pathology in the ageing brain, may be suggestive of a causal link via neuronal dysfunction. [ABSTRACT FROM AUTHOR]