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Sample records for delayed neuron damage

  1. Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

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    Haelewyn Benoit

    2011-04-01

    Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

  2. Spiking Activity of a LIF Neuron in Distributed Delay Framework

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    Saket Kumar Choudhary

    2016-06-01

    Full Text Available Evolution of membrane potential and spiking activity for a single leaky integrate-and-fire (LIF neuron in distributed delay framework (DDF is investigated. DDF provides a mechanism to incorporate memory element in terms of delay (kernel function into a single neuron models. This investigation includes LIF neuron model with two different kinds of delay kernel functions, namely, gamma distributed delay kernel function and hypo-exponential distributed delay kernel function. Evolution of membrane potential for considered models is studied in terms of stationary state probability distribution (SPD. Stationary state probability distribution of membrane potential (SPDV for considered neuron models are found asymptotically similar which is Gaussian distributed. In order to investigate the effect of membrane potential delay, rate code scheme for neuronal information processing is applied. Firing rate and Fano-factor for considered neuron models are calculated and standard LIF model is used for comparative study. It is noticed that distributed delay increases the spiking activity of a neuron. Increase in spiking activity of neuron in DDF is larger for hypo-exponential distributed delay function than gamma distributed delay function. Moreover, in case of hypo-exponential delay function, a LIF neuron generates spikes with Fano-factor less than 1.

  3. Delayed chromosomal instability induced by DNA damage

    International Nuclear Information System (INIS)

    Morgan, W.F.; Marder, B.A.; Day, J.P.

    1994-01-01

    Cellular exposure to DNA damaging agents rapidly results in a dose dependent increase in chromosomal breakage and gross structural chromosomal rearrangements. Over recent years, evidence has been accumulating indicating genomic instability can manifest multiple generations after cellular exposure to physical and chemical DNA damaging agents. Genomic instability manifests in the progeny of surviving cells, and has been implicated in mutation, gene application, cellular transformation, and cell killing. To investigate chromosome instability following DNA damage, we have used fluorescence in situ hybridization to detect chromosomal rearrangements in a human/hamster somatic hybrid cell line following exposure to ionizing radiation. Delayed chromosomal instability was detected when multiple populations of uniquely arranged metaphases were observed in clonal isolates raised from single cells surviving X-irradiation many generations after exposure. At higher radiation doses, chromosomal instability was observed in a relatively high frequency of surviving clones and, in general, those clones showed delayed chromosome instability also showed reduced survival as measured by colony forming ability

  4. Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury

    International Nuclear Information System (INIS)

    Li, Yonggang; Lein, Pamela J.; Liu, Cuimei; Bruun, Donald A.; Giulivi, Cecilia; Ford, Gregory D.; Tewolde, Teclemichael; Ross-Inta, Catherine; Ford, Byron D.

    2012-01-01

    Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylflurophosphate (DFP). Adult male Sprague–Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. -- Highlights: ► NRG-1 blocked DFP induced neuronal injury. ► NRG-1 did not protect against seizures in rats exposed to DFP. ► NRG-1 blocked apoptosis and oxidative stress in the brains of DFP-intoxicated rats. ► Administration of NRG-1 at 1 h after DFP injection prevented delayed neuronal injury.

  5. Computational Stimulation of the Basal Ganglia Neurons with Cost Effective Delayed Gaussian Waveforms.

    Science.gov (United States)

    Daneshzand, Mohammad; Faezipour, Miad; Barkana, Buket D

    2017-01-01

    Deep brain stimulation (DBS) has compelling results in the desynchronization of the basal ganglia neuronal activities and thus, is used in treating the motor symptoms of Parkinson's disease (PD). Accurate definition of DBS waveform parameters could avert tissue or electrode damage, increase the neuronal activity and reduce energy cost which will prolong the battery life, hence avoiding device replacement surgeries. This study considers the use of a charge balanced Gaussian waveform pattern as a method to disrupt the firing patterns of neuronal cell activity. A computational model was created to simulate ganglia cells and their interactions with thalamic neurons. From the model, we investigated the effects of modified DBS pulse shapes and proposed a delay period between the cathodic and anodic parts of the charge balanced Gaussian waveform to desynchronize the firing patterns of the GPe and GPi cells. The results of the proposed Gaussian waveform with delay outperformed that of rectangular DBS waveforms used in in-vivo experiments. The Gaussian Delay Gaussian (GDG) waveforms achieved lower number of misses in eliciting action potential while having a lower amplitude and shorter length of delay compared to numerous different pulse shapes. The amount of energy consumed in the basal ganglia network due to GDG waveforms was dropped by 22% in comparison with charge balanced Gaussian waveforms without any delay between the cathodic and anodic parts and was also 60% lower than a rectangular charged balanced pulse with a delay between the cathodic and anodic parts of the waveform. Furthermore, by defining a Synchronization Level metric, we observed that the GDG waveform was able to reduce the synchronization of GPi neurons more effectively than any other waveform. The promising results of GDG waveforms in terms of eliciting action potential, desynchronization of the basal ganglia neurons and reduction of energy consumption can potentially enhance the performance of DBS

  6. Computational Stimulation of the Basal Ganglia Neurons with Cost Effective Delayed Gaussian Waveforms

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    Mohammad Daneshzand

    2017-08-01

    Full Text Available Deep brain stimulation (DBS has compelling results in the desynchronization of the basal ganglia neuronal activities and thus, is used in treating the motor symptoms of Parkinson's disease (PD. Accurate definition of DBS waveform parameters could avert tissue or electrode damage, increase the neuronal activity and reduce energy cost which will prolong the battery life, hence avoiding device replacement surgeries. This study considers the use of a charge balanced Gaussian waveform pattern as a method to disrupt the firing patterns of neuronal cell activity. A computational model was created to simulate ganglia cells and their interactions with thalamic neurons. From the model, we investigated the effects of modified DBS pulse shapes and proposed a delay period between the cathodic and anodic parts of the charge balanced Gaussian waveform to desynchronize the firing patterns of the GPe and GPi cells. The results of the proposed Gaussian waveform with delay outperformed that of rectangular DBS waveforms used in in-vivo experiments. The Gaussian Delay Gaussian (GDG waveforms achieved lower number of misses in eliciting action potential while having a lower amplitude and shorter length of delay compared to numerous different pulse shapes. The amount of energy consumed in the basal ganglia network due to GDG waveforms was dropped by 22% in comparison with charge balanced Gaussian waveforms without any delay between the cathodic and anodic parts and was also 60% lower than a rectangular charged balanced pulse with a delay between the cathodic and anodic parts of the waveform. Furthermore, by defining a Synchronization Level metric, we observed that the GDG waveform was able to reduce the synchronization of GPi neurons more effectively than any other waveform. The promising results of GDG waveforms in terms of eliciting action potential, desynchronization of the basal ganglia neurons and reduction of energy consumption can potentially enhance the

  7. Delay-dependent asymptotic stability of a two-neuron system with different time delays

    International Nuclear Information System (INIS)

    Tu Fenghua; Liao Xiaofeng; Zhang Wei

    2006-01-01

    In this paper, we consider a two-neuron system with time-delayed connections between neurons. Based on the construction of Lyapunov functionals, we obtain sufficient criteria to ensure local and global asymptotic stability of the equilibrium of the neural network. The obtained conditions are shown to be less conservative and restrictive than those reported in the literature. Some examples are included to illustrate our results

  8. Carbon monoxide-induced delayed amnesia, delayed neuronal death and change in acetylcholine concentration in mice

    International Nuclear Information System (INIS)

    Nabeshima, T.; Katoh, A.; Ishimaru, H.; Yoneda, Y.; Ogita, K.; Murase, K.; Ohtsuka, H.; Inari, K.; Fukuta, T.; Kameyama, T.

    1991-01-01

    We investigated the interrelationship of delayed amnesia, delayed neuronal death and changes in acetylcholine concentration induced by carbon monoxide (CO)-exposure in mice. In the test for retention of the passive avoidance task, amnesia was observed 5 and 7 days after CO-exposure when the mice were exposed to CO 1 day after training; in the case when the mice were exposed to CO 5 and 7 days before training, amnesia was also observed in a retention test given 1 day after training. The number of pyramidal cells in the hippocampal CA1 subfield was lower than that of the control 3, 5 and 7 days after CO-exposure. But the neurodegeneration in the parietal cortex, area 1, was not observed until 7 days after CO-exposure. The findings indicated that the amnesia and the neuronal death were produced after a delay when the mice were exposed to CO. In addition, the delayed amnesia was closely related to the delayed neuronal death in the hippocampal CA1 subfield. Moreover, [3H]glutamate and [3H]glycine binding sites did not change after CO-exposure but, 7 days after CO-exposure, the concentration of acetylcholine and the binding of [3H]quinuclidinyl benzilate in the frontal cortex and the striatum were found to have significantly changed, but those in the hippocampus did not show significant change. Therefore, we suggest that delayed amnesia induced by CO-exposure may result from delayed neuronal death in the hippocampal CA1 subfield and dysfunction in the acetylcholinergic neurons, in the frontal cortex, the striatum and/or the hippocampus

  9. Carbon monoxide-induced delayed amnesia, delayed neuronal death and change in acetylcholine concentration in mice

    Energy Technology Data Exchange (ETDEWEB)

    Nabeshima, T.; Katoh, A.; Ishimaru, H.; Yoneda, Y.; Ogita, K.; Murase, K.; Ohtsuka, H.; Inari, K.; Fukuta, T.; Kameyama, T. (Meijo Univ., Nagoya (Japan))

    1991-01-01

    We investigated the interrelationship of delayed amnesia, delayed neuronal death and changes in acetylcholine concentration induced by carbon monoxide (CO)-exposure in mice. In the test for retention of the passive avoidance task, amnesia was observed 5 and 7 days after CO-exposure when the mice were exposed to CO 1 day after training; in the case when the mice were exposed to CO 5 and 7 days before training, amnesia was also observed in a retention test given 1 day after training. The number of pyramidal cells in the hippocampal CA1 subfield was lower than that of the control 3, 5 and 7 days after CO-exposure. But the neurodegeneration in the parietal cortex, area 1, was not observed until 7 days after CO-exposure. The findings indicated that the amnesia and the neuronal death were produced after a delay when the mice were exposed to CO. In addition, the delayed amnesia was closely related to the delayed neuronal death in the hippocampal CA1 subfield. Moreover, (3H)glutamate and (3H)glycine binding sites did not change after CO-exposure but, 7 days after CO-exposure, the concentration of acetylcholine and the binding of (3H)quinuclidinyl benzilate in the frontal cortex and the striatum were found to have significantly changed, but those in the hippocampus did not show significant change. Therefore, we suggest that delayed amnesia induced by CO-exposure may result from delayed neuronal death in the hippocampal CA1 subfield and dysfunction in the acetylcholinergic neurons, in the frontal cortex, the striatum and/or the hippocampus.

  10. Electrical Activity in a Time-Delay Four-Variable Neuron Model under Electromagnetic Induction

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    Keming Tang

    2017-11-01

    Full Text Available To investigate the effect of electromagnetic induction on the electrical activity of neuron, the variable for magnetic flow is used to improve Hindmarsh–Rose neuron model. Simultaneously, due to the existence of time-delay when signals are propagated between neurons or even in one neuron, it is important to study the role of time-delay in regulating the electrical activity of the neuron. For this end, a four-variable neuron model is proposed to investigate the effects of electromagnetic induction and time-delay. Simulation results suggest that the proposed neuron model can show multiple modes of electrical activity, which is dependent on the time-delay and external forcing current. It means that suitable discharge mode can be obtained by selecting the time-delay or external forcing current, which could be helpful for further investigation of electromagnetic radiation on biological neuronal system.

  11. Phenolic antioxidants attenuate hippocampal neuronal cell damage ...

    Indian Academy of Sciences (India)

    Unknown

    CP had lower Fe3+ reducing activity in comparison to WS and AV. Plant extracts given singly ... modulators of nervous system damage. In epilepsy, ex- ..... D 1978 Antimicrobial agents from higher plants, Glycy- rrhiza glabra L. I. Some ...

  12. Climate Change : Behavioral Responses from Extreme Events and Delayed Damages

    NARCIS (Netherlands)

    Ghidoni, Riccardo; Calzolari, G.; Casari, Marco

    2017-01-01

    Understanding how to sustain cooperation in the climate change global dilemma is crucial to mitigate its harmful consequences. Damages from climate change typically occurs after long delays and can take the form of more frequent realizations of extreme and random events. These features generate a

  13. Climate change : Behavioral responses from extreme events and delayed damages

    NARCIS (Netherlands)

    Ghidoni, Riccardo; Calzolari, Giacomo; Casari, Marco

    2017-01-01

    Understanding how to sustain cooperation in the climate change global dilemma is crucial to mitigate its harmful consequences. Damages from climate change typically occur after long delays and can take the form of more frequent realizations of extreme and random events. These features generate a

  14. Damage of hippocampal neurons in rats with chronic alcoholism

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    Du, Ailin; Jiang, Hongbo; Xu, Lei; An, Na; Liu, Hui; Li, Yinsheng; Zhang, Ruiling

    2014-01-01

    Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons i...

  15. Hypoxic pretreatment protects against neuronal damage of the rat hippocampus induced by severe hypoxia.

    Science.gov (United States)

    Gorgias, N; Maidatsi, P; Tsolaki, M; Alvanou, A; Kiriazis, G; Kaidoglou, K; Giala, M

    1996-04-01

    The present study investigates whether under conditions of successive hypoxic exposures pretreatment with mild (15% O(2)) or moderate (10% O(2)) hypoxia, protects hippocampal neurones against damage induced by severe (3% O(2)) hypoxia. The ultrastructural findings were also correlated with regional superoxide dismutase (SOD) activity changes. In unpretreated rats severe hypoxia induced ultrastructural changes consistent with the aspects of delayed neuronal death (DND). However, in preexposed animals hippocampal damage was attenuated in an inversely proportional way with the severity of the hypoxic pretreatment. The ultrastructural hypoxic tolerance findings were also closely related to increased regional SOD activity levels. Thus the activation of the endogenous antioxidant defense by hypoxic preconditioning, protects against hippocampal damage induced by severe hypoxia. The eventual contribution of increased endogenous adenosine and/or reduced excitotoxicity to induce hypoxic tolerance is discussed.

  16. Necessary and sufficient conditions for Hopf bifurcation in tri-neuron equation with a delay

    International Nuclear Information System (INIS)

    Liu Xiaoming; Liao Xiaofeng

    2009-01-01

    In this paper, we consider the delayed differential equations modeling three-neuron equations with only a time delay. Using the time delay as a bifurcation parameter, necessary and sufficient conditions for Hopf bifurcation to occur are derived. Numerical results indicate that for this model, Hopf bifurcation is likely to occur at suitable delay parameter values.

  17. Heterogeneous delay-induced asynchrony and resonance in a small-world neuronal network system

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    Yu, Wen-Ting; Tang, Jun; Ma, Jun; Yang, Xianqing

    2016-06-01

    A neuronal network often involves time delay caused by the finite signal propagation time in a given biological network. This time delay is not a homogenous fluctuation in a biological system. The heterogeneous delay-induced asynchrony and resonance in a noisy small-world neuronal network system are numerically studied in this work by calculating synchronization measure and spike interval distribution. We focus on three different delay conditions: double-values delay, triple-values delay, and Gaussian-distributed delay. Our results show the following: 1) the heterogeneity in delay results in asynchronous firing in the neuronal network, and 2) maximum synchronization could be achieved through resonance given that the delay values are integer or half-integer times of each other.

  18. Relaxation Cycles in a Generalized Neuron Model with Two Delays

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    S. D. Glyzin

    2013-01-01

    Full Text Available A method of modeling the phenomenon of bursting behavior in neural systems based on delay equations is proposed. A singularly perturbed scalar nonlinear differentialdifference equation of Volterra type is a mathematical model of a neuron and a separate pulse containing one function without delay and two functions with different lags. It is established that this equation, for a suitable choice of parameters, has a stable periodic motion with any preassigned number of bursts in the time interval of the period length. To prove this assertion we first go to a relay-type equation and then determine the asymptotic solutions of a singularly perturbed equation. On the basis of this asymptotics the Poincare operator is constructed. The resulting operator carries a closed bounded convex set of initial conditions into itself, which suggests that it has at least one fixed point. The Frechet derivative evaluation of the succession operator, made in the paper, allows us to prove the uniqueness and stability of the resulting relax of the periodic solution.

  19. Determination of relevant neuron-neuron connections for neural prosthetics using time-delayed mutual information: tutorial and preliminary results.

    Science.gov (United States)

    Taghva, Alexander; Song, Dong; Hampson, Robert E; Deadwyler, Sam A; Berger, Theodore W

    2012-12-01

    Identification of functional dependence among neurons is a necessary component in both the rational design of neural prostheses as well as in the characterization of network physiology. The objective of this article is to provide a tutorial for neurosurgeons regarding information theory, specifically time-delayed mutual information, and to compare time-delayed mutual information, an information theoretic quantity based on statistical dependence, with cross-correlation, a commonly used metric for this task in a preliminary analysis of rat hippocampal neurons. Spike trains were recorded from rats performing delayed nonmatch-to-sample task using an array of electrodes surgically implanted into the hippocampus of each hemisphere of the brain. In addition, spike train simulations of positively correlated neurons, negatively correlated neurons, and neurons correlated by nonlinear functions were generated. These were evaluated by time-delayed mutual information (MI) and cross-correlation. Application of time-delayed MI to experimental data indicated the optimal bin size for information capture in the CA3-CA1 system was 40 ms, which may provide some insight into the spatiotemporal nature of encoding in the rat hippocampus. On simulated data, time-delayed MI showed peak values at appropriate time lags in positively correlated, negatively correlated, and complexly correlated data. Cross-correlation showed peak and troughs with positively correlated and negatively correlated data, but failed to capture some higher order correlations. Comparison of time-delayed MI to cross-correlation in identification of functionally dependent neurons indicates that the methods are not equivalent. Time-delayed MI appeared to capture some interactions between CA3-CA1 neurons at physiologically plausible time delays missed by cross-correlation. It should be considered as a method for identification of functional dependence between neurons and may be useful in the development of neural

  20. Motor impairment and neuronal damage following hypothermia in tropical amphibians.

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    Daló, Nelson L; Bracho, Gustavo A; Piña-Crespo, Juan C

    2007-02-01

    Although the induction of mild to moderate cerebral hypothermia in mammals can have neuroprotective activity, some deleterious effects have been described when inducing deep hypothermia during cooling of the brain. In the spinal cord, rapid deep cooling can induce seizure activity accompanied by release of the excitatory neurotransmitters, glutamate and aspartate. We used cold-sensitive tropical amphibians as a model to determine (a) the critical temperature inside the central nervous system necessary to induce seizures during rapid cooling; (b) the survival rate during slow deep cooling of the whole animal; and (c) whether deep cooling can cause neuronal cell damage. Seizures induced by deep rapid (or=30 min) deep cooling of the whole animal (12 h at 2-3 degrees C), around 70% of animals died. Spinal reflexes were enhanced when temperatures within the spinal cord reached between 9.0 degrees C and 11.6 degrees C. A fivefold increase in blood glucose level was observed during slow deep cooling. Recovery after slow deep cooling was accompanied by motor impairment and the main histological findings were condensation of the cytoplasm and nuclear pyknosis. Severe neuronal cell damage was characterized by swelling, vacuolated cytoplasm with distended neuronal bodies. These results indicate that deep cooling can easily induce neuronal cell damage in the central nervous system of cold-sensitive animals. They also warn us to the potential sequels associated with the use of deep brain cooling as a neuroprotective strategy.

  1. Delay-enhanced coherence of spiral waves in noisy Hodgkin-Huxley neuronal networks

    International Nuclear Information System (INIS)

    Wang Qingyun; Perc, Matjaz; Duan Zhisheng; Chen Guanrong

    2008-01-01

    We study the spatial dynamics of spiral waves in noisy Hodgkin-Huxley neuronal ensembles evoked by different information transmission delays and network topologies. In classical settings of coherence resonance the intensity of noise is fine-tuned so as to optimize the system's response. Here, we keep the noise intensity constant, and instead, vary the length of information transmission delay amongst coupled neurons. We show that there exists an intermediate transmission delay by which the spiral waves are optimally ordered, hence indicating the existence of delay-enhanced coherence of spatial dynamics in the examined system. Additionally, we examine the robustness of this phenomenon as the diffusive interaction topology changes towards the small-world type, and discover that shortcut links amongst distant neurons hinder the emergence of coherent spiral waves irrespective of transmission delay length. Presented results thus provide insights that could facilitate the understanding of information transmission delay on realistic neuronal networks

  2. An electronic implementation for Liao's chaotic delayed neuron model with non-monotonous activation function

    International Nuclear Information System (INIS)

    Duan Shukai; Liao Xiaofeng

    2007-01-01

    A new chaotic delayed neuron model with non-monotonously increasing transfer function, called as chaotic Liao's delayed neuron model, was recently reported and analyzed. An electronic implementation of this model is described in detail. At the same time, some methods in circuit design, especially for circuit with time delayed unit and non-monotonously increasing activation unit, are also considered carefully. We find that the dynamical behaviors of the designed circuits are closely similar to the results predicted by numerical experiments

  3. Neuronal Rat Brain Damage Caused by Endogenous and Exogenous Hyperthermia

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    Mustafa Aydın

    2012-03-01

    Full Text Available OBJECTIVE: Hyperthermia may induce pathologic alterations within body systems and organs including brain. In this study, neuronal effects of endogenous and exogenous hyperthermia (41°C were studied in rats. METHODS: The endogenous hyperthermia (41°C was induced by lipopolysaccharide and the exogenous by an (electric heater. Possible neuronal damage was evaluated by examining healthy, apoptotic and necrotic cells, and heat shock proteins (HSP 27, HSP 70 in the cerebral cortex, cerebellum and hypothalamus RESULTS: At cellular level, when all neuronal tissues are taken into account; (i a significant increase in the necrotic cells was observed in the both groups (p0.05. CONCLUSION: The neural tissue of brain can show different degree of response to hyperthermia. But we can conclude that endogenous hyperthermia is more harmful to central nervous system than exogenous hyperthermia

  4. Damage of hippocampal neurons in rats with chronic alcoholism.

    Science.gov (United States)

    Du, Ailin; Jiang, Hongbo; Xu, Lei; An, Na; Liu, Hui; Li, Yinsheng; Zhang, Ruiling

    2014-09-01

    Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear membrane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin.

  5. Stability switches, Hopf bifurcation and chaos of a neuron model with delay-dependent parameters

    International Nuclear Information System (INIS)

    Xu, X.; Hu, H.Y.; Wang, H.L.

    2006-01-01

    It is very common that neural network systems usually involve time delays since the transmission of information between neurons is not instantaneous. Because memory intensity of the biological neuron usually depends on time history, some of the parameters may be delay dependent. Yet, little attention has been paid to the dynamics of such systems. In this Letter, a detailed analysis on the stability switches, Hopf bifurcation and chaos of a neuron model with delay-dependent parameters is given. Moreover, the direction and the stability of the bifurcating periodic solutions are obtained by the normal form theory and the center manifold theorem. It shows that the dynamics of the neuron model with delay-dependent parameters is quite different from that of systems with delay-independent parameters only

  6. Glial degeneration with oxidative damage drives neuronal demise in MPSII disease.

    Science.gov (United States)

    Zalfa, Cristina; Verpelli, Chiara; D'Avanzo, Francesca; Tomanin, Rosella; Vicidomini, Cinzia; Cajola, Laura; Manara, Renzo; Sala, Carlo; Scarpa, Maurizio; Vescovi, Angelo Luigi; De Filippis, Lidia

    2016-08-11

    Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression.

  7. Effects of partial time delays on phase synchronization in Watts-Strogatz small-world neuronal networks

    Science.gov (United States)

    Sun, Xiaojuan; Perc, Matjaž; Kurths, Jürgen

    2017-05-01

    In this paper, we study effects of partial time delays on phase synchronization in Watts-Strogatz small-world neuronal networks. Our focus is on the impact of two parameters, namely the time delay τ and the probability of partial time delay pdelay, whereby the latter determines the probability with which a connection between two neurons is delayed. Our research reveals that partial time delays significantly affect phase synchronization in this system. In particular, partial time delays can either enhance or decrease phase synchronization and induce synchronization transitions with changes in the mean firing rate of neurons, as well as induce switching between synchronized neurons with period-1 firing to synchronized neurons with period-2 firing. Moreover, in comparison to a neuronal network where all connections are delayed, we show that small partial time delay probabilities have especially different influences on phase synchronization of neuronal networks.

  8. Ordering chaos and synchronization transitions by chemical delay and coupling on scale-free neuronal networks

    International Nuclear Information System (INIS)

    Gong Yubing; Xie Yanhang; Lin Xiu; Hao Yinghang; Ma Xiaoguang

    2010-01-01

    Research highlights: → Chemical delay and chemical coupling can tame chaotic bursting. → Chemical delay-induced transitions from bursting synchronization to intermittent multiple spiking synchronizations. → Chemical coupling-induced different types of delay-dependent firing transitions. - Abstract: Chemical synaptic connections are more common than electric ones in neurons, and information transmission delay is especially significant for the synapses of chemical type. In this paper, we report a phenomenon of ordering spatiotemporal chaos and synchronization transitions by the delays and coupling through chemical synapses of modified Hodgkin-Huxley (MHH) neurons on scale-free networks. As the delay τ is increased, the neurons exhibit transitions from bursting synchronization (BS) to intermittent multiple spiking synchronizations (SS). As the coupling g syn is increased, the neurons exhibit different types of firing transitions, depending on the values of τ. For a smaller τ, there are transitions from spatiotemporal chaotic bursting (SCB) to BS or SS; while for a larger τ, there are transitions from SCB to intermittent multiple SS. These findings show that the delays and coupling through chemical synapses can tame the chaotic firings and repeatedly enhance the firing synchronization of neurons, and hence could play important roles in the firing activity of the neurons on scale-free networks.

  9. Delay-induced diversity of firing behavior and ordered chaotic firing in adaptive neuronal networks

    International Nuclear Information System (INIS)

    Gong Yubing; Wang Li; Xu Bo

    2012-01-01

    In this paper, we study the effect of time delay on the firing behavior and temporal coherence and synchronization in Newman–Watts thermosensitive neuron networks with adaptive coupling. At beginning, the firing exhibit disordered spiking in absence of time delay. As time delay is increased, the neurons exhibit diversity of firing behaviors including bursting with multiple spikes in a burst, spiking, bursting with four, three and two spikes, firing death, and bursting with increasing amplitude. The spiking is the most ordered, exhibiting coherence resonance (CR)-like behavior, and the firing synchronization becomes enhanced with the increase of time delay. As growth rate of coupling strength or network randomness increases, CR-like behavior shifts to smaller time delay and the synchronization of firing increases. These results show that time delay can induce diversity of firing behaviors in adaptive neuronal networks, and can order the chaotic firing by enhancing and optimizing the temporal coherence and enhancing the synchronization of firing. However, the phenomenon of firing death shows that time delay may inhibit the firing of adaptive neuronal networks. These findings provide new insight into the role of time delay in the firing activity of adaptive neuronal networks, and can help to better understand the complex firing phenomena in neural networks.

  10. Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration.

    Science.gov (United States)

    Romero, Juan Ignacio; Holubiec, Mariana Inés; Tornatore, Tamara Logica; Rivière, Stéphanie; Hanschmann, Eva-Maria; Kölliker-Frers, Rodolfo Alberto; Tau, Julia; Blanco, Eduardo; Galeano, Pablo; Rodríguez de Fonseca, Fernando; Lillig, Christopher Horst; Capani, Francisco

    2017-01-01

    The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

  11. Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration

    Directory of Open Access Journals (Sweden)

    Juan Ignacio Romero

    2017-01-01

    Full Text Available The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

  12. A novel perspective on neuron study: damaging and promoting effects in different neurons induced by mechanical stress.

    Science.gov (United States)

    Wang, Yazhou; Wang, Wei; Li, Zong; Hao, Shilei; Wang, Bochu

    2016-10-01

    A growing volume of experimental evidence demonstrates that mechanical stress plays a significant role in growth, proliferation, apoptosis, gene expression, electrophysiological properties and many other aspects of neurons. In this review, first, the mechanical microenvironment and properties of neurons under in vivo conditions are introduced and analyzed. Second, research works in recent decades on the effects of different mechanical forces, especially compression and tension, on various neurons, including dorsal root ganglion neurons, retinal ganglion cells, cerebral cortex neurons, hippocampus neurons, neural stem cells, and other neurons, are summarized. Previous research results demonstrate that mechanical stress can not only injure neurons by damaging their morphology, impacting their electrophysiological characteristics and gene expression, but also promote neuron self-repair. Finally, some future perspectives in neuron research are discussed.

  13. Chaos and its synchronization in two-neuron systems with discrete delays

    International Nuclear Information System (INIS)

    Zhou Shangbo; Liao Xiaofeng; Yu Juebang; Wong Kwokwo

    2004-01-01

    It is well known that complex dynamic behaviors exist in time-delayed neural systems. Infinite positive Lyapunov exponents can be found in time-delayed chaotic systems since the dimension of such systems is infinite. However, theoretical and experimental models studied thus far are low dimensional systems with only one positive Lyapunov exponent. Consequently, messages masked by such chaotic systems are shown to be easily extracted in some cases. Therefore, communication system with a higher security level can be design by means of the time-delayed neuron systems. In this paper, we firstly investigate the dynamical behaviors of two-neuron systems with discrete delays. Then, the chaos synchronization in time-delayed neuron system is studied based on the method of designing the coupled system and employing Krasovskii-Lyapunov theory to search the synchronization conditions. Numerical results illustrate the correctness of our theoretical analyses

  14. Synchronization of map-based neurons with memory and synaptic delay

    Energy Technology Data Exchange (ETDEWEB)

    Sausedo-Solorio, J.M. [Universidad Autónoma del Estado de Hidalgo, Carretera Pachuca-Tulancingo Km. 4.5, 42074 Pachuca, Hidalgo (Mexico); Pisarchik, A.N., E-mail: apisarch@cio.mx [Centro de Investigaciones en Optica, Loma del Bosque 115, Lomas del Campestre, 37150 Leon, Guanajuato (Mexico); Centre for Biomedical Technology, Technical University of Madrid, Campus Montegancedo, 28223 Pozuelo de Alarcon, Madrid (Spain)

    2014-06-13

    Synchronization of two synaptically coupled neurons with memory and synaptic delay is studied using the Rulkov map, one of the simplest neuron models which displays specific features inherent to bursting dynamics. We demonstrate a transition from lag to anticipated synchronization as the relationship between the memory duration and the synaptic delay time changes. The neuron maps synchronize either with anticipation, if the memory is longer than the synaptic delay time, or with lag otherwise. The mean anticipation time is equal to the difference between the memory and synaptic delay independently of the coupling strength. Frequency entrainment and phase-locking phenomena as well as a transition from regular spikes to chaos are demonstrated with respect to the coupling strength. - Highlights: • We study synchronization of neurons with memory and synaptic delay in the map model. • Neurons synchronize either with anticipation or with lag depending on delay time. • Mean anticipation time is equal to the difference between memory and synaptic delay. • Frequency entrainment and phase locking are studied with respect to the coupling.

  15. Dynamics of Time Delay-Induced Multiple Synchronous Behaviors in Inhibitory Coupled Neurons

    Science.gov (United States)

    Gu, Huaguang; Zhao, Zhiguo

    2015-01-01

    The inhibitory synapse can induce synchronous behaviors different from the anti-phase synchronous behaviors, which have been reported in recent studies. In the present paper, synchronous behaviors are investigated in the motif model composed of reciprocal inhibitory coupled neurons with endogenous bursting and time delay. When coupling strength is weak, synchronous behavior appears at a single interval of time delay within a bursting period. When coupling strength is strong, multiple synchronous behaviors appear at different intervals of time delay within a bursting period. The different bursting patterns of synchronous behaviors, and time delays and coupling strengths that can induce the synchronous bursting patterns can be well interpreted by the dynamics of the endogenous bursting pattern of isolated neuron, which is acquired by the fast-slow dissection method, combined with the inhibitory coupling current. For an isolated neuron, when a negative impulsive current with suitable strength is applied at different phases of the bursting, multiple different bursting patterns can be induced. For a neuron in the motif, the inhibitory coupling current, of which the application time and strength is modulated by time delay and coupling strength, can cause single or multiple synchronous firing patterns like the negative impulsive current when time delay and coupling strength is suitable. The difference compared to the previously reported multiple synchronous behaviors that appear at time delays wider than a period of the endogenous firing is discussed. The results present novel examples of synchronous behaviors in the neuronal network with inhibitory synapses and provide a reasonable explanation. PMID:26394224

  16. Diapause formation and downregulation of insulin-like signaling via DAF-16/FOXO delays axonal degeneration and neuronal loss.

    Directory of Open Access Journals (Sweden)

    Andrea Calixto

    Full Text Available Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS pathway protects neurons from degenerating in a DAF-16/FOXO-dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment.

  17. Delay-active damage versus non-local enhancement for anisotropic damage dynamics computations with alternated loading

    International Nuclear Information System (INIS)

    Desmorat, R.; Chambart, M.; Gatuingt, F.; Guilbaud, D.

    2010-01-01

    Anisotropic damage thermodynamics framework allows to model the concrete-like materials behavior and in particular their dissymmetric tension/compression response. To deal with dynamics applications such as impact, it is furthermore necessary to take into account the strain rate effect observed experimentally. This is done in the present work by means of anisotropic visco-damage, by introducing a material strain rate effect in the cases of positive hydrostatic stresses only. The proposed delay-damage law assumes no viscous effect in compression as the consideration of inertia effects proves sufficient to model the apparent material strength increase. High-rate dynamics applications imply to deal with wave propagation and reflection which can generate alternated loading in the impacted structure. In order to do so, the key concept of active damage is defined and introduced within both the damage criterion and the delay-damage evolution law. At the structural level, strain localization often leads to spurious mesh dependency. Three-dimensional Finite Element computations of dynamic tensile tests by spalling are presented, with visco-damage and either without or with non-local enhancement. Delay-damage, as introduced, regularizes the solution in fast dynamics. The location of the macro-crack initiated is found influenced by non-local regularization. The strain rate range in which each enhancement, delay-damage or non-local enhancement, has a regularizing effect is studied. (authors)

  18. Impact of Partial Time Delay on Temporal Dynamics of Watts-Strogatz Small-World Neuronal Networks

    Science.gov (United States)

    Yan, Hao; Sun, Xiaojuan

    2017-06-01

    In this paper, we mainly discuss effects of partial time delay on temporal dynamics of Watts-Strogatz (WS) small-world neuronal networks by controlling two parameters. One is the time delay τ and the other is the probability of partial time delay pdelay. Temporal dynamics of WS small-world neuronal networks are discussed with the aid of temporal coherence and mean firing rate. With the obtained simulation results, it is revealed that for small time delay τ, the probability pdelay could weaken temporal coherence and increase mean firing rate of neuronal networks, which indicates that it could improve neuronal firings of the neuronal networks while destroying firing regularity. For large time delay τ, temporal coherence and mean firing rate do not have great changes with respect to pdelay. Time delay τ always has great influence on both temporal coherence and mean firing rate no matter what is the value of pdelay. Moreover, with the analysis of spike trains and histograms of interspike intervals of neurons inside neuronal networks, it is found that the effects of partial time delays on temporal coherence and mean firing rate could be the result of locking between the period of neuronal firing activities and the value of time delay τ. In brief, partial time delay could have great influence on temporal dynamics of the neuronal networks.

  19. From Quasiperiodic Partial Synchronization to Collective Chaos in Populations of Inhibitory Neurons with Delay.

    Science.gov (United States)

    Pazó, Diego; Montbrió, Ernest

    2016-06-10

    Collective chaos is shown to emerge, via a period-doubling cascade, from quasiperiodic partial synchronization in a population of identical inhibitory neurons with delayed global coupling. This system is thoroughly investigated by means of an exact model of the macroscopic dynamics, valid in the thermodynamic limit. The collective chaotic state is reproduced numerically with a finite population, and persists in the presence of weak heterogeneities. Finally, the relationship of the model's dynamics with fast neuronal oscillations is discussed.

  20. Delayed rectifier potassium channels are involved in SO2 derivative-induced hippocampal neuronal injury.

    Science.gov (United States)

    Li, Guangke; Sang, Nan

    2009-01-01

    Recent studies implicate the possible neurotoxicity of SO(2), however, its mechanisms remain unclear. In the present study, we investigated SO(2) derivative-induced effect on delayed rectifier potassium channels (I(K)) and cellular death/apoptosis in primary cultured hippocampal neurons. The results demonstrate that SO(2) derivatives (NaHSO(3) and Na(2)SO(3), 3:1M/M) effectively augmented I(K) and promoted the activation of delayed rectifier potassium channels. Also, SO(2) derivatives increased neuronal death percentage and contributed to the formation of DNA ladder in concentration-dependent manners. Interestingly, the neuronal death and DNA ladder formation, caused by SO(2) derivatives, could be attenuated by the delayed rectifier potassium channel blocker (tetraethylammonium, TEA), but not by the transient outward potassium channel blocker (4-aminopyridine, 4-AP). It implies that stimulating delayed rectifier potassium channels were involved in SO(2) derivative-caused hippocampal neuronal insults, and blocking these channels might be one of the possibly clinical treatment for SO(2)-caused neuronal dysfunction.

  1. Hopf bifurcation of an (n + 1) -neuron bidirectional associative memory neural network model with delays.

    Science.gov (United States)

    Xiao, Min; Zheng, Wei Xing; Cao, Jinde

    2013-01-01

    Recent studies on Hopf bifurcations of neural networks with delays are confined to simplified neural network models consisting of only two, three, four, five, or six neurons. It is well known that neural networks are complex and large-scale nonlinear dynamical systems, so the dynamics of the delayed neural networks are very rich and complicated. Although discussing the dynamics of networks with a few neurons may help us to understand large-scale networks, there are inevitably some complicated problems that may be overlooked if simplified networks are carried over to large-scale networks. In this paper, a general delayed bidirectional associative memory neural network model with n + 1 neurons is considered. By analyzing the associated characteristic equation, the local stability of the trivial steady state is examined, and then the existence of the Hopf bifurcation at the trivial steady state is established. By applying the normal form theory and the center manifold reduction, explicit formulae are derived to determine the direction and stability of the bifurcating periodic solution. Furthermore, the paper highlights situations where the Hopf bifurcations are particularly critical, in the sense that the amplitude and the period of oscillations are very sensitive to errors due to tolerances in the implementation of neuron interconnections. It is shown that the sensitivity is crucially dependent on the delay and also significantly influenced by the feature of the number of neurons. Numerical simulations are carried out to illustrate the main results.

  2. Role of Delays in Shaping Spatiotemporal Dynamics of Neuronal Activity in Large Networks

    International Nuclear Information System (INIS)

    Roxin, Alex; Brunel, Nicolas; Hansel, David

    2005-01-01

    We study the effect of delays on the dynamics of large networks of neurons. We show that delays give rise to a wealth of bifurcations and to a rich phase diagram, which includes oscillatory bumps, traveling waves, lurching waves, standing waves arising via a period-doubling bifurcation, aperiodic regimes, and regimes of multistability. We study the existence and the stability of the various dynamical patterns analytically and numerically in a simplified rate model as a function of the interaction parameters. The results derived in that framework allow us to understand the origin of the diversity of dynamical states observed in large networks of spiking neurons

  3. Convergent input from brainstem coincidence detectors onto delay-sensitive neurons in the inferior colliculus.

    Science.gov (United States)

    McAlpine, D; Jiang, D; Shackleton, T M; Palmer, A R

    1998-08-01

    Responses of low-frequency neurons in the inferior colliculus (IC) of anesthetized guinea pigs were studied with binaural beats to assess their mean best interaural phase (BP) to a range of stimulating frequencies. Phase plots (stimulating frequency vs BP) were produced, from which measures of characteristic delay (CD) and characteristic phase (CP) for each neuron were obtained. The CD provides an estimate of the difference in travel time from each ear to coincidence-detector neurons in the brainstem. The CP indicates the mechanism underpinning the coincidence detector responses. A linear phase plot indicates a single, constant delay between the coincidence-detector inputs from the two ears. In more than half (54 of 90) of the neurons, the phase plot was not linear. We hypothesized that neurons with nonlinear phase plots received convergent input from brainstem coincidence detectors with different CDs. Presentation of a second tone with a fixed, unfavorable delay suppressed the response of one input, linearizing the phase plot and revealing other inputs to be relatively simple coincidence detectors. For some neurons with highly complex phase plots, the suppressor tone altered BP values, but did not resolve the nature of the inputs. For neurons with linear phase plots, the suppressor tone either completely abolished their responses or reduced their discharge rate with no change in BP. By selectively suppressing inputs with a second tone, we are able to reveal the nature of underlying binaural inputs to IC neurons, confirming the hypothesis that the complex phase plots of many IC neurons are a result of convergence from simple brainstem coincidence detectors.

  4. Differential transcriptional profiling of damaged and intact adjacent dorsal root ganglia neurons in neuropathic pain.

    Directory of Open Access Journals (Sweden)

    A K Reinhold

    Full Text Available Neuropathic pain, caused by a lesion in the somatosensory system, is a severely impairing mostly chronic disease. While its underlying molecular mechanisms are not thoroughly understood, neuroimmune interactions as well as changes in the pain pathway such as sensitization of nociceptors have been implicated. It has been shown that not only are different cell types involved in generation and maintenance of neuropathic pain, like neurons, immune and glial cells, but, also, intact adjacent neurons are relevant to the process. Here, we describe an experimental approach to discriminate damaged from intact adjacent neurons in the same dorsal root ganglion (DRG using differential fluorescent neuronal labelling and fluorescence-activated cell sorting (FACS. Two fluorescent tracers, Fluoroemerald (FE and 1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI, were used, whose properties allow us to distinguish between damaged and intact neurons. Subsequent sorting permitted transcriptional analysis of both groups. Results and qPCR validation show a strong regulation in damaged neurons versus contralateral controls as well as a moderate regulation in adjacent neurons. Data for damaged neurons reveal an mRNA expression pattern consistent with established upregulated genes like galanin, which supports our approach. Moreover, novel genes were found strongly regulated such as corticotropin-releasing hormone (CRH, providing novel targets for further research. Differential fluorescent neuronal labelling and sorting allows for a clear distinction between primarily damaged neuropathic neurons and "bystanders," thereby facilitating a more detailed understanding of their respective roles in neuropathic processes in the DRG.

  5. Phase-coherence transitions and communication in the gamma range between delay-coupled neuronal populations.

    Directory of Open Access Journals (Sweden)

    Alessandro Barardi

    2014-07-01

    Full Text Available Synchronization between neuronal populations plays an important role in information transmission between brain areas. In particular, collective oscillations emerging from the synchronized activity of thousands of neurons can increase the functional connectivity between neural assemblies by coherently coordinating their phases. This synchrony of neuronal activity can take place within a cortical patch or between different cortical regions. While short-range interactions between neurons involve just a few milliseconds, communication through long-range projections between different regions could take up to tens of milliseconds. How these heterogeneous transmission delays affect communication between neuronal populations is not well known. To address this question, we have studied the dynamics of two bidirectionally delayed-coupled neuronal populations using conductance-based spiking models, examining how different synaptic delays give rise to in-phase/anti-phase transitions at particular frequencies within the gamma range, and how this behavior is related to the phase coherence between the two populations at different frequencies. We have used spectral analysis and information theory to quantify the information exchanged between the two networks. For different transmission delays between the two coupled populations, we analyze how the local field potential and multi-unit activity calculated from one population convey information in response to a set of external inputs applied to the other population. The results confirm that zero-lag synchronization maximizes information transmission, although out-of-phase synchronization allows for efficient communication provided the coupling delay, the phase lag between the populations, and the frequency of the oscillations are properly matched.

  6. Optimal autaptic and synaptic delays enhanced synchronization transitions induced by each other in Newman–Watts neuronal networks

    International Nuclear Information System (INIS)

    Wang, Baoying; Gong, Yubing; Xie, Huijuan; Wang, Qi

    2016-01-01

    Highlights: • Optimal autaptic delay enhanced synchronization transitions induced by synaptic delay in neuronal networks. • Optimal synaptic delay enhanced synchronization transitions induced by autaptic delay. • Optimal coupling strength enhanced synchronization transitions induced by autaptic or synaptic delay. - Abstract: In this paper, we numerically study the effect of electrical autaptic and synaptic delays on synchronization transitions induced by each other in Newman–Watts Hodgkin–Huxley neuronal networks. It is found that the synchronization transitions induced by synaptic delay vary with varying autaptic delay and become strongest when autaptic delay is optimal. Similarly, the synchronization transitions induced by autaptic delay vary with varying synaptic delay and become strongest at optimal synaptic delay. Also, there is optimal coupling strength by which the synchronization transitions induced by either synaptic or autaptic delay become strongest. These results show that electrical autaptic and synaptic delays can enhance synchronization transitions induced by each other in the neuronal networks. This implies that electrical autaptic and synaptic delays can cooperate with each other and more efficiently regulate the synchrony state of the neuronal networks. These findings could find potential implications for the information transmission in neural systems.

  7. Robust Synchronization of Delayed Chaotic FitzHugh-Nagumo Neurons under External Electrical Stimulation

    Directory of Open Access Journals (Sweden)

    Muhammad Rehan

    2012-01-01

    Full Text Available Synchronization of chaotic neurons under external electrical stimulation (EES is studied in order to understand information processing in the brain and to improve the methodologies employed in the treatment of cognitive diseases. This paper investigates the dynamics of uncertain coupled chaotic delayed FitzHugh-Nagumo (FHN neurons under EES for incorporated parametric variations. A global nonlinear control law for synchronization of delayed neurons with known parameters is developed. Based on local and global Lipschitz conditions, knowledge of the bounds on the neuronal states, the Lyapunov-Krasovskii functional, and the L2 gain reduction, a less conservative local robust nonlinear control law is formulated to address the problem of robust asymptotic synchronization of delayed FHN neurons under parametric uncertainties. The proposed local control law guarantees both robust stability and robust performance and provides the L2 bound for uncertainty rejection in the synchronization error dynamics. Separate conditions for single-input and multiple-input control schemes for synchronization of a wide class of FHN systems are provided. The results of the proposed techniques are verified through numerical simulations.

  8. Impact of delays on the synchronization transitions of modular neuronal networks with hybrid synapses

    Science.gov (United States)

    Liu, Chen; Wang, Jiang; Yu, Haitao; Deng, Bin; Wei, Xile; Tsang, Kaiming; Chan, Wailok

    2013-09-01

    The combined effects of the information transmission delay and the ratio of the electrical and chemical synapses on the synchronization transitions in the hybrid modular neuronal network are investigated in this paper. Numerical results show that the synchronization of neuron activities can be either promoted or destroyed as the information transmission delay increases, irrespective of the probability of electrical synapses in the hybrid-synaptic network. Interestingly, when the number of the electrical synapses exceeds a certain level, further increasing its proportion can obviously enhance the spatiotemporal synchronization transitions. Moreover, the coupling strength has a significant effect on the synchronization transition. The dominated type of the synapse always has a more profound effect on the emergency of the synchronous behaviors. Furthermore, the results of the modular neuronal network structures demonstrate that excessive partitioning of the modular network may result in the dramatic detriment of neuronal synchronization. Considering that information transmission delays are inevitable in intra- and inter-neuronal networks communication, the obtained results may have important implications for the exploration of the synchronization mechanism underlying several neural system diseases such as Parkinson's Disease.

  9. Oxidative DNA Damage in Neurons: Implication of Ku in Neuronal Homeostasis and Survival

    Directory of Open Access Journals (Sweden)

    Daniela De Zio

    2012-01-01

    Full Text Available Oxidative DNA damage is produced by reactive oxygen species (ROS which are generated by exogenous and endogenous sources and continuously challenge the cell. One of the most severe DNA lesions is the double-strand break (DSB, which is mainly repaired by nonhomologous end joining (NHEJ pathway in mammals. NHEJ directly joins the broken ends, without using the homologous template. Ku70/86 heterodimer, also known as Ku, is the first component of NHEJ as it directly binds DNA and recruits other NHEJ factors to promote the repair of the broken ends. Neurons are particularly metabolically active, displaying high rates of transcription and translation, which are associated with high metabolic and mitochondrial activity as well as oxygen consumption. In such a way, excessive oxygen radicals can be generated and constantly attack DNA, thereby producing several lesions. This condition, together with defective DNA repair systems, can lead to a high accumulation of DNA damage resulting in neurodegenerative processes and defects in neurodevelopment. In light of recent findings, in this paper, we will discuss the possible implication of Ku in neurodevelopment and in mediating the DNA repair dysfunction observed in certain neurodegenerations.

  10. DNA damage preceding dopamine neuron degeneration in A53T human α-synuclein transgenic mice

    International Nuclear Information System (INIS)

    Wang, Degui; Yu, Tianyu; Liu, Yongqiang; Yan, Jun; Guo, Yingli; Jing, Yuhong; Yang, Xuguang; Song, Yanfeng; Tian, Yingxia

    2016-01-01

    Defective DNA repair has been linked with age-associated neurodegenerative disorders. Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Whether damages to nuclear DNA contribute to neurodegeneration of PD still remain obscure. in this study we aim to explore whether nuclear DNA damage induce dopamine neuron degeneration in A53T human α-Synuclein over expressed mouse model. We investigated the effects of X-ray irradiation on A53T-α-Syn MEFs and A53T-α-Syn transgene mice. Our results indicate that A53T-α-Syn MEFs show a prolonged DNA damage repair process and senescense phenotype. DNA damage preceded onset of motor phenotype in A53T-α-Syn transgenic mice and decrease the number of nigrostriatal dopaminergic neurons. Neurons of A53T-α-Syn transgenic mice are more fragile to DNA damages. - Highlights: • This study explore contribution of DNA damage to neurodegeneration in Parkinson's disease mice. • A53T-α-Syn MEF cells show a prolonged DNA damage repair process and senescense phenotype. • DNA damage preceded onset of motor phenotype in A53T-α-Syn transgenic mice. • DNA damage decrease the number of nigrostriatal dopaminergic neurons. • Neurons of A53T-α-Syn transgenic mice are more fragile to DNA damages.

  11. Neuronal model with distributed delay: analysis and simulation study for gamma distribution memory kernel.

    Science.gov (United States)

    Karmeshu; Gupta, Varun; Kadambari, K V

    2011-06-01

    A single neuronal model incorporating distributed delay (memory)is proposed. The stochastic model has been formulated as a Stochastic Integro-Differential Equation (SIDE) which results in the underlying process being non-Markovian. A detailed analysis of the model when the distributed delay kernel has exponential form (weak delay) has been carried out. The selection of exponential kernel has enabled the transformation of the non-Markovian model to a Markovian model in an extended state space. For the study of First Passage Time (FPT) with exponential delay kernel, the model has been transformed to a system of coupled Stochastic Differential Equations (SDEs) in two-dimensional state space. Simulation studies of the SDEs provide insight into the effect of weak delay kernel on the Inter-Spike Interval(ISI) distribution. A measure based on Jensen-Shannon divergence is proposed which can be used to make a choice between two competing models viz. distributed delay model vis-á-vis LIF model. An interesting feature of the model is that the behavior of (CV(t))((ISI)) (Coefficient of Variation) of the ISI distribution with respect to memory kernel time constant parameter η reveals that neuron can switch from a bursting state to non-bursting state as the noise intensity parameter changes. The membrane potential exhibits decaying auto-correlation structure with or without damped oscillatory behavior depending on the choice of parameters. This behavior is in agreement with empirically observed pattern of spike count in a fixed time window. The power spectral density derived from the auto-correlation function is found to exhibit single and double peaks. The model is also examined for the case of strong delay with memory kernel having the form of Gamma distribution. In contrast to fast decay of damped oscillations of the ISI distribution for the model with weak delay kernel, the decay of damped oscillations is found to be slower for the model with strong delay kernel.

  12. Early MEK1/2 Inhibition after Global Cerebral Ischemia in Rats Reduces Brain Damage and Improves Outcome by Preventing Delayed Vasoconstrictor Receptor Upregulation

    DEFF Research Database (Denmark)

    Johansson, Sara Ellinor; Larsen, Stine Schmidt; Povlsen, Gro Klitgaard

    2014-01-01

    BACKGROUND: Global cerebral ischemia following cardiac arrest is associated with increased cerebral vasoconstriction and decreased cerebral blood flow, contributing to delayed neuronal cell death and neurological detriments in affected patients. We hypothesize that upregulation of contractile ETB...... and 5-HT1B receptors, previously demonstrated in cerebral arteries after experimental global ischemia, are a key mechanism behind insufficient perfusion of the post-ischemic brain, proposing blockade of this receptor upregulation as a novel target for prevention of cerebral hypoperfusion and delayed...... neuronal cell death after global cerebral ischemia. The aim was to characterize the time-course of receptor upregulation and associated neuronal damage after global ischemia and investigate whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and thereby...

  13. Stability and bifurcation in a simplified four-neuron BAM neural network with multiple delays

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available We first study the distribution of the zeros of a fourth-degree exponential polynomial. Then we apply the obtained results to a simplified bidirectional associated memory (BAM neural network with four neurons and multiple time delays. By taking the sum of the delays as the bifurcation parameter, it is shown that under certain assumptions the steady state is absolutely stable. Under another set of conditions, there are some critical values of the delay, when the delay crosses these critical values, the Hopf bifurcation occurs. Furthermore, some explicit formulae determining the stability and the direction of periodic solutions bifurcating from Hopf bifurcations are obtained by applying the normal form theory and center manifold reduction. Numerical simulations supporting the theoretical analysis are also included.

  14. Time-delay-induced phase-transition to synchrony in coupled bursting neurons

    Science.gov (United States)

    Adhikari, Bhim Mani; Prasad, Awadhesh; Dhamala, Mukeshwar

    2011-06-01

    Signal transmission time delays in a network of nonlinear oscillators are known to be responsible for a variety of interesting dynamic behaviors including phase-flip transitions leading to synchrony or out of synchrony. Here, we uncover that phase-flip transitions are general phenomena and can occur in a network of coupled bursting neurons with a variety of coupling types. The transitions are marked by nonlinear changes in both temporal and phase-space characteristics of the coupled system. We demonstrate these phase-transitions with Hindmarsh-Rose and Leech-Heart interneuron models and discuss the implications of these results in understanding collective dynamics of bursting neurons in the brain.

  15. Tp53 gene mediates distinct dopaminergic neuronal damage in different dopaminergic neurotoxicant models

    Directory of Open Access Journals (Sweden)

    Tao Lu

    2017-01-01

    Full Text Available Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson's disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic (DA neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by pharmacological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal terminal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuronal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.

  16. Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process

    NARCIS (Netherlands)

    Bate, Clive; Veerhuis, Robert; Eikelenboom, Piet; Williams, Alun

    2004-01-01

    Activated microglia are closely associated with neuronal damage in Alzheimer's disease. In the present study, neurons exposed to low concentrations of amyloid-beta1-42, a toxic fragment of the amyloid-beta protein, were killed by microglia in a process that required cell-cell contact. Pre-treating

  17. DNA damage preceding dopamine neuron degeneration in A53T human α-synuclein transgenic mice.

    Science.gov (United States)

    Wang, Degui; Yu, Tianyu; Liu, Yongqiang; Yan, Jun; Guo, Yingli; Jing, Yuhong; Yang, Xuguang; Song, Yanfeng; Tian, Yingxia

    2016-12-02

    Defective DNA repair has been linked with age-associated neurodegenerative disorders. Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Whether damages to nuclear DNA contribute to neurodegeneration of PD still remain obscure. in this study we aim to explore whether nuclear DNA damage induce dopamine neuron degeneration in A53T human α-Synuclein over expressed mouse model. We investigated the effects of X-ray irradiation on A53T-α-Syn MEFs and A53T-α-Syn transgene mice. Our results indicate that A53T-α-Syn MEFs show a prolonged DNA damage repair process and senescense phenotype. DNA damage preceded onset of motor phenotype in A53T-α-Syn transgenic mice and decrease the number of nigrostriatal dopaminergic neurons. Neurons of A53T-α-Syn transgenic mice are more fragile to DNA damages. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Dynamics in a Delayed Neural Network Model of Two Neurons with Inertial Coupling

    Directory of Open Access Journals (Sweden)

    Changjin Xu

    2012-01-01

    Full Text Available A delayed neural network model of two neurons with inertial coupling is dealt with in this paper. The stability is investigated and Hopf bifurcation is demonstrated. Applying the normal form theory and the center manifold argument, we derive the explicit formulas for determining the properties of the bifurcating periodic solutions. An illustrative example is given to demonstrate the effectiveness of the obtained results.

  19. Stochastic Wilson–Cowan models of neuronal network dynamics with memory and delay

    International Nuclear Information System (INIS)

    Goychuk, Igor; Goychuk, Andriy

    2015-01-01

    We consider a simple Markovian class of the stochastic Wilson–Cowan type models of neuronal network dynamics, which incorporates stochastic delay caused by the existence of a refractory period of neurons. From the point of view of the dynamics of the individual elements, we are dealing with a network of non-Markovian stochastic two-state oscillators with memory, which are coupled globally in a mean-field fashion. This interrelation of a higher-dimensional Markovian and lower-dimensional non-Markovian dynamics is discussed in its relevance to the general problem of the network dynamics of complex elements possessing memory. The simplest model of this class is provided by a three-state Markovian neuron with one refractory state, which causes firing delay with an exponentially decaying memory within the two-state reduced model. This basic model is used to study critical avalanche dynamics (the noise sustained criticality) in a balanced feedforward network consisting of the excitatory and inhibitory neurons. Such avalanches emerge due to the network size dependent noise (mesoscopic noise). Numerical simulations reveal an intermediate power law in the distribution of avalanche sizes with the critical exponent around −1.16. We show that this power law is robust upon a variation of the refractory time over several orders of magnitude. However, the avalanche time distribution is biexponential. It does not reflect any genuine power law dependence. (paper)

  20. Sodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia.

    Science.gov (United States)

    Yamazaki, Yui; Harada, Shinichi; Wada, Tetsuyuki; Yoshida, Shigeru; Tokuyama, Shogo

    2016-07-01

    We recently demonstrated that the cerebral sodium-glucose transporter (SGLT) is involved in postischaemic hyperglycaemia-induced exacerbation of cerebral ischaemia. However, the associated SGLT-mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT-induced excessive sodium ion influx in the development of cerebral ischaemic neuronal damage. [Na+]i was estimated according to sodium-binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO). In these experiments, treatment with high concentrations of glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT-specific inhibitor phlorizin. SGLT-specific sodium ion influx was induced using a-methyl-D-glucopyranoside (a-MG) treatments, which led to significant concentration-dependent declines in neuronal survival rates and exacerbated hydrogen peroxide-induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a-MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin. Hence, excessive influx of sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage. © 2016 Royal Pharmaceutical Society.

  1. DL-ReSuMe: A Delay Learning-Based Remote Supervised Method for Spiking Neurons.

    Science.gov (United States)

    Taherkhani, Aboozar; Belatreche, Ammar; Li, Yuhua; Maguire, Liam P

    2015-12-01

    Recent research has shown the potential capability of spiking neural networks (SNNs) to model complex information processing in the brain. There is biological evidence to prove the use of the precise timing of spikes for information coding. However, the exact learning mechanism in which the neuron is trained to fire at precise times remains an open problem. The majority of the existing learning methods for SNNs are based on weight adjustment. However, there is also biological evidence that the synaptic delay is not constant. In this paper, a learning method for spiking neurons, called delay learning remote supervised method (DL-ReSuMe), is proposed to merge the delay shift approach and ReSuMe-based weight adjustment to enhance the learning performance. DL-ReSuMe uses more biologically plausible properties, such as delay learning, and needs less weight adjustment than ReSuMe. Simulation results have shown that the proposed DL-ReSuMe approach achieves learning accuracy and learning speed improvements compared with ReSuMe.

  2. Stability and Hopf Bifurcation of a Reaction-Diffusion Neutral Neuron System with Time Delay

    Science.gov (United States)

    Dong, Tao; Xia, Linmao

    2017-12-01

    In this paper, a type of reaction-diffusion neutral neuron system with time delay under homogeneous Neumann boundary conditions is considered. By constructing a basis of phase space based on the eigenvectors of the corresponding Laplace operator, the characteristic equation of this system is obtained. Then, by selecting time delay and self-feedback strength as the bifurcating parameters respectively, the dynamic behaviors including local stability and Hopf bifurcation near the zero equilibrium point are investigated when the time delay and self-feedback strength vary. Furthermore, the direction of the Hopf bifurcation and the stability of bifurcating periodic solutions are obtained by using the normal form and the center manifold theorem for the corresponding partial differential equation. Finally, two simulation examples are given to verify the theory.

  3. Delayed damage after radiation therapy for head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Yoshiyuki [Osaka Dental Univ., Hirakata (Japan)

    2000-03-01

    I investigated radiation damage, including osteoradionecrosis, arising from tooth extraction in fields that had received radiation therapy for head and neck cancer, and evaluated the effectiveness of pilocarpine for xerostomia. Between January 1990 and April 1996, I examined 30 patients for bone changes after tooth extraction in fields irradiated at the Department of Oral Radiology, Osaka Dental University Hospital. Nineteen of the patients had been treated for nasopharyngeal cancer and 11 for oropharyngeal cancer. Between January and April 1996, 4 additional patients were given pilocarpine hydrochloride (3-mg, 6-mg and 9-mg of KSS-694 orally three times a day) for 12 weeks and evaluated every 4 weeks as a base line. One had been treated for nasopharyngeal carcinoma, two for cancer of the cheek and one for an unknown carcinoma. Eighteen of the patients (11 with nasopharyngeal carcinoma and 7 with oropharyngeal carcinoma) had extractions. Use of preoperative and postoperative radiographs indicated that damage to the bone following tooth extraction after radiation exposure was related to whether antibiotics were administered the day before the extraction, whether forceps or elevators were used, and whether the tooth was in the field of radiation. Xerostomia improved in all 4 of the patients who received 6-mg or 9-mg of pilocarpine. It improved saliva production and relieved the symptoms of xerostomia after radiation therapy for head and neck cancer, although there were minor side effects such as fever. This information can be used to improve the oral environment of patients who have received radiation therapy for head and neck cancer, and to better understand their oral environment. (author)

  4. Delayed damage after radiation therapy for head and neck cancer

    International Nuclear Information System (INIS)

    Matsumoto, Yoshiyuki

    2000-01-01

    I investigated radiation damage, including osteoradionecrosis, arising from tooth extraction in fields that had received radiation therapy for head and neck cancer, and evaluated the effectiveness of pilocarpine for xerostomia. Between January 1990 and April 1996, I examined 30 patients for bone changes after tooth extraction in fields irradiated at the Department of Oral Radiology, Osaka Dental University Hospital. Nineteen of the patients had been treated for nasopharyngeal cancer and 11 for oropharyngeal cancer. Between January and April 1996, 4 additional patients were given pilocarpine hydrochloride (3-mg, 6-mg and 9-mg of KSS-694 orally three times a day) for 12 weeks and evaluated every 4 weeks as a base line. One had been treated for nasopharyngeal carcinoma, two for cancer of the cheek and one for an unknown carcinoma. Eighteen of the patients (11 with nasopharyngeal carcinoma and 7 with oropharyngeal carcinoma) had extractions. Use of preoperative and postoperative radiographs indicated that damage to the bone following tooth extraction after radiation exposure was related to whether antibiotics were administered the day before the extraction, whether forceps or elevators were used, and whether the tooth was in the field of radiation. Xerostomia improved in all 4 of the patients who received 6-mg or 9-mg of pilocarpine. It improved saliva production and relieved the symptoms of xerostomia after radiation therapy for head and neck cancer, although there were minor side effects such as fever. This information can be used to improve the oral environment of patients who have received radiation therapy for head and neck cancer, and to better understand their oral environment. (author)

  5. Isoflurane depolarizes bronchopulmonary C neurons by inhibiting transient A-type and delayed rectifier potassium channels.

    Science.gov (United States)

    Zhang, Zhenxiong; Zhuang, Jianguo; Zhang, Cancan; Xu, Fadi

    2013-04-01

    Inhalation of isoflurane (ISO), a widely used volatile anesthetic, can produce clinical tachypnea. In dogs, this response is reportedly mediated by bronchopulmonary C-fibers (PCFs), but the relevant mechanisms remain unclear. Activation of transient A-type potassium current (IA) channels and delayed rectifier potassium current (IK) channels hyperpolarizes neurons, and inhibition of both channels by ISO increases neural firing. Due to the presence of these channels in the cell bodies of rat PCFs, we determined whether ISO could stimulate PCFs to produce tachypnea in anesthetized rats, and, if so, whether this response resulted from ISO-induced depolarization of the pulmonary C neurons via the inhibition of IA and IK. We recorded ventilatory responses to 5% ISO exposure in anesthetized rats before and after blocking PCF conduction and the responses of pulmonary C neurons (extracellularly recorded) to ISO exposure. ISO-induced (1mM) changes in pulmonary C neuron membrane potential and IA/IK were tested using the perforated patch clamp technique. We found that: (1) ISO inhalation evoked a brief tachypnea (∼7s) and that this response disappeared after blocking PCF conduction; (2) the ISO significantly elevated (by 138%) the firing rate of most pulmonary C neurons (17 out of 21) in the nodose ganglion; and (3) ISO perfusion depolarized the pulmonary C neurons in the vitro and inhibited both IA and IK, and this evoked-depolarization was largely diminished after blocking both IA and IK. Our results suggest that ISO is able to stimulate PCFs to elicit tachypnea in rats, at least partly, via inhibiting IA and IK, thereby depolarizing the pulmonary C neurons. Copyright © 2013. Published by Elsevier B.V.

  6. Synchronization of Coupled FitzHugh-Nagumo Neurons Using Self-Feedback Time Delay

    Science.gov (United States)

    Fan, Denggui; Song, Xinle; Liao, Fucheng

    Many neurological diseases are characterized by abnormally synchronous oscillations of neuronal populations. However, how the neurons can synchronize with each other is still not fully understood, which may have potentially hampered the understanding and diagnosis for these dynamical diseases. In this paper, the self-feedback time delay (SFTD) and adaptive control theory are employed to control the onset of synchronization in the coupled FitzHugh-Nagumo (FHN) neurons. It is found that the larger SFTD can induce the complete synchronization of coupled neuronal system. Further investigation reveals that the reinforcing SFTD can significantly postpone the synchronization onsets. In addition, for the case that synchronization cannot be achieved by adjusting SFTD, the parameter estimation update laws and adaptive controller with respect to SFTD of coupled system are investigated to deduce the sufficient condition for complete synchronization. Simulations are also provided to illustrate the effectiveness of the proposed methods. In particular, we observed the fascinating dynamical synchronization transitions, such as chaotic synchronization and bursting synchronization transitions, as well as the transition from anti-synchronization to complete synchronization.

  7. An electronic implementation for Liao's chaotic delayed neuron model with non-monotonous activation function

    Energy Technology Data Exchange (ETDEWEB)

    Duan Shukai [Department of Computer Science and Engineering, Chongqing University, Chongqing 400044 (China); School of Electronic and Information Engineering, Southwest University, Chongqing 400715 (China)], E-mail: duansk@swu.edu.cn; Liao Xiaofeng [Department of Computer Science and Engineering, Chongqing University, Chongqing 400044 (China)], E-mail: xfliao@cqu.edu.cn

    2007-09-10

    A new chaotic delayed neuron model with non-monotonously increasing transfer function, called as chaotic Liao's delayed neuron model, was recently reported and analyzed. An electronic implementation of this model is described in detail. At the same time, some methods in circuit design, especially for circuit with time delayed unit and non-monotonously increasing activation unit, are also considered carefully. We find that the dynamical behaviors of the designed circuits are closely similar to the results predicted by numerical experiments.

  8. Delayed repair of DNA single-strand breaks does not increase cytogenetic damage

    International Nuclear Information System (INIS)

    Morgan, W.F.; Djordjevic, M.C.; Jostes, R.F.; Pantelias, G.E.

    1985-01-01

    DNA damage and cytogenetic effects of ionizing radiation were investigated in Chinese hamster ovary (CHO) cells and unstimulated human peripheral blood lymphocytes. DNA damage and repair were analysed by alkaline elution under conditions that predominantly measured DNA single-strand breaks (ssb). X-radiation (2.5 Gy) induced ssb in both CHO cells and unstimulated lymphocytes, and the breaks were repaired within 30 and 90 min, respectively. This rapid repair was delayed by the poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide (3AB). The cytogenetic effects of the 3AB-induced delay in DNA repair were examined by analysing sister chromatid exchange (SCE) frequency in CHO cells and fragmentation of prematurely condensed chromosomes (PCC) in unstimulated human lymphocytes after 2.5 Gy of X-rays. Although 3AB delayed the rejoining of DNA ssb, this delay did not result in increased cytogenetic damage manifested as either SCE or fragmentation of PCC. These results indicate that the rapidly rejoining DNA ssb are not important in the production of chromosome damage. (author)

  9. Effect of delayed onset prostacyclin on markers of endothelial function and damage after subarachnoid hemorrhage

    DEFF Research Database (Denmark)

    Gybel-Brask, Mikkel; Rasmussen, Rune; Stensballe, Jakob

    2017-01-01

    Background: Subarachnoid hemorrhage (SAH) is a neurological emergency. Delayed ischemic neurological deficit is one of the main causes of poor outcome after SAH and is probably caused, at least in part, by cerebral vasospasm. The pathophysiology of this is multifaceted, but endothelial damage...

  10. Quinacrine pretreatment reduces microwave-induced neuronal damage by stabilizing the cell membrane

    Science.gov (United States)

    Ding, Xue-feng; Wu, Yan; Qu, Wen-rui; Fan, Ming; Zhao, Yong-qi

    2018-01-01

    Quinacrine, widely used to treat parasitic diseases, binds to cell membranes. We previously found that quinacrine pretreatment reduced microwave radiation damage in rat hippocampal neurons, but the molecular mechanism remains poorly understood. Considering the thermal effects of microwave radiation and the protective effects of quinacrine on heat damage in cells, we hypothesized that quinacrine would prevent microwave radiation damage to cells in a mechanism associated with cell membrane stability. To test this, we used retinoic acid to induce PC12 cells to differentiate into neuron-like cells. We then pretreated the neurons with quinacrine (20 and 40 mM) and irradiated them with 50 mW/cm2 microwaves for 3 or 6 hours. Flow cytometry, atomic force microscopy and western blot assays revealed that irradiated cells pretreated with quinacrine showed markedly less apoptosis, necrosis, and membrane damage, and greater expression of heat shock protein 70, than cells exposed to microwave irradiation alone. These results suggest that quinacrine stabilizes the neuronal membrane structure by upregulating the expression of heat shock protein 70, thus reducing neuronal injury caused by microwave radiation. PMID:29623929

  11. Characterization of neuronal damage by iomazenil binding and cerebral blood flow in an ischemic rat model

    International Nuclear Information System (INIS)

    Toyama, Hiroshi; Takeuchi, Akira; Koga, Sukehiko; Matsumura, Kaname; Nakashima, Hiromichi; Takeda, Kan; Yoshida, Toshimichi; Ichise, Masanori

    1998-01-01

    I-123-iomazenil is a SPECT probe for central benzodiazepine receptors (BZR) which may reflect intact cortical neuron density after ischemic insults. We evaluated whether neuronal damage in rats could be characterized by iomazenil as compared with cerebral blood flow (CBF). Serial changes in I-125-iomazenil for BZR and I-123-IMP for CBF were analyzed after the unilateral middle cerebral artery occlusion in rats by using an in vivo dualtracer technique. Uptake ratios of affected to contralateral regions were calculated. The iomazenil as well as IMP were decreased in all regions except for the cerebellum (remote area). Both iomazenil and IMP increased over time except in the temporal region (ischemic core). The iomazenil uptake was higher than IMP except in the ischemic core between 1 and 3-4 wk when iomazenil was lower than IMP. Iomazenil showed a moderate decrease in the proximal and middle parietal regions (peri-infarct areas) at 3-4 wk. The triphenyl-tetrazolium-chloride (TTC) stain at 1 wk demonstrated unstained tissue in the temporal region indicating tissue necrosis. With hematoxylin-eosin (HE) stain at 1 wk, widespread neuronal necrosis with occasional intact neurons were found in the proximal parietal region, and isolated necrotic neurons were represented in the distal parietal region. Iomazenil correlated well with the neuron distribution and the finding of a discrepancy between iomazenil and IMP might be useful in evaluating the neuronal damage. (author)

  12. Assessment of delay-and-sum algorithms for damage detection in aluminium and composite plates

    International Nuclear Information System (INIS)

    Sharif-Khodaei, Z; Aliabadi, M H

    2014-01-01

    Piezoelectric sensors are increasingly being used in active structural health monitoring, due to their durability, light weight and low power consumption. In the present work damage detection and characterization methodologies based on Lamb waves have been evaluated for aircraft panels. The applicability of various proposed delay-and-sum algorithms on isotropic and composite stiffened panels have been investigated, both numerically and experimentally. A numerical model for ultrasonic wave propagation in composite laminates is proposed and compared to signals recorded from experiments. A modified delay-and-sum algorithm is then proposed for detecting impact damage in composite plates with and without a stiffener which is shown to capture and localize damage with only four transducers. (papers)

  13. Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

    Directory of Open Access Journals (Sweden)

    Eun Joo Bae

    2015-01-01

    Full Text Available The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions (CA1- 3 between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia. p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group. p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.

  14. Effects of dynamic synapses on noise-delayed response latency of a single neuron

    Science.gov (United States)

    Uzuntarla, M.; Ozer, M.; Ileri, U.; Calim, A.; Torres, J. J.

    2015-12-01

    The noise-delayed decay (NDD) phenomenon emerges when the first-spike latency of a periodically forced stochastic neuron exhibits a maximum for a particular range of noise intensity. Here, we investigate the latency response dynamics of a single Hodgkin-Huxley neuron that is subject to both a suprathreshold periodic stimulus and a background activity arriving through dynamic synapses. We study the first-spike latency response as a function of the presynaptic firing rate f . This constitutes a more realistic scenario than previous works, since f provides a suitable biophysically realistic parameter to control the level of activity in actual neural systems. We first report on the emergence of classical NDD behavior as a function of f for the limit of static synapses. Second, we show that when short-term depression and facilitation mechanisms are included at the synapses, different NDD features can be found due to their modulatory effect on synaptic current fluctuations. For example, an intriguing double NDD (DNDD) behavior occurs for different sets of relevant synaptic parameters. Moreover, depending on the balance between synaptic depression and synaptic facilitation, single NDD or DNDD can prevail, in such a way that synaptic facilitation favors the emergence of DNDD whereas synaptic depression favors the existence of single NDD. Here we report the existence of the DNDD effect in the response latency dynamics of a neuron.

  15. Single-cell resolution mapping of neuronal damage in acute focal cerebral ischemia using thallium autometallography.

    Science.gov (United States)

    Stöber, Franziska; Baldauf, Kathrin; Ziabreva, Iryna; Harhausen, Denise; Zille, Marietta; Neubert, Jenni; Reymann, Klaus G; Scheich, Henning; Dirnagl, Ulrich; Schröder, Ulrich H; Wunder, Andreas; Goldschmidt, Jürgen

    2014-01-01

    Neuronal damage shortly after onset or after brief episodes of cerebral ischemia has remained difficult to assess with clinical and preclinical imaging techniques as well as with microscopical methods. We here show, in rodent models of middle cerebral artery occlusion (MCAO), that neuronal damage in acute focal cerebral ischemia can be mapped with single-cell resolution using thallium autometallography (TlAMG), a histochemical technique for the detection of the K(+)-probe thallium (Tl(+)) in the brain. We intravenously injected rats and mice with thallium diethyldithiocarbamate (TlDDC), a lipophilic chelate complex that releases Tl(+) after crossing the blood-brain barrier. We found, within the territories of the affected arteries, areas of markedly reduced neuronal Tl(+) uptake in all animals at all time points studied ranging from 15 minutes to 24 hours after MCAO. In large lesions at early time points, areas with neuronal and astrocytic Tl(+) uptake below thresholds of detection were surrounded by putative penumbral zones with preserved but diminished Tl(+) uptake. At 24 hours, the areas of reduced Tl(+)uptake matched with areas delineated by established markers of neuronal damage. The results suggest the use of (201)TlDDC for preclinical and clinical single-photon emission computed tomography (SPECT) imaging of hyperacute alterations in brain K(+) metabolism and prediction of tissue viability in cerebral ischemia.

  16. Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage

    Directory of Open Access Journals (Sweden)

    Jiaxiang Shao

    2016-03-01

    Full Text Available Abstract SIRT6 is a NAD+-dependent histone deacetylase and has been implicated in the regulation of genomic stability, DNA repair, metabolic homeostasis and several diseases. The effect of SIRT6 in cerebral ischemia and oxygen/glucose deprivation (OGD has been reported, however the role of SIRT6 in oxidative stress damage remains unclear. Here we used SH-SY5Y neuronal cells and found that overexpression of SIRT6 led to decreased cell viability and increased necrotic cell death and reactive oxygen species (ROS production under oxidative stress. Mechanistic study revealed that SIRT6 induced autophagy via attenuation of AKT signaling and treatment with autophagy inhibitor 3-MA or knockdown of autophagy-related protein Atg5 rescued H2O2-induced neuronal injury. Conversely, SIRT6 inhibition suppressed autophagy and reduced oxidative stress-induced neuronal damage. These results suggest that SIRT6 might be a potential therapeutic target for neuroprotection.

  17. Failure of delayed nonsynaptic neuronal plasticity underlies age-associated long-term associative memory impairment

    Directory of Open Access Journals (Sweden)

    Watson Shawn N

    2012-08-01

    Full Text Available Abstract Background Cognitive impairment associated with subtle changes in neuron and neuronal network function rather than widespread neuron death is a feature of the normal aging process in humans and animals. Despite its broad evolutionary conservation, the etiology of this aging process is not well understood. However, recent evidence suggests the existence of a link between oxidative stress in the form of progressive membrane lipid peroxidation, declining neuronal electrical excitability and functional decline of the normal aging brain. The current study applies a combination of behavioural and electrophysiological techniques and pharmacological interventions to explore this hypothesis in a gastropod model (Lymnaea stagnalis feeding system that allows pinpointing the molecular and neurobiological foundations of age-associated long-term memory (LTM failure at the level of individual identified neurons and synapses. Results Classical appetitive reward-conditioning induced robust LTM in mature animals in the first quartile of their lifespan but failed to do so in animals in the last quartile of their lifespan. LTM failure correlated with reduced electrical excitability of two identified serotonergic modulatory interneurons (CGCs critical in chemosensory integration by the neural network controlling feeding behaviour. Moreover, while behavioural conditioning induced delayed-onset persistent depolarization of the CGCs known to underlie appetitive LTM formation in this model in the younger animals, it failed to do so in LTM-deficient senescent animals. Dietary supplementation of the lipophilic anti-oxidant α-tocopherol reversed the effect of age on CGCs electrophysiological characteristics but failed to restore appetitive LTM function. Treatment with the SSRI fluoxetine reversed both the neurophysiological and behavioural effects of age in senior animals. Conclusions The results identify the CGCs as cellular loci of age-associated appetitive

  18. The Carrier's Liability for Damage Caused by Delay in International Air Transport

    Science.gov (United States)

    Lee, Kang Bin

    2003-01-01

    Delay in the air transport occurs when passengers, baggage or cargo do not arrive at their destination at the time indicated in the contract of carriage. The causes of delay in the carriage of passengers are booking errors or double booking, delayed departure of aircraft, incorrect information regarding the time of departure, failure to land at the scheduled destination and changes in flight schedule or addition of extra landing stops. Delay in the carriage of baggage or cargo may have different causes: no reservation, lack of space, failure to load the baggage or cargo at the right place, or to deliver the covering documents at the right place. The Montreal Convention of 1999 Article 19 provides that 'The carrier is liable for damage occasioned by delay in the carriage by air of passengers, baggage or cargo. Nevertheless, the carder shall not be liable for damage occasioned by delay if it proves that it and its servants and agents took all measures that could reasonably be required to avoid the damage or that it was impossible for it or them to take such measures'. The Montreal Convention Article 22 provides liability limits of the carrier in case of delay for passengers and their baggage and for cargo. In the carriage of persons, the liability of the carrier for each passenger is limited to 4,150 SDR. In the carriage of baggage, the liability of the carrier is limited to 1,000 SDR for each passenger unless a special declaration as to the value of the baggage has been made. In the carriage of cargo, the liability of the carrier is limited to 17 SDR per kilogram unless a special declaration as to the value of the cargo has been made. The Montreal Convention Article 19 has shortcomings: it is silent on the duration of the liability for carriage,andit does not make any distinction between persons and good. It does not give any indication concerning the circumstances to be taken into account in cases of delay, and about the length of delay. In conclusion, it is

  19. Spatiotemporal dynamics on small-world neuronal networks: The roles of two types of time-delayed coupling

    Energy Technology Data Exchange (ETDEWEB)

    Wu Hao; Jiang Huijun [Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemical Physics, University of Science and Technology of China, Hefei, Anhui 230026 (China); Hou Zhonghuai, E-mail: hzhlj@ustc.edu.cn [Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemical Physics, University of Science and Technology of China, Hefei, Anhui 230026 (China)

    2011-10-15

    Highlights: > We compare neuronal dynamics in dependence on two types of delayed coupling. > Distinct results induced by different delayed coupling can be achieved. > Time delays in type 1 coupling can induce a most spatiotemporal ordered state. > For type 2 coupling, the systems exhibit synchronization transitions with delay. - Abstract: We investigate temporal coherence and spatial synchronization on small-world networks consisting of noisy Terman-Wang (TW) excitable neurons in dependence on two types of time-delayed coupling: {l_brace}x{sub j}(t - {tau}) - x{sub i}(t){r_brace} and {l_brace}x{sub j}(t - {tau}) - x{sub i}(t - {tau}){r_brace}. For the former case, we show that time delay in the coupling can dramatically enhance temporal coherence and spatial synchrony of the noise-induced spike trains. In addition, if the delay time {tau} is tuned to nearly match the intrinsic spike period of the neuronal network, the system dynamics reaches a most ordered state, which is both periodic in time and nearly synchronized in space, demonstrating an interesting resonance phenomenon with delay. For the latter case, however, we cannot achieve a similar spatiotemporal ordered state, but the neuronal dynamics exhibits interesting synchronization transitions with time delay from zigzag fronts of excitations to dynamic clustering anti-phase synchronization (APS), and further to clustered chimera states which have spatially distributed anti-phase coherence separated by incoherence. Furthermore, we also show how these findings are influenced by the change of the noise intensity and the rewiring probability of the small-world networks. Finally, qualitative analysis is given to illustrate the numerical results.

  20. Spatiotemporal dynamics on small-world neuronal networks: The roles of two types of time-delayed coupling

    International Nuclear Information System (INIS)

    Wu Hao; Jiang Huijun; Hou Zhonghuai

    2011-01-01

    Highlights: → We compare neuronal dynamics in dependence on two types of delayed coupling. → Distinct results induced by different delayed coupling can be achieved. → Time delays in type 1 coupling can induce a most spatiotemporal ordered state. → For type 2 coupling, the systems exhibit synchronization transitions with delay. - Abstract: We investigate temporal coherence and spatial synchronization on small-world networks consisting of noisy Terman-Wang (TW) excitable neurons in dependence on two types of time-delayed coupling: {x j (t - τ) - x i (t)} and {x j (t - τ) - x i (t - τ)}. For the former case, we show that time delay in the coupling can dramatically enhance temporal coherence and spatial synchrony of the noise-induced spike trains. In addition, if the delay time τ is tuned to nearly match the intrinsic spike period of the neuronal network, the system dynamics reaches a most ordered state, which is both periodic in time and nearly synchronized in space, demonstrating an interesting resonance phenomenon with delay. For the latter case, however, we cannot achieve a similar spatiotemporal ordered state, but the neuronal dynamics exhibits interesting synchronization transitions with time delay from zigzag fronts of excitations to dynamic clustering anti-phase synchronization (APS), and further to clustered chimera states which have spatially distributed anti-phase coherence separated by incoherence. Furthermore, we also show how these findings are influenced by the change of the noise intensity and the rewiring probability of the small-world networks. Finally, qualitative analysis is given to illustrate the numerical results.

  1. Complex dynamics of a delayed discrete neural network of two nonidentical neurons

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yuanlong [Mathematics Department, GuangDong University of Finance, Guangzhou 510521 (China); Huang, Tingwen [Mathematics Department, Texas A and M University at Qatar, P. O. Box 23874, Doha (Qatar); Huang, Yu, E-mail: stshyu@mail.sysu.edu.cn [Mathematics Department, Sun Yat-Sen University, Guangzhou 510275, People' s Republic China (China)

    2014-03-15

    In this paper, we discover that a delayed discrete Hopfield neural network of two nonidentical neurons with self-connections and no self-connections can demonstrate chaotic behaviors. To this end, we first transform the model, by a novel way, into an equivalent system which has some interesting properties. Then, we identify the chaotic invariant set for this system and show that the dynamics of this system within this set is topologically conjugate to the dynamics of the full shift map with two symbols. This confirms chaos in the sense of Devaney. Our main results generalize the relevant results of Huang and Zou [J. Nonlinear Sci. 15, 291–303 (2005)], Kaslik and Balint [J. Nonlinear Sci. 18, 415–432 (2008)] and Chen et al. [Sci. China Math. 56(9), 1869–1878 (2013)]. We also give some numeric simulations to verify our theoretical results.

  2. Complex dynamics of a delayed discrete neural network of two nonidentical neurons

    International Nuclear Information System (INIS)

    Chen, Yuanlong; Huang, Tingwen; Huang, Yu

    2014-01-01

    In this paper, we discover that a delayed discrete Hopfield neural network of two nonidentical neurons with self-connections and no self-connections can demonstrate chaotic behaviors. To this end, we first transform the model, by a novel way, into an equivalent system which has some interesting properties. Then, we identify the chaotic invariant set for this system and show that the dynamics of this system within this set is topologically conjugate to the dynamics of the full shift map with two symbols. This confirms chaos in the sense of Devaney. Our main results generalize the relevant results of Huang and Zou [J. Nonlinear Sci. 15, 291–303 (2005)], Kaslik and Balint [J. Nonlinear Sci. 18, 415–432 (2008)] and Chen et al. [Sci. China Math. 56(9), 1869–1878 (2013)]. We also give some numeric simulations to verify our theoretical results

  3. Complex dynamics of a delayed discrete neural network of two nonidentical neurons.

    Science.gov (United States)

    Chen, Yuanlong; Huang, Tingwen; Huang, Yu

    2014-03-01

    In this paper, we discover that a delayed discrete Hopfield neural network of two nonidentical neurons with self-connections and no self-connections can demonstrate chaotic behaviors. To this end, we first transform the model, by a novel way, into an equivalent system which has some interesting properties. Then, we identify the chaotic invariant set for this system and show that the dynamics of this system within this set is topologically conjugate to the dynamics of the full shift map with two symbols. This confirms chaos in the sense of Devaney. Our main results generalize the relevant results of Huang and Zou [J. Nonlinear Sci. 15, 291-303 (2005)], Kaslik and Balint [J. Nonlinear Sci. 18, 415-432 (2008)] and Chen et al. [Sci. China Math. 56(9), 1869-1878 (2013)]. We also give some numeric simulations to verify our theoretical results.

  4. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

    Science.gov (United States)

    Wang, Wei-Ping; Iyo, Abiye H.; Miguel-Hidalgo, Javier; Regunathan, Soundar; Zhu, Meng-Yang

    2010-01-01

    Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-d-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 µM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property. PMID:16546145

  5. Delay selection by spike-timing-dependent plasticity in recurrent networks of spiking neurons receiving oscillatory inputs.

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    Robert R Kerr

    Full Text Available Learning rules, such as spike-timing-dependent plasticity (STDP, change the structure of networks of neurons based on the firing activity. A network level understanding of these mechanisms can help infer how the brain learns patterns and processes information. Previous studies have shown that STDP selectively potentiates feed-forward connections that have specific axonal delays, and that this underlies behavioral functions such as sound localization in the auditory brainstem of the barn owl. In this study, we investigate how STDP leads to the selective potentiation of recurrent connections with different axonal and dendritic delays during oscillatory activity. We develop analytical models of learning with additive STDP in recurrent networks driven by oscillatory inputs, and support the results using simulations with leaky integrate-and-fire neurons. Our results show selective potentiation of connections with specific axonal delays, which depended on the input frequency. In addition, we demonstrate how this can lead to a network becoming selective in the amplitude of its oscillatory response to this frequency. We extend this model of axonal delay selection within a single recurrent network in two ways. First, we show the selective potentiation of connections with a range of both axonal and dendritic delays. Second, we show axonal delay selection between multiple groups receiving out-of-phase, oscillatory inputs. We discuss the application of these models to the formation and activation of neuronal ensembles or cell assemblies in the cortex, and also to missing fundamental pitch perception in the auditory brainstem.

  6. Sildenafil Attenuates Inflammation and Oxidative Stress in Pelvic Ganglia Neurons after Bilateral Cavernosal Nerve Damage

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    Leah A. Garcia

    2014-09-01

    Full Text Available Erectile dysfunction is a common complication for patients undergoing surgeries for prostate, bladder, and colorectal cancers, due to damage of the nerves associated with the major pelvic ganglia (MPG. Functional re-innervation of target organs depends on the capacity of the neurons to survive and switch towards a regenerative phenotype. PDE5 inhibitors (PDE5i have been successfully used in promoting the recovery of erectile function after cavernosal nerve damage (BCNR by up-regulating the expression of neurotrophic factors in MPG. However, little is known about the effects of PDE5i on markers of neuronal damage and oxidative stress after BCNR. This study aimed to investigate the changes in gene and protein expression profiles of inflammatory, anti-inflammatory cytokines and oxidative stress related-pathways in MPG neurons after BCNR and subsequent treatment with sildenafil. Our results showed that BCNR in Fisher-344 rats promoted up-regulation of cytokines (interleukin- 1 (IL-1 β, IL-6, IL-10, transforming growth factor β 1 (TGFβ1, and oxidative stress factors (Nicotinamide adenine dinucleotide phosphate (NADPH oxidase, Myeloperoxidase (MPO, inducible nitric oxide synthase (iNOS, TNF receptor superfamily member 5 (CD40 that were normalized by sildenafil treatment given in the drinking water. In summary, PDE5i can attenuate the production of damaging factors and can up-regulate the expression of beneficial factors in the MPG that may ameliorate neuropathic pain, promote neuroprotection, and favor nerve regeneration.

  7. Neuronal damage in chick and rat embryos following X-irradiation

    International Nuclear Information System (INIS)

    Schneider, B.F.; Norton, S.

    1980-01-01

    Exposure of rat and chick embryos to X-irradiation at the time of development of neurons at the telencephalic-diencephalic border results in prolonged damage to neurons in this area as measured by neuronal nuclear size. A dose of 100 rads to the seven-day-old chick embryo has about the same effect as 125 rads to the 15-day-old rat fetus. The nuclear volume of large, multipolar neurons in the chick paleostriatum primitivum and the rat lateral preoptic area are reduced from 10 to 15%. Larger doses of X-irradiation to the chick (150 and 200 rads) cause progressively greater reductions in nuclear size. The large neurons which were measured in the rat and chick are morphologically similar in the two species. Both contain cytoplasmic acetylcholinesterase and have several branched, spiny dendritic processes. The similarity of response of chick and rat neurons to X-irradiation diminishes the significance of maternal factors as the cause of the effects of fetal irradiation in these experiments

  8. Delayed repair of radiation induced clustered DNA damage: Friend or foe?

    Science.gov (United States)

    Eccles, Laura J.; O’Neill, Peter; Lomax, Martine E.

    2011-01-01

    A signature of ionizing radiation exposure is the induction of DNA clustered damaged sites, defined as two or more lesions within one to two helical turns of DNA by passage of a single radiation track. Clustered damage is made up of double strand breaks (DSB) with associated base lesions or abasic (AP) sites, and non-DSB clusters comprised of base lesions, AP sites and single strand breaks. This review will concentrate on the experimental findings of the processing of non-DSB clustered damaged sites. It has been shown that non-DSB clustered damaged sites compromise the base excision repair pathway leading to the lifetime extension of the lesions within the cluster, compared to isolated lesions, thus the likelihood that the lesions persist to replication and induce mutation is increased. In addition certain non-DSB clustered damaged sites are processed within the cell to form additional DSB. The use of E. coli to demonstrate that clustering of DNA lesions is the major cause of the detrimental consequences of ionizing radiation is also discussed. The delayed repair of non-DSB clustered damaged sites in humans can be seen as a “friend”, leading to cell killing in tumour cells or as a “foe”, resulting in the formation of mutations and genetic instability in normal tissue. PMID:21130102

  9. Delayed repair of radiation induced clustered DNA damage: Friend or foe?

    International Nuclear Information System (INIS)

    Eccles, Laura J.; O'Neill, Peter; Lomax, Martine E.

    2011-01-01

    A signature of ionizing radiation exposure is the induction of DNA clustered damaged sites, defined as two or more lesions within one to two helical turns of DNA by passage of a single radiation track. Clustered damage is made up of double strand breaks (DSB) with associated base lesions or abasic (AP) sites, and non-DSB clusters comprised of base lesions, AP sites and single strand breaks. This review will concentrate on the experimental findings of the processing of non-DSB clustered damaged sites. It has been shown that non-DSB clustered damaged sites compromise the base excision repair pathway leading to the lifetime extension of the lesions within the cluster, compared to isolated lesions, thus the likelihood that the lesions persist to replication and induce mutation is increased. In addition certain non-DSB clustered damaged sites are processed within the cell to form additional DSB. The use of E. coli to demonstrate that clustering of DNA lesions is the major cause of the detrimental consequences of ionizing radiation is also discussed. The delayed repair of non-DSB clustered damaged sites in humans can be seen as a 'friend', leading to cell killing in tumour cells or as a 'foe', resulting in the formation of mutations and genetic instability in normal tissue.

  10. Stability and Hopf Bifurcation of Fractional-Order Complex-Valued Single Neuron Model with Time Delay

    Science.gov (United States)

    Wang, Zhen; Wang, Xiaohong; Li, Yuxia; Huang, Xia

    2017-12-01

    In this paper, the problems of stability and Hopf bifurcation in a class of fractional-order complex-valued single neuron model with time delay are addressed. With the help of the stability theory of fractional-order differential equations and Laplace transforms, several new sufficient conditions, which ensure the stability of the system are derived. Taking the time delay as the bifurcation parameter, Hopf bifurcation is investigated and the critical value of the time delay for the occurrence of Hopf bifurcation is determined. Finally, two representative numerical examples are given to show the effectiveness of the theoretical results.

  11. Effects of time delays on stability and Hopf bifurcation in a fractional ring-structured network with arbitrary neurons

    Science.gov (United States)

    Huang, Chengdai; Cao, Jinde; Xiao, Min; Alsaedi, Ahmed; Hayat, Tasawar

    2018-04-01

    This paper is comprehensively concerned with the dynamics of a class of high-dimension fractional ring-structured neural networks with multiple time delays. Based on the associated characteristic equation, the sum of time delays is regarded as the bifurcation parameter, and some explicit conditions for describing delay-dependent stability and emergence of Hopf bifurcation of such networks are derived. It reveals that the stability and bifurcation heavily relies on the sum of time delays for the proposed networks, and the stability performance of such networks can be markedly improved by selecting carefully the sum of time delays. Moreover, it is further displayed that both the order and the number of neurons can extremely influence the stability and bifurcation of such networks. The obtained criteria enormously generalize and improve the existing work. Finally, numerical examples are presented to verify the efficiency of the theoretical results.

  12. Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Nabi Shamsaei; Mehdi Khaksari; Sohaila Erfani; Hamid Rajabi; Nahid Aboutaleb

    2015-01-01

    Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral isch-emic injury. However, the role of physical exercise in cerebral ischemia-induced hippocampal damage remains controversial. The aim of the present study was to evaluate the effects of pre-ischemia treadmill training on hippocampal CA1 neuronal damage after cerebral ischemia. Male adult rats were randomly divided into control, ischemia and exercise + ischemia groups. In the exercise + ischemia group, rats were subjected to running on a treadmill in a designated time schedule (5 days per week for 4 weeks). Then rats underwent cerebral ischemia induction th rough occlusion of common carotids followed by reperfusion. At 4 days after cerebral ischemia, rat learning and memory abilities were evaluated using passive avoidance memory test and rat hippocampal neuronal damage was detected using Nissl and TUNEL staining. Pre-ischemic ex-ercise signiifcantly reduced the number of TUNEL-positive cells and necrotic cell death in the hippocampal CA1 region as compared to the ischemia group. Moreover, pre-ischemic exercise significantly prevented ischemia-induced memory dysfunction. Pre-ischemic exercise mighct prevent memory deficits after cerebral ischemia through rescuing hippocampal CA1 neurons from ischemia-induced degeneration.

  13. Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference.

    Science.gov (United States)

    Pang, Kevin C H; Jiao, Xilu; Sinha, Swamini; Beck, Kevin D; Servatius, Richard J

    2011-08-01

    The medial septum and diagonal band (MSDB) are important in spatial learning and memory. On the basis of the excitotoxic damage of GABAergic MSDB neurons, we have recently suggested a role for these neurons in controlling proactive interference. Our study sought to test this hypothesis in different behavioral procedures using a new GABAergic immunotoxin. GABA-transporter-saporin (GAT1-SAP) was administered into the MSDB of male Sprague-Dawley rats. Following surgery, rats were trained in a reference memory water maze procedure for 5 days, followed by a working memory (delayed match to position) water maze procedure. Other rats were trained in a lever-press avoidance procedure after intraseptal GAT1-SAP or sham surgery. Intraseptal GAT1-SAP extensively damaged GABAergic neurons while sparing most cholinergic MSDB neurons. Rats treated with GAT1-SAP were not impaired in acquiring a spatial reference memory, learning the location of the escape platform as rapidly as sham rats. In contrast, GAT1-SAP rats were slower than sham rats to learn the platform location in a delayed match to position procedure, in which the platform location was changed every day. Moreover, GAT1-SAP rats returned to previous platform locations more often than sham rats. In the active avoidance procedure, intraseptal GAT1-SAP impaired extinction but not acquisition of the avoidance response. Using a different neurotoxin and behavioral procedures than previous studies, the results of this study paint a similar picture that GABAergic MSDB neurons are important for controlling proactive interference. Copyright © 2010 Wiley-Liss, Inc.

  14. Neural Damage in Experimental Trypanosoma brucei gambiense Infection: Hypothalamic Peptidergic Sleep and Wake-Regulatory Neurons

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    Claudia Laperchia

    2018-02-01

    Full Text Available Neuron populations of the lateral hypothalamus which synthesize the orexin (OX/hypocretin or melanin-concentrating hormone (MCH peptides play crucial, reciprocal roles in regulating wake stability and sleep. The disease human African trypanosomiasis (HAT, also called sleeping sickness, caused by extracellular Trypanosoma brucei (T. b. parasites, leads to characteristic sleep-wake cycle disruption and narcoleptic-like alterations of the sleep structure. Previous studies have revealed damage of OX and MCH neurons during systemic infection of laboratory rodents with the non-human pathogenic T. b. brucei subspecies. No information is available, however, on these peptidergic neurons after systemic infection with T. b. gambiense, the etiological agent of 97% of HAT cases. The present study was aimed at the investigation of immunohistochemically characterized OX and MCH neurons after T. b. gambiense or T. b. brucei infection of a susceptible rodent, the multimammate mouse, Mastomysnatalensis. Cell counts and evaluation of OX fiber density were performed at 4 and 8 weeks post-infection, when parasites had entered the brain parenchyma from the periphery. A significant decrease of OX neurons (about 44% reduction and MCH neurons (about 54% reduction was found in the lateral hypothalamus and perifornical area at 8 weeks in T. b. gambiense-infected M. natalensis. A moderate decrease (21% and 24% reduction, respectively, which did not reach statistical significance, was found after T. b. brucei infection. In two key targets of diencephalic orexinergic innervation, the peri-suprachiasmatic nucleus (SCN region and the thalamic paraventricular nucleus (PVT, densitometric analyses showed a significant progressive decrease in the density of orexinergic fibers in both infection paradigms, and especially during T. b. gambiense infection. Altogether the findings provide novel information showing that OX and MCH neurons are highly vulnerable to chronic

  15. Inflammatory responses are not sufficient to cause delayed neuronal death in ATP-induced acute brain injury.

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    Hey-Kyeong Jeong

    Full Text Available BACKGROUND: Brain inflammation is accompanied by brain injury. However, it is controversial whether inflammatory responses are harmful or beneficial to neurons. Because many studies have been performed using cultured microglia and neurons, it has not been possible to assess the influence of multiple cell types and diverse factors that dynamically and continuously change in vivo. Furthermore, behavior of microglia and other inflammatory cells could have been overlooked since most studies have focused on neuronal death. Therefore, it is essential to analyze the precise roles of microglia and brain inflammation in the injured brain, and determine their contribution to neuronal damage in vivo from the onset of injury. METHODS AND FINDINGS: Acute neuronal damage was induced by stereotaxic injection of ATP into the substantia nigra pars compacta (SNpc and the cortex of the rat brain. Inflammatory responses and their effects on neuronal damage were investigated by immunohistochemistry, electron microscopy, quantitative RT-PCR, and stereological counting, etc. ATP acutely caused death of microglia as well as neurons in a similar area within 3 h. We defined as the core region the area where both TH(+ and Iba-1(+ cells acutely died, and as the penumbra the area surrounding the core where Iba-1(+ cells showed activated morphology. In the penumbra region, morphologically activated microglia arranged around the injury sites. Monocytes filled the damaged core after neurons and microglia died. Interestingly, neither activated microglia nor monocytes expressed iNOS, a major neurotoxic inflammatory mediator. Monocytes rather expressed CD68, a marker of phagocytic activity. Importantly, the total number of dopaminergic neurons in the SNpc at 3 h (∼80% of that in the contralateral side did not decrease further at 7 d. Similarly, in the cortex, ATP-induced neuron-damage area detected at 3 h did not increase for up to 7 d. CONCLUSIONS: Different cellular

  16. Time Delay and Long-Range Connection Induced Synchronization Transitions in Newman-Watts Small-World Neuronal Networks

    Science.gov (United States)

    Qian, Yu

    2014-01-01

    The synchronization transitions in Newman-Watts small-world neuronal networks (SWNNs) induced by time delay and long-range connection (LRC) probability have been investigated by synchronization parameter and space-time plots. Four distinct parameter regions, that is, asynchronous region, transition region, synchronous region, and oscillatory region have been discovered at certain LRC probability as time delay is increased. Interestingly, desynchronization is observed in oscillatory region. More importantly, we consider the spatiotemporal patterns obtained in delayed Newman-Watts SWNNs are the competition results between long-range drivings (LRDs) and neighboring interactions. In addition, for moderate time delay, the synchronization of neuronal network can be enhanced remarkably by increasing LRC probability. Furthermore, lag synchronization has been found between weak synchronization and complete synchronization as LRC probability is a little less than 1.0. Finally, the two necessary conditions, moderate time delay and large numbers of LRCs, are exposed explicitly for synchronization in delayed Newman-Watts SWNNs. PMID:24810595

  17. Accumulation of neuronal DNA damage as an early covariate of determinant of death after whole-brain irradiaton

    International Nuclear Information System (INIS)

    Wheeler, K.T.; Weinstein, R.E.

    1979-01-01

    The state of the DNA from cerebellar neurons of male Sprague-Dawley rats after whole-brain irradiation with 2000 rad of x rays was determined at various times by obtaining DNA sedimentation profiles using alkaline sucrose gradients in slow reorienting zonal rotors. It took more than 4 weeks after irradiation for the neuronal DNA distributions to return to those obtained from the unirradiated controls. At 7 weeks, the DNA from irradiated neurons sedimented more rapidly than that from unirradiated neurons. Accumulation of the neuronal DNA damage (degradation.) which led to slower sedimenting DNA species began by Week 10 and continued until the majority of the irradiated rats began to die at Week 20. We propose as a working hypothesis that the accumulation of neuronal DNA damage initially observed 10 weeks after 2000 rad of whole-brain irradiation may reflect or cause changes in the central nervous system that later result in the death of the animal

  18. Chronic Ca2+ influx through voltage-dependent Ca2+ channels enhance delayed rectifier K+ currents via activating Src family tyrosine kinase in rat hippocampal neurons.

    Science.gov (United States)

    Yang, Yoon-Sil; Jeon, Sang-Chan; Kim, Dong-Kwan; Eun, Su-Yong; Jung, Sung-Cherl

    2017-03-01

    Excessive influx and the subsequent rapid cytosolic elevation of Ca 2+ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca 2+ level in normal as well as pathological conditions. Delayed rectifier K + channels (I DR channels) play a role to suppress membrane excitability by inducing K + outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca 2+ -mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of I DR channels to hyperexcitable conditions induced by high Ca 2+ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca 2+ -treatment significantly increased the amplitude of I DR without changes of gating kinetics. Nimodipine but not APV blocked Ca 2+ -induced I DR enhancement, confirming that the change of I DR might be targeted by Ca 2+ influx through voltage-dependent Ca 2+ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I DR enhancement was not affected by either Ca 2+ -induced Ca 2+ release (CICR) or small conductance Ca 2+ -activated K + channels (SK channels). Furthermore, PP2 but not H89 completely abolished I DR enhancement under high Ca 2+ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca 2+ -mediated I DR enhancement. Thus, SFKs may be sensitive to excessive Ca 2+ influx through VDCCs and enhance I DR to activate a neuroprotective mechanism against Ca 2+ -mediated hyperexcitability in neurons.

  19. Disruption of Fractalkine Signaling Leads to Microglial Activation and Neuronal Damage in the Diabetic Retina

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    Sandra M. Cardona

    2015-10-01

    Full Text Available Fractalkine (CX3CL1 or FKN is a membrane-bound chemokine expressed on neuronal membranes and is proteolytically cleaved to shed a soluble chemoattractant domain. FKN signals via its unique receptor CX3CR1 expressed on microglia and other peripheral leukocytes. The aim of this study is to determine the role of CX3CR1 in inflammatory-mediated damage to retinal neurons using a model of diabetic retinopathy. For this, we compared neuronal, microglial, and astroglial densities and inflammatory response in nondiabetic and diabetic (Ins2Akita CX3CR1-wild-type and CX3CR1-deficient mice at 10 and 20 weeks of age. Our results show that Ins2Akita CX3CR1-knockout mice exhibited (a decreased neuronal cell counts in the retinal ganglion cell layer, (b increased microglial cell numbers, and (c decreased astrocyte responses comparable with Ins2Akita CX3CR1-Wild-type mice at 20 weeks of age. Analyses of the inflammatory response using PCR arrays showed several inflammatory genes differentially regulated in diabetic tissues. From those, the response in Ins2Akita CX3CR1-deficient mice at 10 weeks of age revealed a significant upregulation of IL-1β at the transcript level that was confirmed by enzyme-linked immunosorbent assay in soluble retinal extracts. Overall, IL-1β, VEGF, and nitrite levels as a read out of nitric oxide production were abundant in Ins2Akita CX3CR1-deficient retina. Notably, double immunofluorescence staining shows that astrocytes act as a source of IL-1β in the Ins2Akita retina, and CX3CR1-deficient microglia potentiate the inflammatory response via IL-1β release. Collectively, these data demonstrate that dysregulated microglial responses in absence of CX3CR1 contribute to inflammatory-mediated damage of neurons in the diabetic retina.

  20. The Effects of Pre-Exercise Ginger Supplementation on Muscle Damage and Delayed Onset Muscle Soreness.

    Science.gov (United States)

    Matsumura, Melissa D; Zavorsky, Gerald S; Smoliga, James M

    2015-06-01

    Ginger possesses analgesic and pharmacological properties mimicking non-steroidal antiinflammatory drugs. We aimed to determine if ginger supplementation is efficacious for attenuating muscle damage and delayed onset muscle soreness (DOMS) following high-intensity resistance exercise. Following a 5-day supplementation period of placebo or 4 g ginger (randomized groups), 20 non-weight trained participants performed a high-intensity elbow flexor eccentric exercise protocol to induce muscle damage. Markers associated with muscle damage and DOMS were repeatedly measured before supplementation and for 4 days following the exercise protocol. Repeated measures analysis of variance revealed one repetition maximum lift decreased significantly 24 h post-exercise in both groups (p ginger group (p = 0.002), and improved at 72 (p = 0.021) and 96 h (p = 0.044) only in the placebo group. Blood creatine kinase significantly increased for both groups (p = 0.015) but continued to increase only in the ginger group 72 (p = 0.006) and 96 h (p = 0.027) post-exercise. Visual analog scale of pain was significantly elevated following eccentric exercise (p ginger. In conclusion, 4 g of ginger supplementation may be used to accelerate recovery of muscle strength following intense exercise but does not influence indicators of muscle damage or DOMS. Copyright © 2015 John Wiley & Sons, Ltd.

  1. Neuronal damage biomarkers in the identification of patients at risk of long-term postoperative cognitive dysfunction after cardiac surgery

    NARCIS (Netherlands)

    Kok, W F; Koerts, Janneke; Tucha, O; Scheeren, T W L; Absalom, A R

    Biomarkers of neurological injury can potentially predict postoperative cognitive dysfunction. We aimed to identify whether classical neuronal damage-specific biomarkers, including brain fatty acid-binding protein, neuron-specific enolase and S100 calcium-binding protein β, as well as plasma-free

  2. The influence of single neuron dynamics and network topology on time delay-induced multiple synchronous behaviors in inhibitory coupled network

    International Nuclear Information System (INIS)

    Zhao, Zhiguo; Gu, Huaguang

    2015-01-01

    Highlights: • Time delay-induced multiple synchronous behaviors was simulated in neuronal networks. • Multiple behaviors appear at time delays shorter than a bursting period of neurons. • The more spikes per burst of bursting, the more synchronous regions of time delay. • From regular to random via small-world networks, synchronous degree becomes weak. • An interpretation of the multiple behaviors and the influence of network are provided. - Abstract: Time delay induced-multiple synchronous behaviors are simulated in neuronal network composed of many inhibitory neurons and appear at different time delays shorter than a period of endogenous bursting of individual neurons. It is different from previous investigations wherein only one of multiple synchronous behaviors appears at time delay shorter than a period of endogenous firing and others appear at time delay longer than the period duration. The bursting patterns of the synchronous behaviors are identified based on the dynamics of an individual neuron stimulated by a signal similar to the inhibitory coupling current, which is applied at the decaying branch of a spike and suitable phase within the quiescent state of the endogenous bursting. If a burst of endogenous bursting contains more spikes, the synchronous behaviors appear at more regions of time delay. As the coupling strength increases, the multiple synchronous behaviors appear in a sequence because the different threshold of coupling current or strength is needed to achieve synchronous behaviors. From regular, to small-world, and to random networks, synchronous degree of the multiple synchronous behaviors becomes weak, and synchronous bursting patterns with lower spikes per burst disappear, which is properly interpreted by the difference of coupling current between neurons induced by different degree and the high threshold of coupling current to achieve synchronization for the absent synchronous bursting patterns. The results of the influence of

  3. Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

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    Hakuba Nobuhiro

    2010-09-01

    Full Text Available Abstract Background Because of the lack of reproducible brainstem ischemia models in rodents, the temporal profile of ischemic lesions in the brainstem after transient brainstem ischemia has not been evaluated intensively. Previously, we produced a reproducible brainstem ischemia model of Mongolian gerbils. Here, we showed the temporal profile of ischemic lesions after transient brainstem ischemia. Results Brainstem ischemia was produced by occlusion of the bilateral vertebral arteries just before their entry into the transverse foramina of the cervical vertebrae of Mongolian gerbils. Animals were subjected to brainstem ischemia for 15 min, and then reperfused for 0 d (just after ischemia, 1 d, 3 d and 7 d (n = 4 in each group. Sham-operated animals (n = 4 were used as control. After deep anesthesia, the gerbils were perfused with fixative for immunohistochemical investigation. Ischemic lesions were detected by immunostaining for microtubule-associated protein 2 (MAP2. Just after 15-min brainstem ischemia, ischemic lesions were detected in the lateral vestibular nucleus and the ventral part of the spinal trigeminal nucleus, and these ischemic lesions disappeared one day after reperfusion in all animals examined. However, 3 days and 7 days after reperfusion, ischemic lesions appeared again and clusters of ionized calcium-binding adapter molecule-1(IBA-1-positive cells were detected in the same areas in all animals. Conclusion These results suggest that delayed neuronal cell death took place in the brainstem after transient brainstem ischemia in gerbils.

  4. Taurine activates delayed rectifier KV channels via a metabotropic pathway in retinal neurons

    Science.gov (United States)

    Bulley, Simon; Liu, Yufei; Ripps, Harris; Shen, Wen

    2013-01-01

    Taurine is one of the most abundant amino acids in the retina, throughout the CNS, and in heart and muscle cells. In keeping with its broad tissue distribution, taurine serves as a modulator of numerous basic processes, such as enzyme activity, cell development, myocardial function and cytoprotection. Despite this multitude of functional roles, the precise mechanism underlying taurine's actions has not yet been identified. In this study we report findings that indicate a novel role for taurine in the regulation of voltage-gated delayed rectifier potassium (KV) channels in retinal neurons by means of a metabotropic receptor pathway. The metabotropic taurine response was insensitive to the Cl− channel blockers, picrotoxin and strychnine, but it was inhibited by a specific serotonin 5-HT2A receptor antagonist, MDL11939. Moreover, we found that taurine enhanced KV channels via intracellular protein kinase C-mediated pathways. When 5-HT2A receptors were expressed in human embryonic kidney cells, taurine and AL34662, a non-specific 5-HT2 receptor activator, produced a similar regulation of KIR channels. In sum, this study provides new evidence that taurine activates a serotonin system, apparently via 5-HT2A receptors and related intracellular pathways. PMID:23045337

  5. DNA damage and cell cycle events implicate cerebellar dentate nucleus neurons as targets of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Yang Yan

    2010-12-01

    Full Text Available Abstract Background Although the cerebellum is considered to be predominantly involved in fine motor control, emerging evidence documents its participation in language, impulsive behavior and higher cognitive functions. While the specific connections of the cerebellar deep nuclei (CDN that are responsible for these functions are still being worked out, their deficiency has been termed "cerebellar cognitive affective syndrome" - a syndrome that bears a striking similarity to many of the symptoms of Alzheimer's disease (AD. Using ectopic cell cycle events and DNA damage markers as indexes of cellular distress, we have explored the neuropathological involvement of the CDN in human AD. Results We examined the human cerebellar dentate nucleus in 22 AD cases and 19 controls for the presence of neuronal cell cycle events and DNA damage using immunohistochemistry and fluorescence in situ hybridization. Both techniques revealed several instances of highly significant correlations. By contrast, neither amyloid plaque nor neurofibrillary tangle pathology was detected in this region, consistent with previous reports of human cerebellar pathology. Five cases of early stage AD were examined and while cell cycle and DNA damage markers were well advanced in the hippocampus of all five, few indicators of either cell cycle events (1 case or a DNA damage response (1 case were found in CDN. This implies that CDN neurons are most likely affected later in the course of AD. Clinical-pathological correlations revealed that cases with moderate to high levels of cell cycle activity in their CDN are highly likely to show deficits in unorthodox cerebellar functions including speech, language and motor planning. Conclusion Our results reveal that the CDN neurons are under cellular stress in AD and suggest that some of the non-motor symptoms found in patients with AD may be partly cerebellar in origin.

  6. ATM-Dependent Phosphorylation of MEF2D Promotes Neuronal Survival after DNA Damage

    Science.gov (United States)

    Chan, Shing Fai; Sances, Sam; Brill, Laurence M.; Okamoto, Shu-ichi; Zaidi, Rameez; McKercher, Scott R.; Akhtar, Mohd W.; Nakanishi, Nobuki

    2014-01-01

    Mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a kinase critical for the normal DNA damage response, cause the neurodegenerative disorder ataxia-telangiectasia (AT). The substrates of ATM in the brain are poorly understood. Here we demonstrate that ATM phosphorylates and activates the transcription factor myocyte enhancer factor 2D (MEF2D), which plays a critical role in promoting survival of cerebellar granule cells. ATM associates with MEF2D after DNA damage and phosphorylates the transcription factor at four ATM consensus sites. Knockdown of endogenous MEF2D with a short-hairpin RNA (shRNA) increases sensitivity to etoposide-induced DNA damage and neuronal cell death. Interestingly, substitution of endogenous MEF2D with an shRNA-resistant phosphomimetic MEF2D mutant protects cerebellar granule cells from cell death after DNA damage, whereas an shRNA-resistant nonphosphorylatable MEF2D mutant does not. In vivo, cerebella in Mef2d knock-out mice manifest increased susceptibility to DNA damage. Together, our results show that MEF2D is a substrate for phosphorylation by ATM, thus promoting survival in response to DNA damage. Moreover, dysregulation of the ATM–MEF2D pathway may contribute to neurodegeneration in AT. PMID:24672010

  7. Intervention of Peiyuan Huayu Decoction on the neuron damage in model rats with acute subdural hematoma

    Directory of Open Access Journals (Sweden)

    Xiao-Xuan Fan

    2017-07-01

    Full Text Available Objective: To study the intervention effect of Peiyuan Huayu Decoction on the neuron damage in model rats with acute subdural hematoma (ASDH. Methods: 160 SD rats were randomly divided into four groups, and the ASDH model rats were made by stereotactic autoblood injection, and sham operation group received craniotomy without blood injection. Sham operation group and model group were normally bred after model establishment, and 6 h after model establishment, the treatment group received intragastric administration of Peiyuan Huayu Decoction, and control group received intragastric administration of Piracetam Tablets, 1 time a day. On the 1d, 3d, 5d and 7d after model establishment, the general conditions of rats (activity, food intake and mental state were observed, blood was collected via auricula dextra, ELISA method was used to determine peripheral plasma NSE and S100毬 protein contents, routine HE staining was conducted after perfusion fixation, the neurons in blood injection side of brain tissue were counted, and the neuron damage was observed. Results: 26 rats were dead in the experiment. The general conditions of sham operation group were significantly better than those of other groups, treatment group was significantly better than model group and control group on the 5d group (P0.05; neuron count of sham operation group was basically stable, treatment group was not different from model group and control group on the 1d (P>0.05, treatment group was better than model group (P0.05 on the 3d, and treatment group was better than model group and control group on the 5d and 7d (P0.05, S100毬 protein and NSE contents decreased significantly on the 3d, and treatment group was significantly different from model group and control group (P<0.05, S100毬 protein and NSE contents increased on the 5d and 7d, the increase in treatment group was slower than that in model group and control group, and there was significant difference (P<0.05. Conclusion

  8. Gc-protein-derived macrophage activating factor counteracts the neuronal damage induced by oxaliplatin.

    Science.gov (United States)

    Morucci, Gabriele; Branca, Jacopo J V; Gulisano, Massimo; Ruggiero, Marco; Paternostro, Ferdinando; Pacini, Alessandra; Di Cesare Mannelli, Lorenzo; Pacini, Stefania

    2015-02-01

    Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin-induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH-SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA-GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co-cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce

  9. Variational calculation of the limit cycle and its frequency in a two-neuron model with delay

    International Nuclear Information System (INIS)

    Brandt, Sebastian F.; Wessel, Ralf; Pelster, Axel

    2006-01-01

    We consider a model system of two coupled Hopfield neurons, which is described by delay differential equations taking into account the finite signal propagation and processing times. When the delay exceeds a critical value, a limit cycle emerges via a supercritical Hopf bifurcation. First, we calculate its frequency and trajectory perturbatively by applying the Poincare-Lindstedt method. Then, the perturbation series are resummed by means of the Shohat expansion in good agreement with numerical values. However, with increasing delay, the accuracy of the results from the Shohat expansion worsens. We thus apply variational perturbation theory (VPT) to the perturbation expansions to obtain more accurate results, which moreover hold even in the limit of large delays

  10. Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability

    Science.gov (United States)

    Speca, David J.; Ogata, Genki; Mandikian, Danielle; Bishop, Hannah I.; Wiler, Steve W.; Eum, Kenneth; Wenzel, H. Jürgen; Doisy, Emily T.; Matt, Lucas; Campi, Katharine L.; Golub, Mari S.; Nerbonne, Jeanne M.; Hell, Johannes W.; Trainor, Brian C.; Sack, Jon T.; Schwartzkroin, Philip A.; Trimmer, James S.

    2014-01-01

    The Kv2.1 delayed rectifier potassium channel exhibits high-level expression in both principal and inhibitory neurons throughout the central nervous system, including prominent expression in hippocampal neurons. Studies of in vitro preparations suggest that Kv2.1 is a key yet conditional regulator of intrinsic neuronal excitability, mediated by changes in Kv2.1 expression, localization and function via activity-dependent regulation of Kv2.1 phosphorylation. Here we identify neurological and behavioral deficits in mutant (Kv2.1−/−) mice lacking this channel. Kv2.1−/− mice have grossly normal characteristics. No impairment in vision or motor coordination was apparent, although Kv2.1−/− mice exhibit reduced body weight. The anatomic structure and expression of related Kv channels in the brains of Kv2.1−/− mice appears unchanged. Delayed rectifier potassium current is diminished in hippocampal neurons cultured from Kv2.1−/− animals. Field recordings from hippocampal slices of Kv2.1−/− mice reveal hyperexcitability in response to the convulsant bicuculline, and epileptiform activity in response to stimulation. In Kv2.1−/− mice, long-term potentiation at the Schaffer collateral – CA1 synapse is decreased. Kv2.1−/− mice are strikingly hyperactive, and exhibit defects in spatial learning, failing to improve performance in a Morris Water Maze task. Kv2.1−/− mice are hypersensitive to the effects of the convulsants flurothyl and pilocarpine, consistent with a role for Kv2.1 as a conditional suppressor of neuronal activity. Although not prone to spontaneous seizures, Kv2.1−/− mice exhibit accelerated seizure progression. Together, these findings suggest homeostatic suppression of elevated neuronal activity by Kv2.1 plays a central role in regulating neuronal network function. PMID:24494598

  11. Enhancement of delayed-rectifier potassium conductance by low concentrations of local anaesthetics in spinal sensory neurones

    Science.gov (United States)

    Olschewski, Andrea; Wolff, Matthias; Bräu, Michael E; Hempelmann, Gunter; Vogel, Werner; Safronov, Boris V

    2002-01-01

    Combining the patch-clamp recordings in slice preparation with the ‘entire soma isolation' method we studied action of several local anaesthetics on delayed-rectifier K+ currents in spinal dorsal horn neurones.Bupivacaine, lidocaine and mepivacaine at low concentrations (1–100 μM) enhanced delayed-rectifier K+ current in intact neurones within the spinal cord slice, while exhibiting a partial blocking effect at higher concentrations (>100 μM). In isolated somata 0.1–10 μM bupivacaine enhanced delayed-rectifier K+ current by shifting its steady-state activation characteristic and the voltage-dependence of the activation time constant to more negative potentials by 10–20 mV.Detailed analysis has revealed that bupivacaine also increased the maximum delayed-rectifier K+ conductance by changing the open probability, rather than the unitary conductance, of the channel.It is concluded that local anaesthetics show a dual effect on delayed-rectifier K+ currents by potentiating them at low concentrations and partially suppressing at high concentrations. The phenomenon observed demonstrated the complex action of local anaesthetics during spinal and epidural anaesthesia, which is not restricted to a suppression of Na+ conductance only. PMID:12055132

  12. Immediate, but Not Delayed, Microsurgical Skull Reconstruction Exacerbates Brain Damage in Experimental Traumatic Brain Injury Model

    Science.gov (United States)

    Lau, Tsz; Kaneko, Yuji; van Loveren, Harry; Borlongan, Cesario V.

    2012-01-01

    Moderate to severe traumatic brain injury (TBI) often results in malformations to the skull. Aesthetic surgical maneuvers may offer normalized skull structure, but inconsistent surgical closure of the skull area accompanies TBI. We examined whether wound closure by replacement of skull flap and bone wax would allow aesthetic reconstruction of the TBI-induced skull damage without causing any detrimental effects to the cortical tissue. Adult male Sprague-Dawley rats were subjected to TBI using the controlled cortical impact (CCI) injury model. Immediately after the TBI surgery, animals were randomly assigned to skull flap replacement with or without bone wax or no bone reconstruction, then were euthanized at five days post-TBI for pathological analyses. The skull reconstruction provided normalized gross bone architecture, but 2,3,5-triphenyltetrazolium chloride and hematoxylin and eosin staining results revealed larger cortical damage in these animals compared to those that underwent no surgical maneuver at all. Brain swelling accompanied TBI, especially the severe model, that could have relieved the intracranial pressure in those animals with no skull reconstruction. In contrast, the immediate skull reconstruction produced an upregulation of the edema marker aquaporin-4 staining, which likely prevented the therapeutic benefits of brain swelling and resulted in larger cortical infarcts. Interestingly, TBI animals introduced to a delay in skull reconstruction (i.e., 2 days post-TBI) showed significantly reduced edema and infarcts compared to those exposed to immediate skull reconstruction. That immediate, but not delayed, skull reconstruction may exacerbate TBI-induced cortical tissue damage warrants a careful consideration of aesthetic repair of the skull in TBI. PMID:22438975

  13. Global existence of periodic solutions in a simplified four-neuron BAM neural network model with multiple delays

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available We consider a simplified bidirectional associated memory (BAM neural network model with four neurons and multiple time delays. The global existence of periodic solutions bifurcating from Hopf bifurcations is investigated by applying the global Hopf bifurcation theorem due to Wu and Bendixson's criterion for high-dimensional ordinary differential equations due to Li and Muldowney. It is shown that the local Hopf bifurcation implies the global Hopf bifurcation after the second critical value of the sum of two delays. Numerical simulations supporting the theoretical analysis are also included.

  14. Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway.

    Science.gov (United States)

    Cui, Qunli; Li, Xin; Zhu, Hongcan

    2016-02-01

    Parkinson's disease (PD) is an age-related complex neurodegenerative disease that affects ≤ 80% of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It has previously been suggested that mitochondrial dysfunction, oxidative stress and oxidative damage underlie the pathogenesis of PD. Curcumin, which is a major active polyphenol component extracted from the rhizomes of Curcuma longa (Zingiberaceae), has been reported to exert neuroprotective effects on an experimental model of PD. The present study conducted a series of in vivo experiments, in order to investigate the effects of curcumin on behavioral deficits, oxidative damage and related mechanisms. The results demonstrated that curcumin was able to significantly alleviate motor dysfunction and increase suppressed tyrosine hydroxylase (TH) activity in the SNpc of rotenone (ROT)-injured rats. Biochemical measurements indicated that rats pretreated with curcumin exhibited increased glutathione (GSH) levels, and reduced reactive oxygen species activity and malondialdehyde content. Mechanistic studies demonstrated that curcumin significantly restored the expression levels of heme oxygenase-1 and quinone oxidoreductase 1, thus ameliorating ROT-induced damage in vivo, via the phosphorylation of Akt and nuclear factor erythroid 2-related factor 2 (Nrf2). Further studies indicated that the Akt/Nrf2 signaling pathway was associated with the protective role of curcumin in ROT-treated rats. Inhibiting the Akt/Nrf2 pathway using a lentiviral vector containing Nrf2-specific short hairpin RNA, or the phosphoinositide 3-kinase inhibitor LY294002, markedly reduced the expression levels of TH and GSH, ultimately attenuating the neuroprotective effects of curcumin against oxidative damage. These results indicated that curcumin was able to significantly ameliorate ROT-induced dopaminergic neuronal oxidative damage in the SNpc of rats via activation of the Akt/Nrf2 signaling pathway.

  15. Anti-Epileptic Drugs Delay Age-Related Loss of Spiral Ganglion Neurons via T-type Calcium Channel

    Science.gov (United States)

    Lei, Debin; Gao, Xia; Perez, Philip; Ohlemiller, Kevin K; Chen, Chien-Chang; Campbell, Kevin P.; Hood, Aizhen Yang; Bao, Jianxin

    2011-01-01

    Loss of spiral ganglion neurons is a major cause of age-related hearing loss (presbycusis). Despite being the third most prevalent condition afflicting elderly persons, there are no known medications to prevent presbycusis. Because calcium signaling has long been implicated in age-related neuronal death, we investigated T-type calcium channels. This family is comprised of three members (Cav3.1, Cav3.2, and Cav3.3), based on their respective main pore-forming alpha subunits: α1G, α1H, and α1I. In the present study, we report a significant delay of age-related loss of cochlear function and preservation of spiral ganglion neurons in α1H null and heterozygous mice, clearly demonstrating an important role for Cav3.2 in age-related neuronal loss. Furthermore, we show that anticonvulsant drugs from a family of T-type calcium channel blockers can significantly preserve spiral ganglion neurons during aging. To our knowledge, this is the first report of drugs capable of diminishing age-related loss of spiral ganglion neurons. PMID:21640179

  16. Glutathione-deficient Plasmodium berghei parasites exhibit growth delay and nuclear DNA damage.

    Science.gov (United States)

    Padín-Irizarry, Vivian; Colón-Lorenzo, Emilee E; Vega-Rodríguez, Joel; Castro, María Del R; González-Méndez, Ricardo; Ayala-Peña, Sylvette; Serrano, Adelfa E

    2016-06-01

    Plasmodium parasites are exposed to endogenous and exogenous oxidative stress during their complex life cycle. To minimize oxidative damage, the parasites use glutathione (GSH) and thioredoxin (Trx) as primary antioxidants. We previously showed that disruption of the Plasmodium berghei gamma-glutamylcysteine synthetase (pbggcs-ko) or the glutathione reductase (pbgr-ko) genes resulted in a significant reduction of GSH in intraerythrocytic stages, and a defect in growth in the pbggcs-ko parasites. In this report, time course experiments of parasite intraerythrocytic development and morphological studies showed a growth delay during the ring to schizont progression. Morphological analysis shows a significant reduction in size (diameter) of trophozoites and schizonts with increased number of cytoplasmic vacuoles in the pbggcs-ko parasites in comparison to the wild type (WT). Furthermore, the pbggcs-ko mutants exhibited an impaired response to oxidative stress and increased levels of nuclear DNA (nDNA) damage. Reduced GSH levels did not result in mitochondrial DNA (mtDNA) damage or protein carbonylations in neither pbggcs-ko nor pbgr-ko parasites. In addition, the pbggcs-ko mutant parasites showed an increase in mRNA expression of genes involved in oxidative stress detoxification and DNA synthesis, suggesting a potential compensatory mechanism to allow for parasite proliferation. These results reveal that low GSH levels affect parasite development through the impairment of oxidative stress reduction systems and damage to the nDNA. Our studies provide new insights into the role of the GSH antioxidant system in the intraerythrocytic development of Plasmodium parasites, with potential translation into novel pharmacological interventions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Sequestosome 1 Deficiency Delays, but Does Not Prevent Brain Damage Formation Following Acute Brain Injury in Adult Mice

    Directory of Open Access Journals (Sweden)

    Anne Sebastiani

    2017-12-01

    Full Text Available Neuronal degeneration following traumatic brain injury (TBI leads to intracellular accumulation of dysfunctional proteins and organelles. Autophagy may serve to facilitate degradation to overcome protein debris load and therefore be an important pro-survival factor. On the contrary, clearing may serve as pro-death factor by removal of essential or required proteins involved in pro-survival cascades. Sequestosome 1 (SQSTM1/p62 is a main regulator of the autophagic pathway that directs ubiquinated cargoes to autophagosomes for degradation. We show that SQSTM1 protein levels are suppressed 24 h and by trend 5 days after trauma. In line with these data the expression of Sqstm1 mRNA is reduced by 30% at day 3 after and stays depressed until day 5 after injury, indicating an impaired autophagy post controlled cortical impact (CCI. To determine the potential role of SQSTM1-dependent autophagy after TBI, mice lacking SQSTM1 (SQSTM1-KO and littermates (WT were subjected to CCI and brain lesion volume was determined 24 h and 5 days after insult. Lesion volume is 17% smaller at 24 h and immunoblotting reveals a reduction by trend of cell death marker αII-spectrin cleavage. But there is no effect on brain damage and cell death markers 5 days after trauma in SQSTM1-KO compared with WT. In line with these data neurofunctional testing does not reveal any differences. Additionally, gene expression of inflammatory (Tnf-α, iNos, Il-6, and Il-1β and protein degradation markers (Bag1 and Bag3 were quantified by real-time PCR. Protein levels of LC3, BAG1, and BAG3 were analyzed by immunoblotting. Real-time PCR reveals minor changes in inflammatory marker gene expression and reduced Bag3 mRNA levels 5 days after trauma. Immunoblotting of autophagy markers LC3, BAG1, and BAG3 does not show any difference between KO and WT 24 h and 5 days after TBI. In conclusion, genetic ablation of SQSTM1-dependent autophagy leads to a delay but shows no persistent effect on post

  18. [Approach to the relationship between the changes of the content of free zinc in hippocampus and ischemic neuronal damage].

    Science.gov (United States)

    Zhou, Zhu-Juan; Zheng, Jian; He, Ying

    2002-08-01

    To make approach to the relationship between the changes of free zinc and ischemic neuronal damage in hippocampus after forebrain ischemia/reperfusion. The models of forebrain ischemia/reperfusion were established in rats. The contents of free Zn2+ were measured by TSQ fluorescence method. The Zn2+ chelator (CaEDTA) was injected into lateral ventricles in order to evaluate the effect of free Zn2+ on ischemic neuronal damage. (1) Zn2+ fluorescence in the hilus of dentate gyrus, CA3 region and the stratum radiatum and stratum oriens of CA1 decreased slightly at forty-eight hours after reperfusion. From seventy-two hours to ninety-six hour after reperfusion, the decreased fluorescence gradually returned to the normal level, but some fluorescence dots were found in pyramidal neurons of CA1 and the hilus of dentate gyrus. Seven days after reperfusion, all the changes of the fluorescence almost recovered. (2) The cell membrane-impermeable Zn2+ chelator CaEDTA could reduce the intracellular concentration of free Zn2+ and reduced neuronal damage after forebrain ischemia/reperfusion. (1) The synaptic vesicle Zn2+ released and then translocated into postsynaptic neurons after forebrain ischemia/reperfusion and played a role in ischemic neuronal damage. (2) The cell membrane-impermeable chelator CaEDTA could provide neuroprotection.

  19. NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage.

    Science.gov (United States)

    Tang, Li-li; Wu, Yuan-bo; Fang, Chuan-qin; Qu, Ping; Gao, Zong-liang

    2016-01-15

    Microglia microvesicles (MVs) has shown to have significant biological functions under normal conditions. A diversity of miRNAs is involved in neuronal development, survival, function, and plasticity, but the exact functional role of NDRG2 and secreted miR-375 in MVs in neuron damage is poorly understood. We investigated the effect of NDRG2 and secreted miR-375 in MVs shed from M1 microglia on neuron damage. Expression of Nos2, Arg-1, miR-375, syntaxin-1A, NDRG2 and Pdk 1 were evaluated using RT-PCR or western blotting. Cell viability of N2A neuron was quantified by a MTT assay. Microglia can be polarized into different functional phenotypes. Expression of NDRG2 and Nos2 were significantly increased by LPS treatment on N9 cells, whereas treatment with IL-4 dramatically suppressed the expression of NDRG2 and remarkably elevated expression of Arg-1. Besides, MVs shed from LPS-treated N9 microglia significantly inhibited cell viability of N2A neurons and expression of syntaxin-1A, and NDRG2 interference reversed the up-regulated miR-375 in LPS-treated N9 microglia and MVs shed from LPS-treated N9 cells. Furthermore, NDRG2 could modulate miR-375 expression in N9 microglia and MVs. And miR-375 inhibitor remarkably elevated Pdk1 expression in N2A neurons. Finally, miR-375 inhibitor could reverse suppression effect of NDRG2 overexpression on cell viability of N2A neurons and expression of syntaxin-1A. Our results demonstrated that NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage. The suppression of NDRG2 and secreted miR-375 in MVs shed from M1 microglia may be potential targets for alleviation of neuron damage. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

    International Nuclear Information System (INIS)

    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell'Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto; Pellegrino, Teresa; Petretta, Mario; Riccio, Eleonora; Pisani, Antonio

    2017-01-01

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by 123 I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by 123 I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r 2 = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, 123 I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  1. Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Quan-Guang Zhang

    Full Text Available BACKGROUND: Oxidative stress is known to play an important role in the pathology of traumatic brain injury. Mitochondria are thought to be the major source of the damaging reactive oxygen species (ROS following TBI. However, recent work has revealed that the membrane, via the enzyme NADPH oxidase can also generate the superoxide radical (O(2(-, and thereby potentially contribute to the oxidative stress following TBI. The current study thus addressed the potential role of NADPH oxidase in TBI. METHODOLOGY/PRINCIPAL FINDINGS: The results revealed that NADPH oxidase activity in the cerebral cortex and hippocampal CA1 region increases rapidly following controlled cortical impact in male mice, with an early peak at 1 h, followed by a secondary peak from 24-96 h after TBI. In situ localization using oxidized hydroethidine and the neuronal marker, NeuN, revealed that the O(2(- induction occurred in neurons at 1 h after TBI. Pre- or post-treatment with the NADPH oxidase inhibitor, apocynin markedly inhibited microglial activation and oxidative stress damage. Apocynin also attenuated TBI-induction of the Alzheimer's disease proteins β-amyloid and amyloid precursor protein. Finally, both pre- and post-treatment of apocynin was also shown to induce significant neuroprotection against TBI. In addition, a NOX2-specific inhibitor, gp91ds-tat was also shown to exert neuroprotection against TBI. CONCLUSIONS/SIGNIFICANCE: As a whole, the study demonstrates that NADPH oxidase activity and superoxide production exhibit a biphasic elevation in the hippocampus and cortex following TBI, which contributes significantly to the pathology of TBI via mediation of oxidative stress damage, microglial activation, and AD protein induction in the brain following TBI.

  2. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

    Energy Technology Data Exchange (ETDEWEB)

    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell' Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto [University Federico II, Department of Advanced Biomedical Sciences, Naples (Italy); Pellegrino, Teresa [National Council of Research, Institute of Biostructure and Bioimaging, Naples (Italy); Petretta, Mario [University Federico II, Department of Translational Medical Sciences, Naples (Italy); Riccio, Eleonora; Pisani, Antonio [University of Naples Federico II, Department of Public Health, Naples (Italy)

    2017-12-15

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by {sup 123}I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by {sup 123}I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r{sup 2} = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, {sup 123}I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  3. Effects of the network structure and coupling strength on the noise-induced response delay of a neuronal network

    International Nuclear Information System (INIS)

    Ozer, Mahmut; Uzuntarla, Muhammet

    2008-01-01

    The Hodgkin-Huxley (H-H) neuron model driven by stimuli just above threshold shows a noise-induced response delay with respect to time to the first spike for a certain range of noise strengths, an effect called 'noise delayed decay' (NDD). We study the response time of a network of coupled H-H neurons, and investigate how the NDD can be affected by the connection topology of the network and the coupling strength. We show that the NDD effect exists for weak and intermediate coupling strengths, whereas it disappears for strong coupling strength regardless of the connection topology. We also show that although the network structure has very little effect on the NDD for a weak coupling strength, the network structure plays a key role for an intermediate coupling strength by decreasing the NDD effect with the increasing number of random shortcuts, and thus provides an additional operating regime, that is absent in the regular network, in which the neurons may also exploit a spike time code

  4. A Cross-Correlated Delay Shift Supervised Learning Method for Spiking Neurons with Application to Interictal Spike Detection in Epilepsy.

    Science.gov (United States)

    Guo, Lilin; Wang, Zhenzhong; Cabrerizo, Mercedes; Adjouadi, Malek

    2017-05-01

    This study introduces a novel learning algorithm for spiking neurons, called CCDS, which is able to learn and reproduce arbitrary spike patterns in a supervised fashion allowing the processing of spatiotemporal information encoded in the precise timing of spikes. Unlike the Remote Supervised Method (ReSuMe), synapse delays and axonal delays in CCDS are variants which are modulated together with weights during learning. The CCDS rule is both biologically plausible and computationally efficient. The properties of this learning rule are investigated extensively through experimental evaluations in terms of reliability, adaptive learning performance, generality to different neuron models, learning in the presence of noise, effects of its learning parameters and classification performance. Results presented show that the CCDS learning method achieves learning accuracy and learning speed comparable with ReSuMe, but improves classification accuracy when compared to both the Spike Pattern Association Neuron (SPAN) learning rule and the Tempotron learning rule. The merit of CCDS rule is further validated on a practical example involving the automated detection of interictal spikes in EEG records of patients with epilepsy. Results again show that with proper encoding, the CCDS rule achieves good recognition performance.

  5. Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons.

    Science.gov (United States)

    Song, M-K; Liu, H; Jiang, H-L; Yue, J-M; Hu, G-Y; Chen, H-Z

    2008-08-13

    Blocking specific K+ channels has been proposed as a promising strategy for the treatment of neurodegenerative diseases. Using a computational virtual screening approach and electrophysiological testing, we found four Aconitum alkaloids are potent blockers of the delayed rectifier K+ channel in rat hippocampal neurons. In the present study, we first tested the action of the four alkaloids on the voltage-gated K+, Na+ and Ca2+ currents in rat hippocampal neurons, and then identified that talatisamine is a specific blocker for the delayed rectifier K+ channel. External application of talatisamine reversibly inhibited the delayed rectifier K+ current (IK) with an IC50 value of 146.0+/-5.8 microM in a voltage-dependent manner, but exhibited very slight blocking effect on the voltage-gated Na+ and Ca2+ currents even at the high concentration of 1-3 mM. Moreover, talatisamine exerted a significant hyperpolarizing shift of the steady-state activation, but did not influence the steady state inactivation of IK and its recovery from inactivation, suggesting that talatisamine had no allosteric action on IK channel and was a pure blocker binding to the external pore entry of the channel. Our present study made the first discovery of potent and specific IK channel blocker from Aconitum alkaloids. It has been argued that suppressing K+ efflux by blocking IK channel may be favorable for Alzheimer's disease therapy. Talatisamine can therefore be considered as a leading compound worthy of further investigations.

  6. Relationship between physical exercise, muscle damage and delayed-onset muscle soreness

    Directory of Open Access Journals (Sweden)

    Denis Foschini

    2007-03-01

    Full Text Available The objective of the present study was to investigate the relationship between physical exercise involving muscle damage and delayed-onset muscle soreness (DOMS. A literature review of national and international periodicals was carried out. Muscle structures (membranes, Z-line, sarcomeres, T tubules and myofi brils can become damaged as a result of an imposed mechanical overload. Of greatest note are exercises requiring strength, particularly when muscular action is eccentric. Damage to skeletal musculature can be analyzed by direct methods (muscle biopsy or magnetic resonance or by indirect methods (maximum voluntary movement, subjective pain perception scales, analysis of enzyme and protein concentrations in blood. Creatine kinase (CK, lactate dehydrogenase (LDH, myosin heavy chain fragments, troponin-I and myoglobin can be used as indirect markers of muscle damage. Both DOMS and muscle damage can be infl uenced by the type of activity, with emphasis on eccentric muscle movements, type of exercise, velocity of the movement, interval period between series, the level of individual fi tness, this last primarily affecting beginners. When myotrauma occurs, muscle damage repair is initiated by leukocytes migrating to the injured area, although, the histamines, prostaglandins, kinins and K+ produced by neutrophils and macrophages stimulate free nerve endings in the muscle, causing the DOMS. Despite this apparent relationship between muscle damage and DOMS, it is not possible toestablish a linear relationship between these two variables, since published data are divergent. RESUMO O objetivo desse estudo foi investigar as relações do exercício físico com o dano muscular e dor muscular de início tardio (DMIT. Para tanto, foi realizada uma revisão de literatura de periódicos nacionais e internacionais. O dano muscular pode ocorrer em estruturas musculares (membranas, linha Z, sarcolema, túbulos T e miofi brilas em função da sobrecarga mec

  7. Delayed translocation of NGFI-B/RXR in glutamate stimulated neurons allows late protection by 9-cis retinoic acid

    International Nuclear Information System (INIS)

    Mathisen, Gro H.; Fallgren, Asa B.; Strom, Bjorn O.; Boldingh Debernard, Karen A.; Mohebi, Beata U.; Paulsen, Ragnhild E.

    2011-01-01

    Highlights: → NGFI-B and RXR translocate out of the nucleus after glutamate treatment. → Arresting NGFI-B/RXR in the nucleus protects neurons from excitotoxicity. → Late protection by 9-cis RA is possible due to a delayed translocation of NGFI-B/RXR. -- Abstract: Nuclear receptor and apoptosis inducer NGFI-B translocates out of the nucleus as a heterodimer with RXR in response to different apoptosis stimuli, and therefore represents a potential pharmacological target. We found that the cytosolic levels of NGFI-B and RXRα were increased in cultures of cerebellar granule neurons 2 h after treatment with glutamate (excitatory neurotransmitter in the brain, involved in stroke). To find a time-window for potential intervention the neurons were transfected with gfp-tagged expressor plasmids for NGFI-B and RXR. The default localization of NGFI-Bgfp and RXRgfp was nuclear, however, translocation out of the nucleus was observed 2-3 h after glutamate treatment. We therefore hypothesized that the time-window between treatment and translocation would allow late protection against neuronal death. The RXR ligand 9-cis retinoic acid was used to arrest NGFI-B and RXR in the nucleus. Addition of 9-cis retinoic acid 1 h after treatment with glutamate reduced the cytosolic translocation of NGFI-B and RXRα, the cytosolic translocation of NGFI-Bgfp observed in live neurons, as well as the neuronal death. However, the reduced translocation and the reduced cell death were not observed when 9-cis retinoic acid was added after 3 h. Thus, late protection from glutamate induced death by addition of 9-cis retinoic acid is possible in a time-window after apoptosis induction.

  8. PPARγ agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

    International Nuclear Information System (INIS)

    Lee, Seong-Ryong; Kim, Hahn-Young; Hong, Jung-Suk; Baek, Won-Ki; Park, Jong-Wook

    2009-01-01

    Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation with pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.

  9. Iron-induced neuronal damage in a rat model of post-traumatic stress disorder.

    Science.gov (United States)

    Zhao, Ming; Yu, Zhibo; Zhang, Yang; Huang, Xueling; Hou, Jingming; Zhao, YanGang; Luo, Wei; Chen, Lin; Ou, Lan; Li, Haitao; Zhang, Jiqiang

    2016-08-25

    Previous studies have shown that iron redistribution and deposition in the brain occurs in some neurodegenerative diseases, and oxidative damage due to abnormal iron level is a primary cause of neuronal death. In the present study, we used the single prolonged stress (SPS) model to mimic post-traumatic stress disorder (PTSD), and examined whether iron was involved in the progression of PTSD. The anxiety-like behaviors of the SPS group were assessed by the elevated plus maze (EPM) and open field tests, and iron levels were measured by inductively coupled plasma optical emission spectrometer (ICP-OES). Expression of glucocorticoid receptors and transferrin receptor 1 (TfR1) and ferritin (Fn) was detected by Western blot and immunohistochemistry in selected brain areas; TfR1 and Fn mRNA expression were detected by quantitative-polymerase chain reaction (Q-PCR). Ultrastructures of the hippocampus were observed under a transmission electron microscope. Our results showed that SPS exposure induced anxiety-like symptoms and increased the level of serum cortisol and the concentration of iron in key brain areas such as the hippocampus, prefrontal cortex, and striatum. The stress induced region-specific changes in both protein and mRNA levels of TfR1 and Fn. Moreover, swelling mitochondria and cell apoptosis were observed in neurons in brain regions with iron accumulation. We concluded that SPS stress increased iron in some cognition-related brain regions and subsequently cause neuronal injury, indicating that the iron may function in the pathology of PTSD. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Prevention of Hippocampal Neuronal Damage and Cognitive Function Deficits in Vascular Dementia by Dextromethorphan.

    Science.gov (United States)

    Xu, Xiaofeng; Zhang, Bin; Lu, Kaili; Deng, Jiangshan; Zhao, Fei; Zhao, Bing-Qiao; Zhao, Yuwu

    2016-07-01

    Dextromethorphan (DM) is a non-competitive antagonist of NMDA receptors and a widely used component of cough medicine. Recently, its indication has been extended experimentally to a wide range of disorders including inflammation-mediated central nervous system disorders such as Parkinson disease (PD) and multiple sclerosis (MS). In this study, we investigate whether DM treatment has protective effects on the hippocampal neuron damage induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]), an animal model of vascular dementia (VaD). Sprague-Dawley (SD) (10 weeks of age) rats were subjected to the 2VO, and DM was injected intraperitoneally once per day for 37 days. Neuron death, glial activation, and cognitive function were assessed at 37 days after 2VO (0.2 mg/kg, i.p., "DM-0.2" and 2 mg/kg, i.p., "DM-2"). DM-2 treatment provided protection against neuronal death and glial activation in the hippocampal CA1 subfield and reduced cognitive impairment induced by 2VO in rats. The study also demonstrates that activation of the Nrf2-HO-1 pathway and upregulation of superoxide dismutase (SOD) play important roles in these effects. These results suggest that DM is effective in treating VaD and protecting against oxidative stress, which is strongly implicated in the pathogenesis of VaD. Therefore, the present study suggests that DM treatment may represent a new and promising protective strategy for treating VaD.

  11. SIP-Based Single Neuron Stochastic Predictive Control for Non-Gaussian Networked Control Systems with Uncertain Metrology Delays

    Directory of Open Access Journals (Sweden)

    Xinying Xu

    2018-06-01

    Full Text Available In this paper, a novel data-driven single neuron predictive control strategy is proposed for non-Gaussian networked control systems with metrology delays in the information theory framework. Firstly, survival information potential (SIP, instead of minimum entropy, is used to formulate the performance index to characterize the randomness of the considered systems, which is calculated by oversampling method. Then the minimum values can be computed by optimizing the SIP-based performance index. Finally, the proposed strategy, minimum entropy method and mean square error (MSE are applied to a networked motor control system, and results demonstrated the effectiveness of the proposed strategy.

  12. ALK1 heterozygosity delays development of late normal tissue damage in the irradiated mouse kidney

    International Nuclear Information System (INIS)

    Scharpfenecker, Marion; Floot, Ben; Korlaar, Regina; Russell, Nicola S.; Stewart, Fiona A.

    2011-01-01

    Background and Purpose: Activin receptor-like kinase 1 (ALK1) is a transforming growth factor β (TGF-β) receptor, which is mainly expressed in endothelial cells regulating proliferation and migration in vitro and angiogenesis in vivo. Endothelial cells also express the co-receptor endoglin, which modulates ALK1 effects on endothelial cells. Our previous studies showed that mice with reduced endoglin levels develop less irradiation-induced vascular damage and fibrosis, caused by an impaired inflammatory response. This study was aimed at investigating the role of ALK1 in late radiation toxicity. Material and Methods: Kidneys of ALK +/+ and ALK1 +/- mice were irradiated with 14 Gy. Mice were sacrificed at 10, 20, and 30 weeks after irradiation and gene expression and protein levels were analyzed. Results: Compared to wild type littermates, ALK1 +/- mice developed less inflammation and fibrosis at 20 weeks after irradiation, but displayed an increase in pro-inflammatory and pro-fibrotic gene expression at 30 weeks. In addition, ALK1 +/- mice showed superior vascular integrity at 10 and 20 weeks after irradiation which deteriorated at 30 weeks coinciding with changes in the VEGF pathway. Conclusions: ALK1 +/- mice develop a delayed normal tissue response by modulating the inflammatory response and growth factor expression after irradiation.

  13. Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage

    Science.gov (United States)

    Sun, Kai; Fan, Jingyu; Han, Jingyan

    2015-01-01

    Ischemic stroke and ischemia/reperfusion (I/R) injury induced by thrombolytic therapy are conditions with high mortality and serious long-term physical and cognitive disabilities. They have a major impact on global public health. These disorders are associated with multiple insults to the cerebral microcirculation, including reactive oxygen species (ROS) overproduction, leukocyte adhesion and infiltration, brain blood barrier (BBB) disruption, and capillary hypoperfusion, ultimately resulting in tissue edema, hemorrhage, brain injury and delayed neuron damage. Traditional Chinese medicine (TCM) has been used in China, Korea, Japan and other Asian countries for treatment of a wide range of diseases. In China, the usage of compound TCM preparation to treat cerebrovascular diseases dates back to the Han Dynasty. Even thousands of years earlier, the medical formulary recorded many classical prescriptions for treating cerebral I/R-related diseases. This review summarizes current information and underlying mechanisms regarding the ameliorating effects of compound TCM preparation, Chinese materia medica, and active components on I/R-induced cerebral microcirculatory disturbances, brain injury and neuron damage. PMID:26579420

  14. Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions

    DEFF Research Database (Denmark)

    Liu, Dong; Croteau, Deborah L; Souza-Pinto, Nadja

    2011-01-01

    to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential......7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1(-/-)) mice to examine the possible roles of OGG1 in the vulnerability of neurons....... Cortical neurons isolated from OGG1(-/-) mice were more vulnerable to oxidative insults than were OGG1(+/+) neurons, and OGG1(-/-) mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1(+/+) mice. Accumulations of oxidative DNA...

  15. Force spectroscopy measurements show that cortical neurons exposed to excitotoxic agonists stiffen before showing evidence of bleb damage.

    Directory of Open Access Journals (Sweden)

    Shan Zou

    Full Text Available In ischemic and traumatic brain injury, hyperactivated glutamate (N-methyl-D-aspartic acid, NMDA and sodium (Nav channels trigger excitotoxic neuron death. Na(+, Ca(++ and H2O influx into affected neurons elicits swelling (increased cell volume and pathological blebbing (disassociation of the plasma membrane's bilayer from its spectrin-actomyosin matrix. Though usually conflated in injured tissue, cell swelling and blebbing are distinct processes. Around an injury core, salvageable neurons could be mildly swollen without yet having suffered the bleb-type membrane damage that, by rendering channels leaky and pumps dysfunctional, exacerbates the excitotoxic positive feedback spiral. Recognizing when neuronal inflation signifies non-lethal osmotic swelling versus blebbing should further efforts to salvage injury-penumbra neurons. To assess whether the mechanical properties of osmotically-swollen versus excitotoxically-blebbing neurons might be cytomechanically distinguishable, we measured cortical neuron elasticity (gauged via atomic force microscopy (AFM-based force spectroscopy upon brief exposure to hypotonicity or to excitotoxic agonists (glutamate and Nav channel activators, NMDA and veratridine. Though unperturbed by solution exchange per se, elasticity increased abruptly with hypotonicity, with NMDA and with veratridine. Neurons then invariably softened towards or below the pre-treatment level, sometimes starting before the washout. The initial channel-mediated stiffening bespeaks an abrupt elevation of hydrostatic pressure linked to NMDA or Nav channel-mediated ion/H2O fluxes, together with increased [Ca(++]int-mediated submembrane actomyosin contractility. The subsequent softening to below-control levels is consistent with the onset of a lethal level of bleb damage. These findings indicate that dissection/identification of molecular events during the excitotoxic transition from stiff/swollen to soft/blebbing is warranted and should be

  16. Safety of performing a delayed anastomosis during damage control laparotomy in patients with destructive colon injuries.

    Science.gov (United States)

    Ordoñez, Carlos A; Pino, Luis F; Badiel, Marisol; Sánchez, Alvaro I; Loaiza, Jhon; Ballestas, Leonardo; Puyana, Juan Carlos

    2011-12-01

    Recent studies report the safety and feasibility of performing delayed anastomosis (DA) in patients undergoing damage control laparotomy (DCL) for destructive colon injuries (DCIs). Despite accumulating experience in both civilian and military trauma, questions regarding how to best identify high-risk patients and minimize the number of anastomosis-associated complications remain. Our current practice is to perform a definitive closure of the colon during DCL, unless there is persistent acidosis, bowel wall edema, or evidence of intra-abdominal abscess. In this study, we evaluated the safety of this approach by comparing outcomes of patients with DCI who underwent definitive closure of the colon during DCL versus patients managed with colostomy with or without DCL. We performed a retrospective chart review of patients with penetrating DCI during 2003 to 2009. Severity of injury, surgical management, and clinical outcome were assessed. Sixty patients with severe gunshot wounds and three patients with stab wounds were included in the analysis. DCL was required in 30 patients, all with gunshot wounds. Three patients died within the first 48 hours, three underwent colostomy, and 24 were managed with DA. Thirty-three patients were managed with standard laparotomy: 26 patients with primary anastomosis and 7 with colostomy. Overall mortality rate was 9.5%. Three late deaths occurred in the DCL group, and only one death was associated with an anastomotic leak. Performing a DA in DCI during DCL is a reliable and feasible approach as long as severe acidosis, bowel wall edema, and/or persistent intra-abdominal infections are not present.

  17. Stability and attractive basins of multiple equilibria in delayed two-neuron networks

    International Nuclear Information System (INIS)

    Huang Yu-Jiao; Zhang Hua-Guang; Wang Zhan-Shan

    2012-01-01

    Multiple stability for two-dimensional delayed recurrent neural networks with piecewise linear activation functions of 2r (r ≥ 1) corner points is studied. Sufficient conditions are established for checking the existence of (2r + 1) 2 equilibria in delayed recurrent neural networks. Under these conditions, (r + 1) 2 equilibria are locally exponentially stable, and (2r + 1) 2 — (r + 1) 2 — r 2 equilibria are unstable. Attractive basins of stable equilibria are estimated, which are larger than invariant sets derived by decomposing state space. One example is provided to illustrate the effectiveness of our results. (general)

  18. Prediction of partial synchronization in delay-coupled nonlinear oscillators, with application to Hindmarsh–Rose neurons

    International Nuclear Information System (INIS)

    Ünal, Hakkı Ulaş; Michiels, Wim

    2013-01-01

    The full synchronization of coupled nonlinear oscillators has been widely studied. In this paper we investigate conditions for which partial synchronization of time-delayed diffusively coupled systems arises. The coupling configuration of the systems is described by a directed graph. As a novel quantitative result we first give necessary and sufficient conditions for the presence of forward invariant sets characterized by partially synchronous motion. These conditions can easily be checked from the eigenvalues and eigenvectors of the graph Laplacian. Second, we perform stability analysis of the synchronized equilibria in a (gain,delay) parameter space. For this analysis the coupled nonlinear systems are linearized around the synchronized equilibria and then the resulting characteristic function is factorized. By such a factorization, it is shown that the relation between the behaviour of different agents at the zero of the characteristic function depends on the structure of the eigenvectors of the weighted Laplacian matrix. By determining the structure of the solutions in the unstable manifold, combined with the characterization of invariant sets, we predict which partially synchronous regimes occur and estimate the corresponding coupling gain and delay values. We apply the obtained results to networks of coupled Hindmarsh–Rose neurons and verify the occurrence of the expected partially synchronous regimes by using a numerical simulation. We also make a comparison with an existing approach based on Lyapunov functionals. (paper)

  19. H2O2 INDUCES DELAYED HYPEREXCITABILITY IN NUCLEUS TRACTUS SOLITARII NEURONS

    Science.gov (United States)

    Ostrowski, Tim D.; Hasser, Eileen M.; Heesch, Cheryl M.; Kline, David D.

    2014-01-01

    Hydrogen peroxide (H2O2) is a stable reactive oxygen species and potent neuromodulator of cellular and synaptic activity. Centrally, endogenous H2O2 is elevated during bouts of hypoxia-reoxygenation, a variety of disease states, and aging. The nucleus tractus solitarii (nTS) is the central termination site of visceral afferents for homeostatic reflexes and contributes to reflex alterations during these conditions. We determined the extent to which H2O2 modulates synaptic and membrane properties in nTS neurons in rat brainstem slices. Stimulation of the tractus solitarii (which contains the sensory afferent fibers) evoked synaptic currents that were not altered by 10 – 500 μM H2O2. However, 500 μM H2O2 modulated several intrinsic membrane properties of nTS neurons, including a decrease in input resistance, hyperpolarization of resting membrane potential (RMP) and action potential (AP) threshold (THR), and an initial reduction in AP discharge to depolarizing current. H2O2 increased conductance of barium-sensitive potassium currents, and block of these currents ablated H2O2-induced changes in RMP, input resistance and AP discharge. Following washout of H2O2 AP discharge was enhanced due to depolarization of RMP and a partially maintained hyperpolarization of THR. Hyperexcitability persisted with repeated H2O2 exposure. H2O2 effects on RMP and THR were ablated by intracellular administration of the antioxidant catalase, which was immunohistochemically identified in neurons throughout the nTS. Thus, H2O2 initially reduces excitability of nTS neurons that is followed by sustained hyperexcitability, which may play a profound role in cardiorespiratory reflexes. PMID:24397952

  20. A Comparison of the Effects of Neuronal Nitric Oxide Synthase and Inducible Nitric Oxide Synthase Inhibition on Cartilage Damage

    Directory of Open Access Journals (Sweden)

    Nevzat Selim Gokay

    2016-01-01

    Full Text Available The objective of this study was to investigate the effects of selective inducible nitric oxide synthase and neuronal nitric oxide synthase inhibitors on cartilage regeneration. The study involved 27 Wistar rats that were divided into five groups. On Day 1, both knees of 3 rats were resected and placed in a formalin solution as a control group. The remaining 24 rats were separated into 4 groups, and their right knees were surgically damaged. Depending on the groups, the rats were injected with intra-articular normal saline solution, neuronal nitric oxide synthase inhibitor 7-nitroindazole (50 mg/kg, inducible nitric oxide synthase inhibitor amino-guanidine (30 mg/kg, or nitric oxide precursor L-arginine (200 mg/kg. After 21 days, the right and left knees of the rats were resected and placed in formalin solution. The samples were histopathologically examined by a blinded evaluator and scored on 8 parameters. Although selective neuronal nitric oxide synthase inhibition exhibited significant (P=0.044 positive effects on cartilage regeneration following cartilage damage, it was determined that inducible nitric oxide synthase inhibition had no statistically significant effect on cartilage regeneration. It was observed that the nitric oxide synthase activation triggered advanced arthrosis symptoms, such as osteophyte formation. The fact that selective neuronal nitric oxide synthase inhibitors were observed to have mitigating effects on the severity of the damage may, in the future, influence the development of new agents to be used in the treatment of cartilage disorders.

  1. Effects of Scopolamine and Melatonin Cotreatment on Cognition, Neuronal Damage, and Neurogenesis in the Mouse Dentate Gyrus.

    Science.gov (United States)

    Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Choi, Soo Young; Lee, Yun Lyul; Kang, Il Jun; Hwang, In Koo; Lee, Tae-Kyeong; Shin, Bich-Na; Lee, Jae-Chul; Hong, Seongkweon; Jeon, Yong Hwan; Shin, Myoung Cheol; Cho, Jun Hwi; Won, Moo-Ho; Lee, Young Joo

    2018-03-01

    It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double-labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment.

  2. Alkaloids from piper longum protect dopaminergic neurons against inflammation-mediated damage induced by intranigral injection of lipopolysaccharide.

    Science.gov (United States)

    He, Huan; Guo, Wei-Wei; Xu, Rong-Rong; Chen, Xiao-Qing; Zhang, Nan; Wu, Xia; Wang, Xiao-Min

    2016-10-24

    Alkaloids from Piper longum (PLA), extracted from P. longum, have potent anti-inflammatory effects. The aim of this study was to investigate whether PLA could protect dopaminergic neurons against inflammation-mediated damage by inhibiting microglial activation using a lipopolysaccharide (LPS)-induced dopaminergic neuronal damage rat model. The animal behaviors of rotational behavior, rotarod test and open-field test were investigated. The survival ratio of dopaminergic neurons and microglial activation were examined. The dopamine (DA) and its metabolite were detected by high performance liquid chromatography (HPLC). The effects of PLA on the expression of interleukin (IL)-6, interleukin (IL)-1β and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and nitric oxide (NO) were also estimated. We showed that the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) and DA content in the striatum were reduced after a single intranigral dose of LPS (10 μg) treatment. The survival rate of TH-ir neurons in the SNpc and DA levels in the striatum were significantly improved after treatment with PLA for 6 weeks. The over-activated microglial cells were suppressed by PLA treatment. We also observed that the levels of inflammatory cytokines, including TNF-α, IL-6 and IL-1β were decreased and the excessive production of ROS and NO were abolished after PLA treatment. Therefore, the behavioral dysfunctions induced by LPS were improved after PLA treatment. This study suggests that PLA plays a significant role in protecting dopaminergic neurons against inflammatory reaction induced damage.

  3. Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats.

    Directory of Open Access Journals (Sweden)

    Aparajita Ghosh

    Full Text Available Cerebral stroke is the leading cause of death and permanent disability among elderly people. In both humans and animals, cerebral ischemia damages the nerve cells in vulnerable regions of the brain, viz., hippocampus, cerebral cortex, cerebellum, and hypothalamus. The present study was conducted to evaluate the therapeutic efficacy of nanoencapsulated quercetin (QC in combating ischemia-reperfusion-induced neuronal damage in young and aged Swiss Albino rats. Cerebral ischemia was induced by occlusion of the common carotid arteries of both young and aged rats followed by reperfusion. Nanoencapsulated quercetin (2.7 mg/kg b wt was administered to both groups of animals via oral gavage two hours prior to ischemic insults as well as post-operation till day 3. Cerebral ischemia and 30 min consecutive reperfusion caused a substantial increase in lipid peroxidation, decreased antioxidant enzyme activities and tissue osmolality in different brain regions of both groups of animals. It also decreased mitochondrial membrane microviscosity and increased reactive oxygen species (ROS generation in different brain regions of young and aged rats. Among the brain regions studied, the hippocampus appeared to be the worst affected region showing increased upregulation of iNOS and caspase-3 activity with decreased neuronal count in the CA1 and CA3 subfields of both young and aged rats. Furthermore, three days of continuous reperfusion after ischemia caused massive damage to neuronal cells. However, it was observed that oral treatment of nanoencapsulated quercetin (2.7 mg/kg b wt resulted in downregulation of iNOS and caspase-3 activities and improved neuronal count in the hippocampal subfields even 3 days after reperfusion. Moreover, the nanoformulation imparted a significant level of protection in the antioxidant status in different brain regions, thus contributing to a better understanding of the given pathophysiological processes causing ischemic neuronal damage.

  4. The mast cell stabilizer sodium cromoglycate reduces histamine release and status epilepticus-induced neuronal damage in the rat hippocampus.

    Science.gov (United States)

    Valle-Dorado, María Guadalupe; Santana-Gómez, César Emmanuel; Orozco-Suárez, Sandra Adela; Rocha, Luisa

    2015-05-01

    Experiments were designed to evaluate changes in the histamine release, mast cell number and neuronal damage in hippocampus induced by status epilepticus. We also evaluated if sodium cromoglycate, a stabilizer of mast cells with a possible stabilizing effect on the membrane of neurons, was able to prevent the release of histamine, γ-aminobutyric acid (GABA) and glutamate during the status epilepticus. During microdialysis experiments, rats were treated with saline (SS-SE) or sodium cromoglycate (CG-SE) and 30 min later received the administration of pilocarpine to induce status epilepticus. Twenty-four hours after the status epilepticus, the brains were used to determine the neuronal damage and the number of mast cells in hippocampus. During the status epilepticus, SS-SE group showed an enhanced release of histamine (138.5%, p = 0.005), GABA (331 ± 91%, p ≤ 0.001) and glutamate (467%, p ≤ 0.001), even after diazepam administration. One day after the status epilepticus, SS-SE group demonstrated increased number of mast cells in Stratum pyramidale of CA1 (88%, p status epilepticus (p = 0.048), absence of wet-dog shakes, reduced histamine (but not GABA and glutamate) release, lower number of mast cells (p = 0.008) and reduced neuronal damage in hippocampus. Our data revealed that histamine, possibly from mast cells, is released in hippocampus during the status epilepticus. This effect may be involved in the subsequent neuronal damage and is diminished with sodium cromoglycate pretreatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Organotins in Neuronal Damage, Brain Function, and Behavior: A Short Review

    Directory of Open Access Journals (Sweden)

    Igor Ferraz da Silva

    2018-01-01

    Full Text Available The consequences of exposure to environmental contaminants have shown significant effects on brain function and behavior in different experimental models. The endocrine-disrupting chemicals (EDC present various classes of pollutants with potential neurotoxic actions, such as organotins (OTs. OTs have received special attention due to their toxic effects on the central nervous system, leading to abnormal mammalian neuroendocrine axis function. OTs are organometallic pollutants with a tin atom bound to one or more carbon atoms. OT exposure may occur through the food chain and/or contaminated water, since they have multiple applications in industry and agriculture. In addition, OTs have been used with few legal restrictions in the last decades, despite being highly toxic. In addition to their action as EDC, OTs can also cross the blood–brain barrier and show relevant neurotoxic effects, as observed in several animal model studies specifically involving the development of neurodegenerative processes, neuroinflammation, and oxidative stress. Thus, the aim of this short review is to summarize the toxic effects of the most common OT compounds, such as trimethyltin, tributyltin, triethyltin, and triphenyltin, on the brain with a focus on neuronal damage as a result of oxidative stress and neuroinflammation. We also aim to present evidence for the disruption of behavioral functions, neurotransmitters, and neuroendocrine pathways caused by OTs.

  6. Bifurcation analysis for a discrete-time Hopfield neural network of two neurons with two delays and self-connections

    International Nuclear Information System (INIS)

    Kaslik, E.; Balint, St.

    2009-01-01

    In this paper, a bifurcation analysis is undertaken for a discrete-time Hopfield neural network of two neurons with two different delays and self-connections. Conditions ensuring the asymptotic stability of the null solution are found, with respect to two characteristic parameters of the system. It is shown that for certain values of these parameters, Fold or Neimark-Sacker bifurcations occur, but Flip and codimension 2 (Fold-Neimark-Sacker, double Neimark-Sacker, resonance 1:1 and Flip-Neimark-Sacker) bifurcations may also be present. The direction and the stability of the Neimark-Sacker bifurcations are investigated by applying the center manifold theorem and the normal form theory

  7. Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.

    Directory of Open Access Journals (Sweden)

    Luis I Angel-Chavez

    Full Text Available In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV. Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.

  8. Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.

    Science.gov (United States)

    Angel-Chavez, Luis I; Acosta-Gómez, Eduardo I; Morales-Avalos, Mario; Castro, Elena; Cruzblanca, Humberto

    2015-01-01

    In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV). Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.

  9. Regulation of autophagy by AMP-activated protein kinase/ sirtuin 1 pathway reduces spinal cord neurons damage

    Directory of Open Access Journals (Sweden)

    Peng Yan

    2017-09-01

    Full Text Available Objective(s: AMP-activated protein kinase/sirtuin 1 (AMPK/SIRT1 signaling pathway has been proved to be involved in the regulation of autophagy in various models. The aim of this study was to evaluate the effect of AMPK/SIRT1 pathway on autophagy after spinal cord injury (SCI. Materials and Methods:The SCI model was established in rats in vivo and the primary spinal cord neurons were subjected to mechanical injury (MI in vitro. The apoptosis in spinal cord tissue and neurons was assessed by TUNEL staining and Hoechst 33342 staining, respectively. The autophagy-related proteins levels were detected by Western blot. The activation of AMPK/SIRT1 pathway was determined by Western blot and immunohistochemical staining. Results: We found that the apoptosis of spinal cord tissue and cell damage of spinal cord neurons was obvious after the trauma. The ratio of LC3II/LC3I and level of p62 were first increased significantly and then decreased after the trauma in vivo and in vitro, indicating the defect in autophagy. The levels of p-AMPK and SIRT1 were increased obviously after the trauma in vivo and in vitro. Further activation of the AMPK/SIRT1 pathway by pretreatment with resveratrol, a confirmed activator of the AMPK/SIRT1 pathway, alleviated the cell damage and promoted the autophagy flux via downregulation of p62 in spinal cord neurons at 24 hr after MI. Conclusion: Our results demonstrate that regulation of autophagy by AMPK/SIRT1 pathway can restrain spinal cord neurons damage, which may be a potential intervention of SCI.

  10. Regulation of autophagy by AMP-activated protein kinase/sirtuin 1 pathway reduces spinal cord neurons damage.

    Science.gov (United States)

    Yan, Peng; Bai, Liangjie; Lu, Wei; Gao, Yuzhong; Bi, Yunlong; Lv, Gang

    2017-09-01

    AMP-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway has been proved to be involved in the regulation of autophagy in various models. The aim of this study was to evaluate the effect of AMPK/SIRT1 pathway on autophagy after spinal cord injury (SCI). The SCI model was established in rats in vivo and the primary spinal cord neurons were subjected to mechanical injury (MI) in vitro . The apoptosis in spinal cord tissue and neurons was assessed by TUNEL staining and Hoechst 33342 staining, respectively. The autophagy-related proteins levels were detected by Western blot. The activation of AMPK/SIRT1 pathway was determined by Western blot and immunohistochemical staining. We found that the apoptosis of spinal cord tissue and cell damage of spinal cord neurons was obvious after the trauma. The ratio of LC3II/LC3I and level of p62 were first increased significantly and then decreased after the trauma in vivo and in vitro , indicating the defect in autophagy. The levels of p-AMPK and SIRT1 were increased obviously after the trauma in vivo and in vitro . Further activation of the AMPK/SIRT1 pathway by pretreatment with resveratrol, a confirmed activator of the AMPK/SIRT1 pathway, alleviated the cell damage and promoted the autophagy flux via downregulation of p62 in spinal cord neurons at 24 hr after MI. Our results demonstrate that regulation of autophagy by AMPK/SIRT1 pathway can restrain spinal cord neurons damage, which may be a potential intervention of SCI.

  11. Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

    Science.gov (United States)

    Li, Chunyi; Mo, Zhihuai; Lei, Junjie; Li, Huiqing; Fu, Ruying; Huang, Yanxia; Luo, Shijian; Zhang, Lei

    2018-06-01

    Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. Memory retrieval-induced activation of adult-born neurons generated in response to damage to the dentate gyrus.

    Science.gov (United States)

    Aguilar-Arredondo, Andrea; Zepeda, Angélica

    2018-04-16

    The dentate gyrus (DG) is a neurogenic structure that exhibits functional and structural reorganization after injury. Neurogenesis and functional recovery occur after brain damage, and the possible relation between both processes is a matter of study. We explored whether neurogenesis and the activation of new neurons correlated with DG recovery over time. We induced a DG lesion in young adult rats through the intrahippocampal injection of kainic acid and analyzed functional recovery and the activation of new neurons after animals performed a contextual fear memory task (CFM) or a control spatial exploratory task. We analyzed the number of BrdU+ cells that co-localized with doublecortin (DCX) or with NeuN within the damaged DG and evaluated the number of cells in each population that were labelled with the activity marker c-fos after either task. At 10 days post-lesion (dpl), a region of the granular cell layer was devoid of cells, evidencing the damaged area, whereas at 30 dpl this region was significantly smaller. At 10 dpl, the number of BrdU+/DCX+/c-fos positive cells was increased compared to the sham-lesion group, but CFM was impaired. At 30 dpl, a significantly greater number of BrdU+/NeuN+/c-fos positive cells was observed than at 10 dpl, and activation correlated with CFM recovery. Performance in the spatial exploratory task induced marginal c-fos immunoreactivity in the BrdU+/NeuN+ population. We demonstrate that neurons born after the DG was damaged survive and are activated in a time- and task-dependent manner and that activation of new neurons occurs along functional recovery.

  13. Local and global Hopf bifurcation analysis in a neutral-type neuron system with two delays

    Science.gov (United States)

    Lv, Qiuyu; Liao, Xiaofeng

    2018-03-01

    In recent years, neutral-type differential-difference equations have been applied extensively in the field of engineering, and their dynamical behaviors are more complex than that of the delay differential-difference equations. In this paper, the equations used to describe a neutral-type neural network system of differential difference equation with two delays are studied (i.e. neutral-type differential equations). Firstly, by selecting τ1, τ2 respectively as a parameter, we provide an analysis about the local stability of the zero equilibrium point of the equations, and sufficient conditions of asymptotic stability for the system are derived. Secondly, by using the theory of normal form and applying the theorem of center manifold introduced by Hassard et al., the Hopf bifurcation is found and some formulas for deciding the stability of periodic solutions and the direction of Hopf bifurcation are given. Moreover, by applying the theorem of global Hopf bifurcation, the existence of global periodic solution of the system is studied. Finally, an example is given, and some computer numerical simulations are taken to demonstrate and certify the correctness of the presented results.

  14. UV-B induces DNA damage and DNA synthesis delay in the marine diatom Cyclotella sp

    NARCIS (Netherlands)

    Buma, A.G.J.; Van Hannen, E.J.; Veldhuis, M.; Gieskes, W.W.C.

    1996-01-01

    The effect of UV-B on the occurrence of DNA damage and consequences for the cell cycle were studied in the marine diatom Cyclotella sp. DNA damage was quantified by immunofluorescent detection of thymine dimers in nuclear DNA of single cells using flow cytometry. A total UV-B dose (biologically

  15. UV-B induces DNA damage and DNA synthesis delay in the marine diatom Cyclotella sp.

    NARCIS (Netherlands)

    Buma, A.G.J.; van Hannen, E.J; Veldhuis, M.J W; Gieskes, W.W C

    The effect of UV-B on the occurrence of DNA damage and consequences for the cell cycle were studied in the marine diatom Cyclotella sp. DNA damage was quantified by immunofluorescent detection of thymine dimers in nuclear DNA of single cells using flow cytometry. A total UV-B dose (biologically

  16. Curcumin protects neuronal cells against status-epilepticus-induced hippocampal damage through induction of autophagy and inhibition of necroptosis.

    Science.gov (United States)

    Wang, Jin; Liu, Yuan; Li, Xiao-Hui; Zeng, Xiang-Chang; Li, Jian; Zhou, Jun; Xiao, Bo; Hu, Kai

    2017-05-01

    Status epilepticus, the most severe form of epilepsy, is characterized by progressive functional and structural damage in the hippocampus, ultimately leading to the development and clinical appearance of spontaneous, recurrent seizures. Although the pathogenesis underlying epileptogenesis processes remains unclear, a substantial body of evidence has shown that status epilepticus acts as an important initial factor in triggering epileptogenesis. Notably, besides classical cell death mechanisms such as apoptosis and necrosis, 2 novel regulators of cell fate known as necroptosis and autophagy, are demonstrated to be involved in neuronal damage in various neurodegenerative and neuropsychiatric disorders. However, whether necroptosis and autophagy play a role in post-status-epilepticus rat hippocampus and other epilepsy mechanisms deserves further research effort. In addition, research is needed to determine whether compounds from traditional Chinese herbs possess antiepileptic effects through the modulation of necroptosis and autophagy. In this study, we found that curcumin, a polyphenolic phytochemical extracted from the Curcuma longa plant, protects neuronal cells against status-epilepticus-induced hippocampal neuronal damage in the lithium-pilocarpine-induced status epilepticus rat model through induction of autophagy and inhibition of necroptosis.

  17. Repair of traumatic plasmalemmal damage to neurons and other eukar yotic cells

    Institute of Scientific and Technical Information of China (English)

    George D. Bittner; Christopher S. Spaeth§; Andrew D. Poon; Zachary S. Burgess; Christopher H. McGill

    2016-01-01

    The repair (sealing) of plasmalemmal damage, consisting of small holes to complete transections, is criti-cal for cell survival, especially for neurons that rarely regenerate cell bodies. We ifrst describe and evaluate different measures of cell sealing. Some measures, including morphological/ultra-structural observations, membrane potential, and input resistance, provide very ambiguous assessments of plasmalemmal sealing. In contrast, measures of ionic current lfow and dye barriers can, if appropriately used, provide more ac-curate assessments. We describe the effects of various substances (calcium, calpains, cytoskeletal proteins, ESCRT proteins, mUNC-13, NSF, PEG) and biochemical pathways (PKA, PKC, PLC, Epac, cytosolic ox-idation) on plasmalemmal sealing probability, and suggest that substances, pathways, and cellular events associated with plasmalemmal sealing have undergone a very conservative evolution. During sealing, calcium ion inlfux mobilizes vesicles and other membranous structures (lysosomes, mitochondria, etc.) in a continuous fashion to form a vesicular plug that gradually restricts diffusion of increasingly smaller molecules and ions over a period of seconds to minutes. Furthermore, we find no direct evidence that sealing occurs through the collapse and fusion of severed plasmalemmal lealfets, or in a single step involv-ing the fusion of one large wound vesicle with the nearby, undamaged plasmalemma. We describe how increases in perikaryal calcium levels following axonal transection account for observations that cell body survival decreases the closer an axon is transected to the perikaryon. Finally, we speculate on relationships between plasmalemmal sealing, Wallerian degeneration, and the ability of polyethylene glycol (PEG) to seal cell membranes and rejoin severed axonal ends–an important consideration for the future treatment of trauma to peripheral nerves. A better knowledge of biochemical pathways and cytoplasmic structures in-volved in

  18. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury

    Energy Technology Data Exchange (ETDEWEB)

    Milatovic, Dejan, E-mail: dejan.milatovic@vanderbilt.edu [Vanderbilt University School of Medicine, Department of Pediatrics, Nashville, TN (United States); Gupta, Ramesh C. [Murray State University, Breathitt Veterinary Center, Hopkinsville, KY (United States); Yu, Yingchun; Zaja-Milatovic, Snjezana [Vanderbilt University School of Medicine, Department of Pediatrics, Nashville, TN (United States); Aschner, Michael [Vanderbilt University School of Medicine, Department of Pediatrics, Nashville, TN (United States); Pharmacology and the Kennedy Center for Research on Human Development, Nashville, TN (United States)

    2011-11-15

    Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine-containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (p < 0.01) increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes (F{sub 2}-IsoPs), as well as the depletion of ATP in primary rat cortical neurons following exposure to Mn (500 {mu}M) for 2 h. These effects were protected when neurons were pretreated for 30 min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F{sub 2}-IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100 mg/kg, s.c.) 24 h. Additionally, pretreatment with vitamin E (100 mg/kg, i.p.) or ibuprofen (140 {mu}g/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F{sub 2}-IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional

  19. Temporal and spatial relationship between the death of PrP-damaged neurones and microglial activation

    NARCIS (Netherlands)

    Bate, C.; Boshuizen, R.S.; Langeveld, J.P.M.; Williams, A.

    2002-01-01

    Previous studies have demonstrated a role for microglia in the neuronal loss that occurs in the transmissible spongiform encephalopathies or prion diseases. In the present studies, the processes that lead to the death of neurones treated with synthetic peptides derived from the prion protein (PrP)

  20. Anisotropic 3D delay-damage model to simulate concrete structures

    OpenAIRE

    Gatuingt , Fabrice; Desmorat , Rodrigue; Chambart , Marion; Combescure , Didier; Guilbaud , Daniel

    2008-01-01

    International audience; High dynamic loadings lead to material degradation and structural failure. This is even more the case for concrete structures where the parts initially in compression break in ten- sion due to waves propagation and reflection. The dissymmetry of the material behavior plays a major role in such cases, dissymmetry mainly due to damage induced anisotropy. Loading induced damage is most often anisotropic and one proposes here to take advantage of such a feature to build a ...

  1. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury.

    Science.gov (United States)

    Milatovic, Dejan; Gupta, Ramesh C; Yu, Yingchun; Zaja-Milatovic, Snjezana; Aschner, Michael

    2011-11-01

    Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine-containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (pprotected when neurons were pretreated for 30 min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F(2)-IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100mg/kg, s.c.) 24h. Additionally, pretreatment with vitamin E (100mg/kg, i.p.) or ibuprofen (140 μg/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F(2)-IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional dopaminergic transmission and slowing of the progression of Mn-induced neurodegenerative processes. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

    Science.gov (United States)

    Liu, Fang; Rainosek, Shuo W; Frisch-Daiello, Jessica L; Patterson, Tucker A; Paule, Merle G; Slikker, William; Wang, Cheng; Han, Xianlin

    2015-10-01

    Sevoflurane is a volatile anesthetic that has been widely used in general anesthesia, yet its safety in pediatric use is a public concern. This study sought to evaluate whether prolonged exposure of infant monkeys to a clinically relevant concentration of sevoflurane is associated with any adverse effects on the developing brain. Infant monkeys were exposed to 2.5% sevoflurane for 9 h, and frontal cortical tissues were harvested for DNA microarray, lipidomics, Luminex protein, and histological assays. DNA microarray analysis showed that sevoflurane exposure resulted in a broad identification of differentially expressed genes (DEGs) in the monkey brain. In general, these genes were associated with nervous system development, function, and neural cell viability. Notably, a number of DEGs were closely related to lipid metabolism. Lipidomic analysis demonstrated that critical lipid components, (eg, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol) were significantly downregulated by prolonged exposure of sevoflurane. Luminex protein analysis indicated abnormal levels of cytokines in sevoflurane-exposed brains. Consistently, Fluoro-Jade C staining revealed more degenerating neurons after sevoflurane exposure. These data demonstrate that a clinically relevant concentration of sevoflurane (2.5%) is capable of inducing and maintaining an effective surgical plane of anesthesia in the developing nonhuman primate and that a prolonged exposure of 9 h resulted in profound changes in gene expression, cytokine levels, lipid metabolism, and subsequently, neuronal damage. Generally, sevoflurane-induced neuronal damage was also associated with changes in lipid content, composition, or both; and specific lipid changes could provide insights into the molecular mechanism(s) underlying anesthetic-induced neurotoxicity and may be sensitive biomarkers for the early detection of anesthetic-induced neuronal damage. Published by Oxford University Press on behalf of the

  3. Protective effect of green tea polyphenol EGCG against neuronal damage and brain edema after unilateral cerebral ischemia in gerbils.

    Science.gov (United States)

    Lee, Hyung; Bae, Jae Hoon; Lee, Seong-Ryong

    2004-09-15

    Previous studies have demonstrated that a green tea polyphenol, (-)-epigallocatechine gallate (EGCG), has a potent free radical scavenging and antioxidant effect. Glutamate leads to excitotoxicity and oxidative stress, which are important pathophysiologic responses to cerebral ischemia resulting in brain edema and neuronal damage. We investigated the effect of EGCG on excitotoxic neuronal damage in a culture system and the effect on brain edema formation and lesion after unilateral cerebral ischemia in gerbils. In vitro, excitotoxicity was induced by 24-hr incubation with N-methyl-D-aspartate (NMDA; 10 microM), AMPA (10 microM), or kainate (20 microM). EGCG (5 microM) was added to the culture media alone or with excitotoxins. We examined malondialdehyde (MDA) level and neuronal viability to evaluate the effect of EGCG. In vivo, unilateral cerebral ischemia was induced by occlusion of the right common carotid artery for 30, 60, or 90 min and followed by reperfusion of 24 hr. Brain edema, MDA, and infarction were examined to evaluate the protective effect of EGCG. EGCG (25 or 50 mg/kg, intraperitoneally) was administered twice, at 30 min before and immediately after ischemia. EGCG reduced excitotoxin-induced MDA production and neuronal damage in the culture system. In the in vivo study, treatment of gerbils with the lower EGCG dose failed to show neuroprotective effects; however, the higher EGCG dose attenuated the increase in MDA level caused by cerebral ischemia. EGCG also reduced the formation of postischemic brain edema and infarct volume. These results demonstrate EGCG may have future possibilities as a neuroprotective agent against excitotoxicity-related neurologic disorders such as brain ischemia.

  4. The importance of regulation of blood glucose levels through activation of peripheral 5'-AMP-activated protein kinase on ischemic neuronal damage.

    Science.gov (United States)

    Harada, Shinichi; Fujita-Hamabe, Wakako; Tokuyama, Shogo

    2010-09-10

    5'-AMP-activated protein kinase (AMPK) is a serine/threonine kinase that plays a key role in energy homeostasis. Recently, it was reported that centrally activated AMPK is involved in the development of ischemic neuronal damage, while the effect of peripherally activated AMPK on ischemic neuronal damage is not known. In addition, we have previously reported that the development of post-ischemic glucose intolerance could be one of the triggers for the aggravation of neuronal damage. In this study, we focused on effect of activation of peripheral or central AMPK on the development of ischemic neuronal damage. Male ddY mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histological and behavioral analysis after MCAO. In the liver and skeletal muscle, AMPK activity was not affected by MCAO. But, application of intraperitoneal metformin (250 mg/kg), an AMPK activator, significantly suppressed the development of post-ischemic glucose intolerance and ischemic neuronal damage without alteration of central AMPK activity. On the other hand, application of intracerebroventricular metformin (25, 100 microg/mouse) significantly exacerbated the development of neuronal damage observed on day 1 after MCAO, in a dose-dependent manner. These effects were significantly blocked by compound C, a specific AMPK inhibitor. These results suggest that central AMPK was activated by ischemic stress per se, however, peripheral AMPK was not altered. Furthermore, the regulation of post-ischemic glucose intolerance by activation of peripheral AMPK is of assistance for the suppression of cerebral ischemic neuronal damage. 2010 Elsevier B.V. All rights reserved.

  5. Hydrogen peroxide-induced reduction of delayed rectifier potassium current in hippocampal neurons involves oxidation of sulfhydryl groups.

    Science.gov (United States)

    Hasan, Sonia M K; Redzic, Zoran B; Alshuaib, Waleed B

    2013-07-03

    This study examined the effect of H2O2 on the delayed rectifier potassium current (IKDR) in isolated hippocampal neurons. Whole-cell voltage-clamp experiments were performed on freshly dissociated hippocampal CA1 neurons of SD rats before and after treatment with H2O2. To reveal the mechanism behind H2O2-induced changes in IKDR, cells were treated with different oxidizing and reducing agents. External application of membrane permeable H2O2 reduced the amplitude and voltage-dependence of IKDR in a concentration dependent manner. Desferoxamine (DFO), an iron-chelator that prevents hydroxyl radical (OH) generation, prevented H2O2-induced reduction in IKDR. Application of the sulfhydryl-oxidizing agent 5,5 dithio-bis-nitrobenzoic acid (DTNB) mimicked the effect of H2O2. Sulfhydryl-reducing agents dithiothreitol (DTT) and glutathione (GSH) alone did not affect IKDR; however, DTT and GSH reversed and prevented the H2O2-induced inhibition of IKDR, respectively. Membrane impermeable agents GSH and DTNB showed effects only when added intracellularly identifying intracellular sulfhydryl groups as potential targets for hydroxyl-mediated oxidation. However, the inhibitory effects of DTNB and H2O2 at the positive test potentials were completely and partially abolished by DTT, respectively, suggesting an additional mechanism of action for H2O2, that is not shared by DTNB. In summary, this study provides evidence for the redox modulation of IKDR, identifies hydroxyl radical as an intermediate oxidant responsible for the H2O2-induced decrease in current amplitude and identifies intracellular sulfhydryl groups as an oxidative target. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Human recombinant factor VIIa may improve heat intolerance in mice by attenuating hypothalamic neuronal apoptosis and damage.

    Science.gov (United States)

    Hsu, Chuan-Chih; Chen, Sheng-Hsien; Lin, Cheng-Hsien; Yung, Ming-Chi

    2014-10-01

    Intolerance to heat exposure is believed to be associated with hypothalamo-pituitary-adrenocortical (HPA) axis impairment [reflected by decreases in blood concentrations of both adrenocorticotrophic-hormone (ACTH) and corticosterone]. The purpose of this study was to determine the effect of human recombinant factor VIIa (rfVIIa) on heat intolerance, HPA axis impairment, and hypothalamic inflammation, ischemic and oxidative damage, and apoptosis in mice under heat stress. Immediately after heat stress (41.2 °C for 1 h), mice were treated with vehicle (1 mL/kg of body weight) or rfVIIa (65-270 µg/kg of body weight) and then returned to room temperature (26 °C). Mice still alive on day 4 of heat exposure were considered survivors. Cellular ischemia markers (e.g., glutamate, lactate-to-pyruvate ratio), oxidative damage markers (e.g., nitric oxide metabolite, hydroxyl radials), and pro-inflammatory cytokines (e.g., interleukin-6, interleukin-1β, tumor necrosis factor-α) in hypothalamus were determined. In addition, blood concentrations of both ACTH and corticosterone were measured. Hypothalamic cell damage was assessed by determing the neuronal damage scores, whereas the hypothalamic cell apoptosis was determined by assessing the numbers of cells stained with terminal deoxynucleotidyl transferase-mediated αUTP nick-end labeling, caspase-3-positive cells, and platelet endothelial cell adhesion molecula-1-positive cells in hypothalamus. Compared with vehicle-treated heated mice, rfVIIa-treated heated mice had significantly higher fractional survival (8/10 vs 1/10), lesser thermoregulatory deficit (34.1 vs 24.8 °C), lesser extents of ischemic, oxidative, and inflammatory markers in hypothalamus, lesser neuronal damage scores and apoptosis in hypothalamus, and lesser HPA axis impairment. Human recombinant factor VIIa appears to exert a protective effect against heatstroke by attenuating hypothalamic cell apoptosis (due to ischemic, inflammatory, and oxidative damage

  7. Forced treadmill exercise can induce stress and increase neuronal damage in a mouse model of global cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Martina Svensson

    2016-12-01

    Full Text Available Physical exercise is known to be a beneficial factor by increasing the cellular stress tolerance. In ischemic stroke, physical exercise is suggested to both limit the brain injury and facilitate behavioral recovery. In this study we investigated the effect of physical exercise on brain damage following global cerebral ischemia in mice. We aimed to study the effects of 4.5 weeks of forced treadmill running prior to ischemia on neuronal damage, neuroinflammation and its effect on general stress by measuring corticosterone in feces. We subjected C57bl/6 mice (n = 63 to either treadmill running or a sedentary program prior to induction of global ischemia. Anxious, depressive, and cognitive behaviors were analyzed. Stress levels were analyzed using a corticosterone ELISA. Inflammatory and neurological outcomes were analyzed using immunohistochemistry, multiplex electrochemoluminescence ELISA and Western blot. To our surprise, we found that forced treadmill running induced a stress response, with increased anxiety in the Open Field test and increased levels of corticosterone. In accordance, mice subjected to forced exercise prior to ischemia developed larger neuronal damage in the hippocampus and showed higher cytokine levels in the brain and blood compared to non-exercised mice. The extent of neuronal damage correlated with increased corticosterone levels. To compare forced treadmill with voluntary wheel running, we used a different set of mice that exercised freely on running wheels. These mice did not show any anxiety or increased corticosterone levels. Altogether, our results indicate that exercise pre-conditioning may not be beneficial if the animals are forced to run as it can induce a detrimental stress response.

  8. NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage.

    Science.gov (United States)

    Casas, Ana I; Geuss, Eva; Kleikers, Pamela W M; Mencl, Stine; Herrmann, Alexander M; Buendia, Izaskun; Egea, Javier; Meuth, Sven G; Lopez, Manuela G; Kleinschnitz, Christoph; Schmidt, Harald H H W

    2017-11-14

    Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage. We explain this distinct cellular distribution pattern through cell-specific knockouts. Endothelial NOX4 breaks down the BBB, while neuronal NOX4 leads to neuronal autotoxicity. Vascular smooth muscle NOX4, the common denominator of ischemia within all ischemic organs, played no apparent role. The direct neuroprotective potential of pharmacological NOX4 inhibition was confirmed in an ex vivo model, free of vascular and BBB components. Our results demonstrate that the heightened sensitivity of the brain to ischemic damage is due to an organ-specific role of NOX4 in blood-brain-barrier endothelial cells and neurons. This mechanism is conserved in at least two rodents and humans, making NOX4 a prime target for a first-in-class mechanism-based, cytoprotective therapy in the unmet high medical need indication of ischemic stroke. Copyright © 2017 the Author(s). Published by PNAS.

  9. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury

    International Nuclear Information System (INIS)

    Milatovic, Dejan; Gupta, Ramesh C.; Yu, Yingchun; Zaja-Milatovic, Snjezana; Aschner, Michael

    2011-01-01

    Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine-containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (p 2 -isoprostanes (F 2 -IsoPs), as well as the depletion of ATP in primary rat cortical neurons following exposure to Mn (500 μM) for 2 h. These effects were protected when neurons were pretreated for 30 min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F 2 -IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100 mg/kg, s.c.) 24 h. Additionally, pretreatment with vitamin E (100 mg/kg, i.p.) or ibuprofen (140 μg/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F 2 -IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional dopaminergic transmission and slowing of the progression of Mn-induced neurodegenerative

  10. Information in small neuronal ensemble activity in the hippocampal CA1 during delayed non-matching to sample performance in rats

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    Takahashi Susumu

    2009-09-01

    Full Text Available Abstract Background The matrix-like organization of the hippocampus, with its several inputs and outputs, has given rise to several theories related to hippocampal information processing. Single-cell electrophysiological studies and studies of lesions or genetically altered animals using recognition memory tasks such as delayed non-matching-to-sample (DNMS tasks support the theories. However, a complete understanding of hippocampal function necessitates knowledge of the encoding of information by multiple neurons in a single trial. The role of neuronal ensembles in the hippocampal CA1 for a DNMS task was assessed quantitatively in this study using multi-neuronal recordings and an artificial neural network classifier as a decoder. Results The activity of small neuronal ensembles (6-18 cells over brief time intervals (2-50 ms contains accurate information specifically related to the matching/non-matching of continuously presented stimuli (stimulus comparison. The accuracy of the combination of neurons pooled over all the ensembles was markedly lower than those of the ensembles over all examined time intervals. Conclusion The results show that the spatiotemporal patterns of spiking activity among cells in the small neuronal ensemble contain much information that is specifically useful for the stimulus comparison. Small neuronal networks in the hippocampal CA1 might therefore act as a comparator during recognition memory tasks.

  11. 2-Iminobiotin Superimposed on Hypothermia Protects Human Neuronal Cells from Hypoxia-Induced Cell Damage: An in Vitro Study

    Directory of Open Access Journals (Sweden)

    Karina Zitta

    2018-01-01

    Full Text Available Perinatal asphyxia represents one of the major causes of neonatal morbidity and mortality. Hypothermia is currently the only established treatment for hypoxic-ischemic encephalopathy (HIE, but additional pharmacological strategies are being explored to further reduce the damage after perinatal asphyxia. The aim of this study was to evaluate whether 2-iminobiotin (2-IB superimposed on hypothermia has the potential to attenuate hypoxia-induced injury of neuronal cells. In vitro hypoxia was induced for 7 h in neuronal IMR-32 cell cultures. Afterwards, all cultures were subjected to 25 h of hypothermia (33.5°C, and incubated with vehicle or 2-IB (10, 30, 50, 100, and 300 ng/ml. Cell morphology was evaluated by brightfield microscopy. Cell damage was analyzed by LDH assays. Production of reactive oxygen species (ROS was measured using fluorometric assays. Western blotting for PARP, Caspase-3, and the phosphorylated forms of akt and erk1/2 was conducted. To evaluate early apoptotic events and signaling, cell protein was isolated 4 h post-hypoxia and human apoptosis proteome profiler arrays were performed. Twenty-five hour after the hypoxic insult, clear morphological signs of cell damage were visible and significant LDH release as well as ROS production were observed even under hypothermic conditions. Post-hypoxic application of 2-IB (10 and 30 ng/ml reduced the hypoxia-induced LDH release but not ROS production. Phosphorylation of erk1/2 was significantly increased after hypoxia, while phosphorylation of akt, protein expression of Caspase-3 and cleavage of PARP were only slightly increased. Addition of 2-IB did not affect any of the investigated proteins. Apoptosis proteome profiler arrays performed with cellular protein obtained 4 h after hypoxia revealed that post-hypoxic application of 2-IB resulted in a ≥ 25% down regulation of 10/35 apoptosis-related proteins: Bad, Bax, Bcl-2, cleaved Caspase-3, TRAILR1, TRAILR2, PON2, p21, p27, and phospho

  12. Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage

    International Nuclear Information System (INIS)

    Park, Jung Wook; Nickel, Kwangok P.; Torres, Alexandra D.; Lee, Denis; Lambert, Paul F.; Kimple, Randall J.

    2014-01-01

    Background and purpose: Patients with human papillomavirus related (HPV+) head and neck cancers (HNCs) demonstrate improved clinical outcomes compared to traditional HPV negative (HPV−) HNC patients. We have recently shown that HPV+ HNC cells are more sensitive to radiation than HPV− HNC cells. However, roles of HPV oncogenes in regulating the response of DNA damage repair remain unknown. Material and methods: Using immortalized normal oral epithelial cell lines, HPV+ HNC derived cell lines, and HPV16 E7-transgenic mice we assessed the repair of DNA damage using γ-H2AX foci, single and split dose clonogenic survival assays, and immunoblot. The ability of E7 to modulate expression of proteins associated with DNA repair pathways was assessed by immunoblot. Results: HPV16 E7 increased retention of γ-H2AX nuclear foci and significantly decreased sublethal DNA damage repair. While phospho-ATM, phospho-ATR, Ku70, and Ku80 expressions were not altered by E7, Rad51 was induced by E7. Correspondingly, HPV+ HNC cell lines showed retention of Rad51 after γ-radiation. Conclusions: Our findings provide further understanding as to how HPV16 E7 manipulates cellular DNA damage responses that may underlie its oncogenic potential and influence the altered sensitivity to radiation seen in HPV+ HNC as compared to HPV− HNC

  13. STICK: Spike Time Interval Computational Kernel, a Framework for General Purpose Computation Using Neurons, Precise Timing, Delays, and Synchrony.

    Science.gov (United States)

    Lagorce, Xavier; Benosman, Ryad

    2015-11-01

    There has been significant research over the past two decades in developing new platforms for spiking neural computation. Current neural computers are primarily developed to mimic biology. They use neural networks, which can be trained to perform specific tasks to mainly solve pattern recognition problems. These machines can do more than simulate biology; they allow us to rethink our current paradigm of computation. The ultimate goal is to develop brain-inspired general purpose computation architectures that can breach the current bottleneck introduced by the von Neumann architecture. This work proposes a new framework for such a machine. We show that the use of neuron-like units with precise timing representation, synaptic diversity, and temporal delays allows us to set a complete, scalable compact computation framework. The framework provides both linear and nonlinear operations, allowing us to represent and solve any function. We show usability in solving real use cases from simple differential equations to sets of nonlinear differential equations leading to chaotic attractors.

  14. Activation of muscarinic receptors protects against retinal neurons damage and optic nerve degeneration in vitro and in vivo models.

    Science.gov (United States)

    Tan, Pan-Pan; Yuan, Hai-Hong; Zhu, Xu; Cui, Yong-Yao; Li, Hui; Feng, Xue-Mei; Qiu, Yu; Chen, Hong-Zhuan; Zhou, Wei

    2014-03-01

    Muscarinic acetylcholine receptor agonist pilocarpine reduces intraocular pressure (IOP) of glaucoma mainly by stimulating ciliary muscle contraction and then increasing aqueous outflow. It is of our great interest to know whether pilocarpine has the additional properties of retinal neuroprotection independent of IOP lowering in vitro and in vivo models. In rat primary retinal cultures, cell viability was measured using an MTT assay and the trypan blue exclusion method, respectively. Retinal ganglion cells (RGCs) were identified by immunofluorescence and quantified by flow cytometry. For the in vivo study, the retinal damage after retinal ischemia/reperfusion injury in rats was evaluated by histopathological study using hematoxylin and eosin staining, transmission electron microscopy, and immunohistochemical study on cleaved caspase-3, caspase-3, and ChAT. Pretreatment of pilocarpine attenuated glutamate-induced neurotoxicity of primary retinal neurons in a dose-dependent manner. Protection of pilocarpine in both retinal neurons and RGCs was largely abolished by the nonselective muscarinic receptor antagonist atropine and the M1-selective muscarinic receptor antagonist pirenzepine. After ischemia/reperfusion injury in retina, the inner retinal degeneration occurred including ganglion cell layer thinning and neuron lost, and the optic nerve underwent vacuolar changes. These degenerative changes were significantly lessened by topical application of 2% pilocarpine. In addition, the protective effect of pilocarpine on the ischemic rat retina was favorably reflected by downregulating the expression of activated apoptosis marker cleaved caspase-3 and caspase-3 and upregulating the expression of cholinergic cell marker ChAT. Taken together, this highlights pilocarpine through the activation of muscarinic receptors appear to afford significant protection against retinal neurons damage and optic nerve degeneration at clinically relevant concentrations. These data also

  15. Peripheral neuronal damage after operation and irradiation of patients with mastocarcinoma. Periphere Nervenschaeden nach Operation und Bestrahlung wegen Mammakarzinom

    Energy Technology Data Exchange (ETDEWEB)

    Ritz, H J

    1982-01-01

    Three hundred seventy-eight women uniformly operated on for pre-metastatic-spread mammary carcinoma and given, for the major part, uniform irradiation treatment were investigated. 34 women had suffered peripheral neuronal damage in the area of the shoulder and arm of the operated and irradiated side consisting in 20 cases in a lesion of the plexus brachialis, in 13 in an isolated lesion of the medial cutaneous nerve of the arm and in one case in an isolated lesion of the nerve to the serratus anterior muscle. The lesion of the plexus brachialis is generally supposed to have been caused by the irradiation, in individual cases a metastasis or tumor infiltration into the plexus or surgical damage is also considered. The isolated lesions of individual arm nerves are attributed to surgical damage or to tensile and pressure-type stress caused by inappropriate position during surgery. Moreover there was a concomitant lesion of the medial cutaneous nerve of the arm in 4, and of the nerve to the serratus anterior muscle in 8 cases. In these cases radiation-induced damage in the plexus area cannot be excluded. In 7 cases slight atrophy noted at the upper edge of the trapezius muscle led to suspect direct radiation damage of the muscle, the actual frequency of which could, however, not safely be determined because of the common subcutaneous induration at the shoulder contour.

  16. Peripheral neuronal damage after operation and irradiation of patients with mastocarcinoma. Periphere Nervenschaeden nach Operation und Bestrahlung wegen Mammakarzinom

    Energy Technology Data Exchange (ETDEWEB)

    Ritz, H J

    1982-01-01

    378 women uniformly operated on for pre-metastatic-spread mammary carcinoma and given, for the major part, uniform irradiation treatment were investigated. 34 women had suffered peripheral neuronal damage in the area of the shoulder and arm of the operated and irradiated side consisting in 20 cases in a lesion of the plexus brachialis, in 13 in an isolated lesion of the medial cutaneous nerve of the arm and in one case in an isolated lesion of the nerve to the serratus anterior muscle. The lesion of the plexus brachialis is generally supposed to have been caused by the irradiation, in individual cases a metastasis or tumor infiltration into the plexus or surgical damage is also considered. The isolated lesions of individual arm nerves are attributed to surgical damage or to tensile and pressure-type stress caused by inappropriate position during surgery. Moreover there was a concomitant lesion of the medial cutaneous nerve of the arm in 4, and of the nerve to the serratus anterior muscle in 8 cases. In these cases radiation-induced damage in the plexus area cannot be excluded. In 7 cases slight atrophy noted at the upper edge of the trapezius muscle led to suspect direct radiation damage of the muscle, the actual frequency of which could, however, not safely be determined because of the common subcutaneous induration at the shoulder contour.

  17. Neural correlates of sample-coding and reward-coding in the delay activity of neurons in the entopallium and nidopallium caudolaterale of pigeons (Columba livia).

    Science.gov (United States)

    Johnston, Melissa; Anderson, Catrona; Colombo, Michael

    2017-01-15

    We recorded neuronal activity from the nidopallium caudolaterale, the avian equivalent of mammalian prefrontal cortex, and the entopallium, the avian equivalent of the mammalian visual cortex, in four birds trained on a differential outcomes delayed matching-to-sample procedure in which one sample stimulus was followed by reward and the other was not. Despite similar incidence of reward-specific and reward-unspecific delay cell types across the two areas, overall entopallium delay activity occurred following both rewarded and non-rewarded stimuli, whereas nidopallium caudolaterale delay activity tended to occur following the rewarded stimulus but not the non-rewarded stimulus. These findings are consistent with the view that delay activity in entopallium represents a code of the sample stimulus whereas delay activity in nidopallium caudolaterale represents a code of the possibility of an upcoming reward. However, based on the types of delay cells encountered, cells in NCL also code the sample stimulus and cells in ENTO are influenced by reward. We conclude that both areas support the retention of information, but that the activity in each area is differentially modulated by factors such as reward and attentional mechanisms. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Radiation Damage to Nervous System: Designing Optimal Models for Realistic Neuron Morphology in Hippocampus

    Science.gov (United States)

    Batmunkh, Munkhbaatar; Bugay, Alexander; Bayarchimeg, Lkhagvaa; Lkhagva, Oidov

    2018-02-01

    The present study is focused on the development of optimal models of neuron morphology for Monte Carlo microdosimetry simulations of initial radiation-induced events of heavy charged particles in the specific types of cells of the hippocampus, which is the most radiation-sensitive structure of the central nervous system. The neuron geometry and particles track structures were simulated by the Geant4/Geant4-DNA Monte Carlo toolkits. The calculations were made for beams of protons and heavy ions with different energies and doses corresponding to real fluxes of galactic cosmic rays. A simple compartmental model and a complex model with realistic morphology extracted from experimental data were constructed and compared. We estimated the distribution of the energy deposition events and the production of reactive chemical species within the developed models of CA3/CA1 pyramidal neurons and DG granule cells of the rat hippocampus under exposure to different particles with the same dose. Similar distributions of the energy deposition events and concentration of some oxidative radical species were obtained in both the simplified and realistic neuron models.

  19. Are mirror neurons the basis of speech perception? Evidence from five cases with damage to the purported human mirror system

    Science.gov (United States)

    Rogalsky, Corianne; Love, Tracy; Driscoll, David; Anderson, Steven W.; Hickok, Gregory

    2013-01-01

    The discovery of mirror neurons in macaque has led to a resurrection of motor theories of speech perception. Although the majority of lesion and functional imaging studies have associated perception with the temporal lobes, it has also been proposed that the ‘human mirror system’, which prominently includes Broca’s area, is the neurophysiological substrate of speech perception. Although numerous studies have demonstrated a tight link between sensory and motor speech processes, few have directly assessed the critical prediction of mirror neuron theories of speech perception, namely that damage to the human mirror system should cause severe deficits in speech perception. The present study measured speech perception abilities of patients with lesions involving motor regions in the left posterior frontal lobe and/or inferior parietal lobule (i.e., the proposed human ‘mirror system’). Performance was at or near ceiling in patients with fronto-parietal lesions. It is only when the lesion encroaches on auditory regions in the temporal lobe that perceptual deficits are evident. This suggests that ‘mirror system’ damage does not disrupt speech perception, but rather that auditory systems are the primary substrate for speech perception. PMID:21207313

  20. Critical periods during the in situ repair of radiation-induced DNA damage in rat cerebellar neurons and 9L brain tumor cells

    International Nuclear Information System (INIS)

    Wierowski, J.V.; Thomas, R.R.; Ritter, P.; Wheeler, K.T.

    1982-01-01

    The consequences of delivering a second 1250-rad dose at various times during and after the repair of DNA damage produced by an initial 1250-rad dose were assessed in intracerebral 9L tumor cells and rat cerebellar neurons by measuring the sedimentation properties of their DNA through alkaline sucrose gradients in zonal rotors with slow gradient reorienting capabilities.In cerebellar neurons, separating the two doses by 15 min resulted in an accumulation of DNA damage as expressed by an increase in the amount of DNA sedimenting >250 S over that obtained from unirradiated controls. Although not statistically different from unirradiated controls, a slight increase in the amount of fast-sedimenting neuronal DNA also occurred when a 1-hr interval between the two doses was investigated. At intervals of 2 hr or more, no such increase in fast-sedimenting neuronal DNA was observed. None of the periods between doses resulted in an accumulation of DNA damage in intracerebral 9L tumor cells. The accumulation of this type of DNA damage in neurons but not in tumor cells suggests that avoidance of a critical period in neuronal DNA repair may someday be an important concept in the design of brain tumor therapy schedules

  1. Traumatic colon injury in damage control laparotomy-A multicenter trial: Is it safe to do a delayed anastomosis?

    Science.gov (United States)

    Tatebe, Leah Carey; Jennings, Andrew; Tatebe, Ken; Handy, Alexandra; Prajapati, Purvi; Smith, Michael; Do, Tai; Ogola, Gerald O; Gandhi, Rajesh R; Duane, Therese M; Luk, Stephen; Petrey, Laura Bruce

    2017-04-01

    Delayed colonic anastomosis after damage control laparotomy (DCL) is an alternative to colostomies during a single laparotomy (SL) in high-risk patients. However, literature suggests increased colonic leak rates up to 27% with DCL, and various reported risk factors. We evaluated our regional experience to determine if delayed colonic anastomosis was associated with worse outcomes. A multicenter retrospective cohort study was performed across three Level I trauma centers encompassing traumatic colon injuries from January 2006 through June 2014. Patients with rectal injuries or mortality within 24 hours were excluded. Patient and injury characteristics, complications, and interventions were compared between SL and DCL groups. Regional readmission data were utilized to capture complications within 6 months of index trauma. Of 267 patients, 69% had penetrating injuries, 21% underwent DCL, and the mortality rate was 4.9%. Overall, 176 received primary repair (26 in DCL), 90 had resection and anastomosis (28 in DCL), and 26 had a stoma created (10 end colostomies and 2 loop ileostomies in DCL). Thirty-five of 56 DCL patients had definitive colonic repair subsequent to their index operation. DCL patients were more likely to be hypotensive; require more resuscitation; and suffer acute kidney injury, pneumonia, adult respiratory distress syndrome, and death. Five enteric leaks (1.9%) and three enterocutaneous fistulas (ECF, 1.1%) were identified, proportionately distributed between DCL and SL (p = 1.00, p = 0.51). No difference was seen in intraperitoneal abscesses (p = 0.13) or surgical site infections (SSI, p = 0.70) between cohorts. Among SL patients, pancreas injuries portended an increased risk of intraperitoneal abscesses (p = 0.0002), as did liver injuries in DCL patients (p = 0.06). DCL was not associated with increased enteric leaks, ECF, SSI, or intraperitoneal abscesses despite nearly two-thirds having delayed repair. Despite this being a multicenter study, it is

  2. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage

    Energy Technology Data Exchange (ETDEWEB)

    Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio [Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612 (United States); Auta, James [Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612 (United States)

    2009-02-27

    Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at {alpha}1- but is a high efficacy positive allosteric modulator at {alpha}5-containing GABA{sub A} receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5

  3. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage

    International Nuclear Information System (INIS)

    Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio; Auta, James

    2009-01-01

    Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at α1- but is a high efficacy positive allosteric modulator at α5-containing GABA A receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5 mg/kg or a

  4. 25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice.

    Directory of Open Access Journals (Sweden)

    E Danielle Dean

    Full Text Available Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OHD] levels <30 ng/mL and Parkinson's disease. To investigate the effect of 25(OHD depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OHD deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP. We found there was no significant difference between control and 25(OHD-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OHD serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism.

  5. The effects of a repeated bout of eccentric exercise on indices of muscle damage and delayed onset muscle soreness.

    Science.gov (United States)

    Paddon-Jones, D; Muthalib, M; Jenkins, D

    2000-03-01

    This study examined markers of muscle damage following a repeated bout of maximal isokinetic eccentric exercise performed prior to full recovery from a previous bout. Twenty non-resistance trained volunteers were randomly assigned to a control (CON, n=10) or experimental (EXP, n=10) group. Both groups performed 36 maximal isokinetic eccentric contractions of the elbow flexors of the non-dominant arm (ECC1). The EXP group repeated the same eccentric exercise bout two days later (ECC2). Total work and peak eccentric torque were recorded during each set of ECC1 and ECC2. Isometric torque, delayed onset muscle soreness (DOMS), flexed elbow angle and plasma creatine kinase (CK) activity were measured prior to and immediately following ECC1 and ECC2. at 24h intervals for 7 days following ECC1 and finally on day 11. In both groups, all dependent variables changed significantly during the 2 days following ECC1. A further acute post-exercise impairment in isometric torque (30 +/- 5%) and flexed elbow angle (20 +/- 4%) was observed following ECC2 (p0.05). These findings suggest that when maximal isokinetic eccentric exercise is repeated two days after experiencing of contraction-induced muscle damage, the recovery time course is not significantly altered.

  6. Curcumin ameliorates hippocampal neuron damage induced by human immunodeficiency virus-1★

    OpenAIRE

    Tang, Hongmei; Pan, Rui; Fang, Wenli; Xing, Yanyan; Chen, Dexi; Chen, Xiaobao; Yu, Yuanyuan; Wang, Junbing; Gong, Zheng; Xiong, Guoyin; Dong, Jun

    2013-01-01

    Our previous studies have shown that infection with the gp120 V3 loop can cause human immunodeficiency virus-1 associated neurocognitive disorders. Curcumin has been shown to improve these effects to some degree, but the precise mechanisms remain unknown. The present study analyzed the neuroprotective effect and mechanism of curcumin in relation to hippocampal neurons. Results showed that 1 nmol/L gp120 V3 loop suppressed the growth of synapses. After administration of 1 μmol/L curcumin, syna...

  7. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP.

    Science.gov (United States)

    Krashes, Michael J; Shah, Bhavik P; Koda, Shuichi; Lowell, Bradford B

    2013-10-01

    Agouti-related peptide (AgRP) neurons of the hypothalamus release a fast transmitter (GABA) in addition to neuropeptides (neuropeptide Y [NPY] and Agouti-related peptide [AgRP]). This raises questions as to their respective functions. The acute activation of AgRP neurons robustly promotes food intake, while central injections of AgRP, NPY, or GABA agonist results in the marked escalation of food consumption with temporal variance. Given the orexigenic capability of all three of these neuroactive substances in conjunction with their coexpression in AgRP neurons, we looked to unravel their relative temporal role in driving food intake. After the acute stimulation of AgRP neurons with DREADD technology, we found that either GABA or NPY is required for the rapid stimulation of feeding, and the neuropeptide AgRP, through action on MC4 receptors, is sufficient to induce feeding over a delayed yet prolonged period. These studies help to elucidate the neurochemical mechanisms of AgRP neurons in controlling temporally distinct phases of eating. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Delayed Administration of VEGF Rescues Spinal Motor Neurons from Death with a Short Effective Time Frame in Excitotoxic Experimental Models in Vivo

    Directory of Open Access Journals (Sweden)

    Luis B Tovar-y-Romo

    2012-02-01

    Full Text Available VEGF (vascular endothelial growth factor prevents neuronal death in different models of ALS (amyotrophic lateral sclerosis, but few studies have addressed the efficacy of VEGF to protect motor neurons after the onset of symptoms, a critical point when considering VEGF as a potential therapeutic target for ALS. We studied the capability of VEGF to protect motor neurons after an excitotoxic challenge in two models of spinal neurodegeneration in rats induced by AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid administered either chronically with osmotic minipumps or acutely by microdialysis. VEGF was administered through osmotic minipumps in the chronic model or injected intracerebroventricularly in the acute model, and its effects were assessed by immunohistochemical and histological analyses and motor performance tests. In the chronic model, VEGF stopped the progression of the paralysis and protected motor neurons when administered after AMPA before the onset of the motor symptoms, whereas no protection was observed when administered after the onset. VEGF was also protective in the acute model, but with a short time window, since the protection was effective when administered 1 h but not 2 h after AMPA. Our results indicate that while VEGF has an indubitable neuroprotective effect, its therapeutic potential for halting or delaying the progression of motor neuron loss in ALS would likely have a short effective time frame.

  9. Hyperglycemia can delay left ventricular dysfunction but not autonomic damage after myocardial infarction in rodents

    Directory of Open Access Journals (Sweden)

    Brum Patricia C

    2011-04-01

    , and the autonomic dysfunction, more prominent in diabetic group, may lead, in the future, to the cardiovascular damage.

  10. The Neuroprotective Effects of Brazilian Green Propolis on Neurodegenerative Damage in Human Neuronal SH-SY5Y Cells

    Directory of Open Access Journals (Sweden)

    Junjun Ni

    2017-01-01

    Full Text Available Oxidative stress and synapse dysfunction are the major neurodegenerative damage correlated to cognitive impairment in Alzheimer’s disease (AD. We have found that Brazilian green propolis (propolis improves the cognitive functions of mild cognitive impairment patients living at high altitude; however, mechanism underlying the effects of propolis is unknown. In the present study, we investigated the effects of propolis on oxidative stress, expression of brain-derived neurotrophic factor (BDNF, and activity-regulated cytoskeleton-associated protein (Arc, the critical factors of synapse efficacy, using human neuroblastoma SH-SY5Y cells. Pretreatment with propolis significantly ameliorated the hydrogen peroxide- (H2O2- induced cytotoxicity in SH-SY5Y cells. Furthermore, propolis significantly reduced the H2O2-generated reactive oxygen species (ROS derived from mitochondria and 8-oxo-2′-deoxyguanosine (8-oxo-dG, the DNA oxidative damage marker but significantly reversed the fibrillar β-amyloid and IL-1β-impaired BDNF-induced Arc expression in SH-SY5Y cells. Furthermore, propolis significantly upregulated BDNF mRNA expression in time- and dose-dependent manners. In addition, propolis induced Arc mRNA and protein expression via phosphoinositide-3 kinase (PI3K. These observations strongly suggest that propolis protects from the neurodegenerative damage in neurons through the properties of various antioxidants. The present study provides a potential molecular mechanism of Brazilian green propolis in prevention of cognitive impairment in AD as well as aging.

  11. Difference in transient ischemia-induced neuronal damage and glucose transporter-1 immunoreactivity in the hippocampus between adult and young gerbils

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    Seung Min Park

    2016-05-01

    Full Text Available Objective(s: The alteration of glucose transporters is closely related with the pathogenesis of brain edema. We compared neuronal damage/death in the hippocampus between adult and young gerbils following transient cerebral ischemia/reperfusion and changes of glucose transporter-1(GLUT-1-immunoreactive microvessels in their ischemic hippocampal CA1 region. Materials and Methods: Transient cerebral ischemia was developed by 5-min occlusion of both common carotid arteries. Neuronal damage was examined by cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B histofluorescence staining and changes in GLUT-1 expression was carried out by immunohistochemistry. Results: About 90% of pyramidal neurons only in the adult CA1 region were damaged after ischemia/reperfusion; in the young, about 53 % of pyramidal neurons were damaged from 7 days after ischemia/reperfusion. The density of GLUT-1-immunoreactive microvessels was significantly higher in the young sham-group than that in the adult sham-group. In the ischemia-operated-groups, the density of GLUT-1-immunoreactive microvessels was significantly decreased in the adult and young at 1 and 4 days post-ischemia, respectively, thereafter, the density of GLUT-1-immunoreactive microvessels was gradually increased in both groups after ischemia/reperfusion. Conclusion: CA1 pyramidal neurons of the young gerbil were damaged much later than that in the adult and that GLUT-1-immunoreactive microvessels were significantly decreased later in the young. These data indicate that GLUT-1 might differently contribute to neuronal damage according to age after ischemic insults.

  12. Deletion of Suppressor of Cytokine Signaling 3 from Forebrain Neurons Delays Infertility and Onset of Hypothalamic Leptin Resistance in Response to a High Caloric Diet.

    Science.gov (United States)

    McEwen, Hayden J L; Inglis, Megan A; Quennell, Janette H; Grattan, David R; Anderson, Greg M

    2016-07-06

    The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction. Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the

  13. Ebselen (PZ-51) protects the Caudate putamen against hypoxia/ischemia induced neuronal damage.

    NARCIS (Netherlands)

    Knollema, S; Elting, JW; Dijkhuizen, RM; Nicolay, K; Korf, J; TerHorst, GJ

    1996-01-01

    Ebselen, a synthetic selenium-containing compound which exhibits glutathione peroxidase-like activity in vivo, is known for its beneficial effects on inflammation and tissue injury. Experiments were conducted to test whether ebselen dissolved in DiMethylSulfOxide (DMSO) could prevent damage in a rat

  14. Ebselen (PZ-51) protects the caudate putamen against hypoxia/ischemia induced neuronal damage

    NARCIS (Netherlands)

    Knollema, S.; Elting, J.W.; Dijkhuizen, R.M.; Nicolaij, K.; Korf, J.; Horst, ter G.J.

    1996-01-01

    Ebselen, a synthetic selenium-containing compound which exhibits glutathione peroxidase-like activity in vivo, is known for its beneficial effects on inflammation and tissue injury. Experiments were conducted to test whether ebselen dissolved in DiMethylSulfOxide (DMSO) could prevent damage in a rat

  15. VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway.

    Science.gov (United States)

    Wu, K W; Yang, P; Li, S S; Liu, C W; Sun, F Y

    2015-07-09

    We recently indicated that the vascular endothelial growth factor (VEGF) protects neurons against hypoxic death via enhancement of tyrosine phosphorylation of Kv1.2, an isoform of the delayed-rectifier potassium channels through activation of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. The present study investigated whether VEGF could attenuate ischemia-induced increase of the potassium currents in the hippocampal pyramidal neurons of rats after ischemic injury. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) to induce brain ischemia. The whole-cell patch-clamp technique was used to record the potassium currents of hippocampal neurons in brain slices from the ischemically injured brains of the rats 24h after MCAO. We detected that transient MCAO caused a significant increase of voltage-gated potassium currents (Kv) and outward delayed-rectifier potassium currents (IK), but not outward transient potassium currents (IA), in the ipsilateral hippocampus compared with the sham. Moreover, we found that VEGF could acutely, reversibly and voltage-dependently inhibit the ischemia-induced IK increase. This inhibitory effect of VEGF could be completely abolished by wortmannin, an inhibitor of PI3-K. Our data indicate that VEGF attenuates the ischemia-induced increase of IK via activation of the PI3-K signaling pathway. Published by Elsevier Ltd.

  16. Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice.

    Science.gov (United States)

    Sironi, Francesca; Vallarola, Antonio; Violatto, Martina Bruna; Talamini, Laura; Freschi, Mattia; De Gioia, Roberta; Capelli, Chiara; Agostini, Azzurra; Moscatelli, Davide; Tortarolo, Massimo; Bigini, Paolo; Introna, Martino; Bendotti, Caterina

    2017-12-01

    Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression. Copyright © 2017. Published by Elsevier B.V.

  17. BDNF Increases Survival and Neuronal Differentiation of Human Neural Precursor Cells Cotransplanted with a Nanofiber Gel to the Auditory Nerve in a Rat Model of Neuronal Damage

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    Yu Jiao

    2014-01-01

    Full Text Available Objectives. To study possible nerve regeneration of a damaged auditory nerve by the use of stem cell transplantation. Methods. We transplanted HNPCs to the rat AN trunk by the internal auditory meatus (IAM. Furthermore, we studied if addition of BDNF affects survival and phenotypic differentiation of the grafted HNPCs. A bioactive nanofiber gel (PA gel, in selected groups mixed with BDNF, was applied close to the implanted cells. Before transplantation, all rats had been deafened by a round window niche application of β-bungarotoxin. This neurotoxin causes a selective toxic destruction of the AN while keeping the hair cells intact. Results. Overall, HNPCs survived well for up to six weeks in all groups. However, transplants receiving the BDNF-containing PA gel demonstrated significantly higher numbers of HNPCs and neuronal differentiation. At six weeks, a majority of the HNPCs had migrated into the brain stem and differentiated. Differentiated human cells as well as neurites were observed in the vicinity of the cochlear nucleus. Conclusion. Our results indicate that human neural precursor cells (HNPC integration with host tissue benefits from additional brain derived neurotrophic factor (BDNF treatment and that these cells appear to be good candidates for further regenerative studies on the auditory nerve (AN.

  18. Multiple coherence resonances and synchronization transitions by time delay in adaptive scale-free neuronal networks with spike-timing-dependent plasticity

    International Nuclear Information System (INIS)

    Xie, Huijuan; Gong, Yubing

    2017-01-01

    In this paper, we numerically study the effect of spike-timing-dependent plasticity (STDP) on multiple coherence resonances (MCR) and synchronization transitions (ST) induced by time delay in adaptive scale-free Hodgkin–Huxley neuronal networks. It is found that STDP has a big influence on MCR and ST induced by time delay and on the effect of network average degree on the MCR and ST. MCR is enhanced or suppressed as the adjusting rate A p of STDP decreases or increases, and there is optimal A p by which ST becomes strongest. As network average degree 〈k〉 increases, ST is enhanced and there is optimal 〈k〉 at which MCR becomes strongest. Moreover, for a larger A p value, ST is enhanced more rapidly with increasing 〈k〉 and the optimal 〈k〉 for MCR increases. These results show that STDP can either enhance or suppress MCR, and there is optimal STDP that can most strongly enhance ST induced by time delay in the adaptive neuronal networks. These findings could find potential implication for the information processing and transmission in neural systems.

  19. Dental pulp stem cells promote regeneration of damaged neuron cells on the cellular model of Alzheimer's disease.

    Science.gov (United States)

    Wang, Feixiang; Jia, Yali; Liu, Jiajing; Zhai, Jinglei; Cao, Ning; Yue, Wen; He, Huixia; Pei, Xuetao

    2017-06-01

    Alzheimer's disease (AD) is an incurable neurodegenerative disease and many types of stem cells have been used in AD therapy with some favorable effects. In this study, we investigated the potential therapeutical effects of human dental pulp stem cells (hDPSCs) on AD cellular model which established by okadaic acid (OA)-induced damage to human neuroblastoma cell line, SH-SY5Y, in vitro for 24 h. After confirmed the AD cellular model, the cells were co-culture with hDPSCs by transwell co-culture system till 24 h for treatment. Then the cytomorphology of the hDPSCs-treated cells were found to restore gradually with re-elongation of retracted dendrites. Meanwhile, Cell Counting Kit-8 assay and Hoechst 33258 staining showed that hDPSCs caused significant increase in the viability and decrease in apoptosis of the model cells, respectively. Observation of DiI labeling also exhibited the prolongation dendrites in hDPSCs-treated cells which were obviously different from the retraction dendrites in AD model cells. Furthermore, specific staining of α-tubulin and F-actin demonstrated that the hDPSCs-treated cells had the morphology of restored neurons, with elongated dendrites, densely arranged microfilaments, and thickened microtubular fibrils. In addition, results from western blotting revealed that phosphorylation at Ser 396 of Tau protein was significantly suppressed by adding of hDPSCs. These results indicate that hDPSCs may promote regeneration of damaged neuron cells in vitro model of AD and may serve as a useful cell source for treatment of AD. © 2017 International Federation for Cell Biology.

  20. Juliprosopine and juliprosine from prosopis juliflora leaves induce mitochondrial damage and cytoplasmic vacuolation on cocultured glial cells and neurons.

    Science.gov (United States)

    Silva, Victor Diogenes A; Pitanga, Bruno P S; Nascimento, Ravena P; Souza, Cleide S; Coelho, Paulo Lucas C; Menezes-Filho, Noélio; Silva, André Mário M; Costa, Maria de Fátima D; El-Bachá, Ramon S; Velozo, Eudes S; Costa, Silvia L

    2013-12-16

    Prosopis juliflora is a shrub largely used for animal and human consumption. However, ingestion has been shown to induce intoxication in animals, which is characterized by neuromuscular alterations induced by mechanisms that are not yet well understood. In this study, we investigated the cytotoxicity of a total alkaloid extract (TAE) and one alkaloid fraction (F32) obtained from P. juliflora leaves to rat cortical neurons and glial cells. Nuclear magnetic resonance characterization of F32 showed that this fraction is composed of a mixture of two piperidine alkaloids, juliprosopine (majority constituent) and juliprosine. TAE and F32 at concentrations between 0.3 and 45 μg/mL were tested for 24 h on neuron/glial cell primary cocultures. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test revealed that TAE and F32 were cytotoxic to cocultures, and their IC50 values were 31.07 and 7.362 μg/mL, respectively. Exposure to a subtoxic concentration of TAE or F32 (0.3-3 μg/mL) induced vacuolation and disruption of the astrocyte monolayer and neurite network, ultrastructural changes, characterized by formation of double-membrane vacuoles, and mitochondrial damage, associated with changes in β-tubulin III and glial fibrillary acidic protein expression. Microglial proliferation was also observed in cultures exposed to TAE or F32, with increasing levels of OX-42-positive cells. Considering that F32 was more cytotoxic than TAE and that F32 reproduced in vitro the main morphologic and ultrastructural changes of "cara torta" disease, we can also suggest that piperidine alkaloids juliprosopine and juliprosine are primarily responsible for the neurotoxic damage observed in animals after they have consumed the plant.

  1. Neuroprotective effects of α-iso-cubebene against glutamate-induced damage in the HT22 hippocampal neuronal cell line.

    Science.gov (United States)

    Park, Sun Young; Jung, Won Jung; Kang, Jum Soon; Kim, Cheol-Min; Park, Geuntae; Choi, Young-Whan

    2015-02-01

    Since oxidative stress is critically involved in excitotoxic damage, we sought to determine whether the activation of the transcription factors, cAMP-responsive element binding protein (CREB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2, also known as NFE2L2), by α-iso-cubebene is involved in its protective effects against glutamate-induced neuronal cell death. Pre-treatment with α-iso-cubebene significantly attenuated glutamate-induced cytotoxicity in mouse hippocampus-derived neuronal cells. α-iso-cubebene also reduced the glutamate-induced generation of reactive oxygen species and calcium influx, thus preventing apoptotic cell death. α-iso-cubebene inhibited glutamate-induced mitochondrial membrane depolarization and, consequently, inhibited the release of the apoptosis-inducing factor from the mitochondria. Immunoblot anlaysis revealed that the phosphorylation of extracellular signal-regulated kinase (ERK) by glutamate was reduced in the presence of α-iso-cubebene. α-iso-cubebene activated protein kinase A (PKA), CREB and Nrf2, which mediate the expression of the antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1), involved in neuroprotection. In addition, α-iso-cubebene induced the expression of antioxidant responsive element and CRE transcriptional activity, thus conferring neuroprotection against glutamate-induced oxidative injury. α-iso-cubebene also induced the expression of Nrf2-dependent genes encoding HO-1 and NQO1. Furthermore, the knockdown of CREB and Nrf2 by small interfering RNA attenuated the neuroprotective effects of α-iso-cubebene. Taken together, our results indicate that α-iso-cubebene protects HT22 cells from glutamate-induced oxidative damage through the activation of Nrf2/HO-1/NQO-1, as well as through the PKA and CREB signaling pathways.

  2. Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage.

    Science.gov (United States)

    Viveros-Paredes, J M; Gonzalez-Castañeda, R E; Escalante-Castañeda, A; Tejeda-Martínez, A R; Castañeda-Achutiguí, F; Flores-Soto, M E

    2017-01-16

    Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations. Copyright © 2016 Sociedad Española de Neurología. Publicado

  3. Chronic organic manganese administration in the rat does not damage dopaminergic nigrostriatal neurons.

    Science.gov (United States)

    Yong, V W; Perry, T L; Godolphin, W J; Jones, K A; Clavier, R M; Ito, M; Foulks, J G

    1986-01-01

    In an attempt to produce an animal model of Parkinson's disease, we injected rats repeatedly with high doses of methylcyclopentadienyl manganese tricarbonyl (MMT), a compound which has been reported to lower striatal dopamine content in mice. Chronic MMT administration for up to 5 months, even though it produced a substantial elevation in brain manganese content during the period of exposure, did not destroy dopaminergic nigrostriatal neurons. This was assessed by measurements of tyrosine hydroxylase activity and contents of dopamine and its metabolites in the striatum, and by histological examination of the substantia nigra. Our results differ from those of others who administered manganese chloride in drinking water to rats. This discrepancy is unlikely to be a consequence of differences in duration of exposure or route of administration. It could be due to our having used an organic rather than an inorganic manganese compound, or to a species difference in vulnerability to organic manganese between rats and mice.

  4. Effects of adenosine monophosphate on induction of therapeutic hypothermia and neuronal damage after cardiopulmonary resuscitation in rats.

    Science.gov (United States)

    Knapp, Jürgen; Schneider, Andreas; Nees, Corinna; Bruckner, Thomas; Böttiger, Bernd W; Popp, Erik

    2014-09-01

    Animal studies and pathophysiological considerations suggest that therapeutic hypothermia after cardiopulmonary resuscitation is the more effective the earlier it is induced. Therefore this study is sought to examine whether pharmacological facilitated hypothermia by administration of 5'-adenosine monophosphate (AMP) is neuroprotective in a rat model of cardiac arrest (CA) and resuscitation. Sixty-one rats were subjected to CA. After 6 min of ventricular fibrillation advanced cardiac life support was started. After successful return of spontaneous circulation (ROSC, n=40), animals were randomized either to placebo group (n=14) or AMP group (800 mg/kg body weight, n=14). Animals were kept at an ambient temperature of 18°C for 12 h after ROSC and core body temperature was measured using a telemetry temperature probe. Neuronal damage was analyzed by counting Nissl-positive (i.e. viable) neurons and TUNEL-positive (i.e. apoptotic) cells in coronal brain sections 7 days after ROSC. Functional status evaluated on days 1, 3 and 7 after ROSC by a tape removal test. Time until core body temperature dropped to <34.0°C was 31 min [28; 45] in AMP-treated animals and 125 min [90; 180] in the control group (p=0.003). Survival until 7 days after ROSC was comparable in both groups. Also number of Nissl-positive cells (AMP: 1 [1; 7] vs. placebo: 2 [1; 3] per 100 pixel; p=0.66) and TUNEL-positive cells (AMP: 56 [44; 72] vs. placebo: 53 [41; 67] per 100 pixel; p=0.70) did not differ. Neither did AMP affect functional neurological outcome up to 7 days after ROSC. Mean arterial pressure 20 min after ROSC was 49 [45; 55] mmHg in the AMP group in comparison to 91 [83; 95] mmHg in the control group (p<0.001). Although application of AMP reduced the time to reach a core body temperature of <34°C neither survival was improved nor neuronal damage attenuated. Reason for this is probably induction of marked hypotension as an adverse reaction to AMP treatment. Copyright © 2014 Elsevier

  5. Dietary restriction delays the secretion of senescence associated secretory phenotype by reducing DNA damage response in the process of renal aging.

    Science.gov (United States)

    Wang, Wenjuan; Cai, Guangyan; Chen, Xiangmei

    2017-09-13

    Dietary restriction (DR) has multiple and essential effects in protecting against DNA damage in model organisms. Persistent DNA damage plays a central role in the process of aging. Senescence-associated secretory phenotype (SASP), as a product of cellular aging, can accelerate the process of cellular senescence as a feedback. In this study, we directly observed whether a DR of 30% for 6months in aged rats could retard SASP by delaying the progression of DNA damage and also found the specific mechanism. The results revealed that a 30% DR could significantly improve renal pathology and some metabolic characteristics. The biomarkers and products of DNA damage were decreased in the process of renal aging on a 30% DR. A series of SASP, notably cytokine, chemokine, and growth factor, were obviously reduced by DR during renal aging. The phosphorylation levels of NF-κB and IκBα in aged kidneys of DR group were markedly reduced. These findings suggest that a 30% DR for 6months can delay renal aging and reduce the accumulation of SASP by retarding the progression of DNA damage and decreasing the transcription activity of NF-κB, thus providing a target to delay renal aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. O(t-α)-synchronization and Mittag-Leffler synchronization for the fractional-order memristive neural networks with delays and discontinuous neuron activations.

    Science.gov (United States)

    Chen, Jiejie; Chen, Boshan; Zeng, Zhigang

    2018-04-01

    This paper investigates O(t -α )-synchronization and adaptive Mittag-Leffler synchronization for the fractional-order memristive neural networks with delays and discontinuous neuron activations. Firstly, based on the framework of Filippov solution and differential inclusion theory, using a Razumikhin-type method, some sufficient conditions ensuring the global O(t -α )-synchronization of considered networks are established via a linear-type discontinuous control. Next, a new fractional differential inequality is established and two new discontinuous adaptive controller is designed to achieve Mittag-Leffler synchronization between the drive system and the response systems using this inequality. Finally, two numerical simulations are given to show the effectiveness of the theoretical results. Our approach and theoretical results have a leading significance in the design of synchronized fractional-order memristive neural networks circuits involving discontinuous activations and time-varying delays. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Edaravone protects neurons in the rat substantia nigra against 6-hydroxydopamine-induced oxidative stress damage.

    Science.gov (United States)

    Liu, Xiqi; Shao, Rushing; Li, Meng; Yang, Guofeng

    2014-11-01

    To investigate the mechanism of the neuroprotective effect of edaravone in substantia nigra (SN) of the 6-OHDA-induced rat model of Parkinson's disease. Animal model of Parkinson's disease was induced in male Sprague-Dawley rats by injecting 6-OHDA into the left medial forebrain bundle. Subsequently, rats were intraperitoneally injected with 0.3, 1, or 3 mg/kg of edaravone for 14 days or with 3 mg/kg edaravone for 14 days followed by 14 days of no treatment. We evaluated the effect of edaravone on the rotational and normal behavior of the rats, and on the number of tyrosine hydroxylase (TH)-positive cells, the amount of Nissl bodies, and the levels of glutathione (GSH), and malondialdehyde (MDA) in the SN. Edaravone treatment at 3 mg/kg significantly reduced apomorphine-induced rotational behavior (P Edaravone exerted a long-term neuroprotective effects in 6-OHDA-induced PD animal model by attenuating changes in the levels of GSH and MDA in SN, caused by oxidative stress. Edaravone prevented 6-OHDA-induced behavioral changes and de-pigmentation of SN that results from the loss of dopaminergic neurons.

  8. EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages

    International Nuclear Information System (INIS)

    Gu, Da-min; Lu, Pei-Hua; Zhang, Ke; Wang, Xiang; Sun, Min; Chen, Guo-Qian; Wang, Qiong

    2015-01-01

    In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. - Highlights: • Pre-treatment of astragaloside IV (AS-IV) protects murine cortical neurons from OGD/R. • AS-IV activates Nrf2-ARE signaling in murine cortical neurons. • Nrf2 is required for AS-IV-mediated anti-oxidant and neuroprotective activities. • AS-IV stimulates HB-EGF release to trans-activate EGFR in murine cortical neurons. • EGFR mediates AS-IV-induced Nrf2 activation and neuroprotection against OGD/R

  9. EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Da-min [Department of Anesthesiology, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Lu, Pei-Hua, E-mail: lphty1_1@163.com [Department of Medical Oncology, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China); Zhang, Ke; Wang, Xiang [Department of Anesthesiology, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Sun, Min [Department of General Surgery, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Chen, Guo-Qian [Department of Clinical Laboratory, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China); Wang, Qiong, E-mail: WangQiongprof1@126.com [Department of Clinical Laboratory, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China)

    2015-02-13

    In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. - Highlights: • Pre-treatment of astragaloside IV (AS-IV) protects murine cortical neurons from OGD/R. • AS-IV activates Nrf2-ARE signaling in murine cortical neurons. • Nrf2 is required for AS-IV-mediated anti-oxidant and neuroprotective activities. • AS-IV stimulates HB-EGF release to trans-activate EGFR in murine cortical neurons. • EGFR mediates AS-IV-induced Nrf2 activation and neuroprotection against OGD/R.

  10. Phospholipase A2 is involved in galactosylsphingosine-induced astrocyte toxicity, neuronal damage and demyelination.

    Directory of Open Access Journals (Sweden)

    Cedric Misslin

    Full Text Available Krabbe disease is a fatal rare inherited lipid storage disorder affecting 1:100,000 births. This illness is caused by mutations in the galc gene encoding for the enzyme galactosylceramidase (GALC. Dysfunction of GALC has been linked to the toxic build-up of the galactolipid, galactosylsphingosine (psychosine, which induces cell death of oligodendrocytes. Previous studies show that phospholipase A2 (PLA2 may play a role in psychosine induce cell death. Here, we demonstrate that non-selective inhibition of cPLA2/sPLA2 and selective inhibition of cPLA2, but not sPLA2, also attenuates psychosine-induced cell death of human astrocytes. This study shows that extracellular calcium is required for psychosine induced cell death, but intracellular calcium release, reactive oxygen species or release of soluble factors are not involved. These findings suggest a cell autonomous effect, at least in human astrocytes. Supporting a role for PLA2 in psychosine-induced cell death of oligodendrocytes and astrocytes, the results show inhibition of PLA2 attenuates psychosine-induced decrease in the expression of astrocyte marker vimentin as well as myelin basic protein (MBP, myelin oligodendrocyte glycoprotein (MOG and the neuronal marker SMI-32 in organotypic slice cultures. These findings provide further mechanistic details of psychosine-induced death of glia and suggest a role for PLA2 in the process. This work also supports the proposal that novel drugs for Krabbe disease may require testing on astrocytes as well as oligodendrocytes for more holistic prediction of pre-clinical and clinical efficacy.

  11. The Beneficial Effect of Cape Gooseberry Juice on Carbon Tetrachloride- Induced Neuronal Damage.

    Science.gov (United States)

    Al-Olayan, Ebtesam M; El-Khadragy, Manal F; Omer, Sawsan A; Shata, Mohamed T M; Kassab, Rami B; Abdel Moneim, Ahmed E

    2016-01-01

    Cape gooseberry (Physalis peruviana L.) belongs to the Solanaceae family. Physalis has many medicinal properties however, the beneficial effect of physalis in protecting against neurotoxins has not yet been evaluated. This experimental study investigated the protective effect of physalis juice against the oxidative damage induced by carbon tetrachloride (CCl4) in the rat brain. The degrees of protection by physalis in brain tissues were evaluated by determining the brain levels of lipid peroxidation, nitric oxide, glutathione content and antioxidant enzyme activities (superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase and glutathione reductase), after CCl4) induction in the presence or absence of physalis. Adult male albino Wistar rats were divided into 4 groups, Group I served as the control group, Group II was intraperitoneally treated with 2 ml CCl4)/kg bwt for 12 weeks, Group III was supplemented with physalis juice via the drinking water for 12 weeks, Group IV was supplemented with physalis juice and was intraperitoneally injected weekly with CCl4). Treatment with CCl4) was significantly associated with a disturbance in the oxidative status in the brain tissues; this was marked by a significant (pphysalis along with CCl4) juice significantly (pphysalis juice supplemention inhibited apoptosis, as indicated by the increase of Bcl-2 immunoreactivity in brain tissue. Our results suggest that physalis juice could be effective in preventing neurotoxicity and the neuroprotective effect of physalis might be mediated via antioxidant and anti-apoptosis activities.

  12. The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

    Science.gov (United States)

    Angelo, Maria Florencia; Aguirre, Alejandra; Avilés Reyes, Rolando X; Villarreal, Alejandro; Lukin, Jerónimo; Melendez, Matías; Vanasco, Virginia; Barker, Phil; Alvarez, Silvia; Epstein, Alberto; Jerusalinsky, Diana; Ramos, Alberto Javier

    2014-01-01

    Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH) experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE) and its downstream effector Nuclear Factor Kappa B (NF-κB) have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV)-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE) and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

  13. E2F1 and E2F2 induction in response to DNA damage preserves genomic stability in neuronal cells.

    Science.gov (United States)

    Castillo, Daniela S; Campalans, Anna; Belluscio, Laura M; Carcagno, Abel L; Radicella, J Pablo; Cánepa, Eduardo T; Pregi, Nicolás

    2015-01-01

    E2F transcription factors regulate a wide range of biological processes, including the cellular response to DNA damage. In the present study, we examined whether E2F family members are transcriptionally induced following treatment with several genotoxic agents, and have a role on the cell DNA damage response. We show a novel mechanism, conserved among diverse species, in which E2F1 and E2F2, the latter specifically in neuronal cells, are transcriptionally induced after DNA damage. This upregulation leads to increased E2F1 and E2F2 protein levels as a consequence of de novo protein synthesis. Ectopic expression of these E2Fs in neuronal cells reduces the level of DNA damage following genotoxic treatment, while ablation of E2F1 and E2F2 leads to the accumulation of DNA lesions and increased apoptotic response. Cell viability and DNA repair capability in response to DNA damage induction are also reduced by the E2F1 and E2F2 deficiencies. Finally, E2F1 and E2F2 accumulate at sites of oxidative and UV-induced DNA damage, and interact with γH2AX DNA repair factor. As previously reported for E2F1, E2F2 promotes Rad51 foci formation, interacts with GCN5 acetyltransferase and induces histone acetylation following genotoxic insult. The results presented here unveil a new mechanism involving E2F1 and E2F2 in the maintenance of genomic stability in response to DNA damage in neuronal cells.

  14. Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons.

    Science.gov (United States)

    Sendrowski, Krzysztof; Sobaniec, Wojciech; Stasiak-Barmuta, Anna; Sobaniec, Piotr; Popko, Janusz

    2015-04-01

    Alzheimer's disease (AD) is a common neurodegenerative disorder, in which progressive neuron loss, mainly in the hippocampus, is observed. The critical events in the pathogenesis of AD are associated with accumulation of β-amyloid (Aβ) peptides in the brain. Deposits of Aβ initiate a neurotoxic "cascade" leading to apoptotic death of neurons. Aim of this study was to assess a putative neuroprotective effects of two nootropic drugs: piracetam (PIR) and levetiracetam (LEV) on Aβ-injured hippocampal neurons in culture. Primary cultures of rat's hippocampal neurons at 7 day in vitro were exposed to Aβ(25-35) in the presence or absence of nootropics in varied concentrations. Flow cytometry with Annexin V/PI staining was used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Aβ(25-35) caused concentration-dependent death of about one third number of hippocampal neurons, mainly through an apoptotic pathway. In drugs-containing cultures, number of neurons injured with 20 μM Aβ(25-35) was about one-third lesser for PIR and almost two-fold lesser for LEV. When 40 μM Aβ(25-35) was used, only LEV exerted beneficial neuroprotective action, while PIR was ineffective. Our results suggest the protective potential of both studied nootropics against Aβ-induced death of cultured hippocampal neurons with more powerful neuroprotective effects of LEV. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  15. Anti-oxidative and anti-inflammatory effects of cinnamaldehyde on protecting high glucose-induced damage in cultured dorsal root ganglion neurons of rats.

    Science.gov (United States)

    Yang, Dan; Liang, Xiao-Chun; Shi, Yue; Sun, Qing; Liu, Di; Liu, Wei; Zhang, Hong

    2016-01-01

    To examine the mechanism underlying the beneficial role of cinnamaldehyde on oxidative damage and apoptosis in high glucose (HG)-induced dorsal root ganglion (DRG) neurons in vitro. HG-treated DRG neurons were developed as an in vitro model of diabetic neuropathy. The neurons were randomly divided into five groups: the control group, the HG group and the HG groups treated with 25, 50 and 100 nmol/L cinnamaldehyde, respectively. Cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis rate was evaluated by the in situ TdT-mediated dUTP nick end labeling (TUNEL) assay. The intracellular level of reactive oxygen species (ROS) was measured with flow cytometry. Expression of nuclear factor-kappa B (NF-κB), inhibitor of κB (IκB), phosphorylated IκB (p-IκB), tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and caspase-3 were determined by western blotting and real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were also measured by western blotting. Cinnamaldehyde reduced HG-induced loss of viability, apoptosis and intracellular generation of ROS in the DRG neurons via inhibiting NF-κB activity. The western blot assay results showed that the HG-induced elevated expressions of NF-κB, IκB and p-IκB were remarkably reduced by cinnamaldehyde treatment in a dose-dependent manner (P neurons, but also lowered the elevated IL-6, TNF-α, cyclo-oxygenase and inducible nitric oxide synthase levels, indicating a reduction in inflammatory damage. Cinnamaldehyde protected DRG neurons from the deleterious effects of HG through inactivation of NF-κB pathway but not through activation of Nrf2/HO-1. And thus cinnamaldehyde may have potential application as a treatment for DPN.

  16. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.

    Directory of Open Access Journals (Sweden)

    Ken Ikeda

    Full Text Available Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3-5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3-4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group or vehicle (n = 10, daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

  17. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.

    Science.gov (United States)

    Ikeda, Ken; Iwasaki, Yasuo

    2015-01-01

    Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3-5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3-4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

  18. Disinhibiting neurons in the dorsomedial hypothalamus delays the onset of exertional fatigue and exhaustion in rats exercising in a warm environment.

    Science.gov (United States)

    Zaretsky, Dmitry V; Kline, Hannah; Zaretskaia, Maria V; Brown, Mary Beth; Durant, Pamela J; Alves, Nathan J; Rusyniak, Daniel E

    2018-06-15

    Stimulants cause hyperthermia, in part, by increasing heat generation through exercise. Stimulants also delay the onset of fatigue and exhaustion allowing animals to exercise longer. If used in a warm environment, this combination (increased exercise and decreased fatigue) can cause heat stroke. The dorsomedial hypothalamus (DMH) is involved in mediating locomotion from stimulants. Furthermore, inhibiting the DMH decreases locomotion and prevents hyperthermia in rats given stimulants in a warm environment. Whether the DMH is involved in mediating exercise-induced fatigue and exhaustion is not known. We hypothesized that disinhibiting neurons in the dorsomedial hypothalamus (DMH) would delay the onset of fatigue and exhaustion in animals exercising in a warm environment. To test this hypothesis, we used automated video tracking software to measure fatigue and exhaustion. In rats, using wearable mini-pumps, we demonstrated that disinhibiting the DMH, via bicuculline perfusion (5 µM), increased the duration of exercise in a warm environment as compared to control animals (25 ± 3 min vs 15 ± 2 min). Bicuculline-perfused animals also had higher temperatures at exhaustion (41.4 ± 0.2 °C vs 40.0 ± 0.4 °C). Disinhibiting neurons in the DMH also increased the time to fatigue. Our data show that the same region of the hypothalamus that is involved in mediating locomotion to stimulants, is also involved in controlling exhaustion and fatigue. These findings have implications for understanding the cause and treatment of stimulant-induced-hyperthermia. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons.

    Science.gov (United States)

    Lopez-Gonzalez, Rodrigo; Lu, Yubing; Gendron, Tania F; Karydas, Anna; Tran, Helene; Yang, Dejun; Petrucelli, Leonard; Miller, Bruce L; Almeida, Sandra; Gao, Fen-Biao

    2016-10-19

    GGGGCC repeat expansions in C9ORF72 are the most common genetic cause of both ALS and FTD. To uncover underlying pathogenic mechanisms, we found that DNA damage was greater, in an age-dependent manner, in motor neurons differentiated from iPSCs of multiple C9ORF72 patients than control neurons. Ectopic expression of the dipeptide repeat (DPR) protein (GR) 80 in iPSC-derived control neurons increased DNA damage, suggesting poly(GR) contributes to DNA damage in aged C9ORF72 neurons. Oxidative stress was also increased in C9ORF72 neurons in an age-dependent manner. Pharmacological or genetic reduction of oxidative stress partially rescued DNA damage in C9ORF72 neurons and control neurons expressing (GR) 80 or (GR) 80 -induced cellular toxicity in flies. Moreover, interactome analysis revealed that (GR) 80 preferentially bound to mitochondrial ribosomal proteins and caused mitochondrial dysfunction. Thus, poly(GR) in C9ORF72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress, revealing another pathogenic mechanism in C9ORF72-related ALS and FTD. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates.

    Science.gov (United States)

    Lange, Sigrun; Rocha-Ferreira, Eridan; Thei, Laura; Mawjee, Priyanka; Bennett, Kate; Thompson, Paul R; Subramanian, Venkataraman; Nicholas, Anthony P; Peebles, Donald; Hristova, Mariya; Raivich, Gennadij

    2014-08-01

    Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post-translational modification caused by Ca(+2) -regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue-specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan-PAD inhibitor Cl-amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS-treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl-amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug-directed intervention in neurotrauma. Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up-regulation of TNFα, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage. © 2014 The Authors. Journal of Neurochemistry

  1. APOEε4 increases trauma induced early apoptosis via reducing delayed rectifier K(+) currents in neuronal/glial co-cultures model.

    Science.gov (United States)

    Chen, Ligang; Sun, Xiaochuan; Jiang, Yong; Kuai, Li

    2015-06-10

    Traumatic brain injury (TBI) is a commonly encountered emergency and severe neurosurgical injury. Previous studies have shown that the presence of the apolipoprotein E (APOE) ε4 allele has adverse outcomes across the spectrum of TBI severity. Our objective was to evaluate the effects of APOE alleles on trauma induced early apoptosis via modification of delayed rectifier K(+) current (Ik(DR)) in neuronal/glial co-cultures model. An ex vivo neuronal/glial co-cultures model carrying individual APOE alleles (ε2, ε3, ε4) of mechanical injury was developed. Flow cytometry and patch clamp recording were performed to analyze the correlations among APOE genotypes, early apoptosis and Ik(DR). We found that APOEε4 increased early apoptosis at 24h (p<0.05) compared to the ones transfected with APOEε3 and APOEε2. Noticeably, APOEε4 significantly reduced the amplitude of the Ik(DR) at 24h compared to the APOEε3 and APOEε2 (p<0.05) which exacerbate Ca(2+) influx. This indicates a possible effect of APOEε4 on early apoptosis via inhibiting Ik(DR) following injury which may adversely affect the outcome of TBI. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model

    Energy Technology Data Exchange (ETDEWEB)

    Heravi, Mitra [Department of Human Genetics, McGill University, Montreal (Canada); Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Kumala, Slawomir [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Rachid, Zakaria; Jean-Claude, Bertrand J. [Cancer Drug Research Laboratory, McGill University Health Center, Montreal (Canada); Radzioch, Danuta [Department of Human Genetics, McGill University, Montreal (Canada); Muanza, Thierry M., E-mail: tmuanza@yahoo.com [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada)

    2015-06-01

    Purpose: ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. Methods and Materials: The triple negative human breast MDA-MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed. Results: Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces significant numbers of DNA strand breaks, prolongs higher DNA damage up to 24 hours after treatment, and significantly increases tumor growth delay in a syngeneic mouse model. Conclusions: Our data suggest that the higher efficacy of this combination could be partially due to increased DNA damage and delayed DNA repair process and to the inhibition of EGFR. The encouraging results of this combination demonstrated a significant improvement in treatment efficiency and therefore could be applicable in early clinical trial settings.

  3. Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease.

    Science.gov (United States)

    Chao, Yin Xia; He, Bei Ping; Tay, Samuel Sam Wah

    2009-11-30

    Immunomodulatory effects of transplanted mesenchymal stem cells (MSCs) in the treatment of Parkinson's disease were studied in the MPTP-induced mouse model. MPTP treatment induced a significant loss of dopaminergic neurons, decreased expressions of claudin 1, claudin 5 and occludin in the substantia nigra compacta (SNc), and functional damage of the blood brain barrier (BBB). Our study further discovered that infiltration of MBLs into the brain to bind with microglia was detected in the SNc of MPTP-treated mice, suggesting that the BBB compromise and MBL infiltration might be involved in the pathogenesis of MPTP-induced PD. In addition, MPTP treatment also increased the expression of mannose-binding lectins (MBLs) in the liver tissue. Intravenous transplantation of MSCs into MPTP-treated mice led to recovery of BBB integrity, suppression of MBL infiltration at SNc and MBL expression in the liver, suppression of microglial activation and prevention of dopaminergic neuron death. No transplanted MSCs were observed to differentiate into dopaminergic neurons, while the MSCs migrated into the SNc and released TGF-beta1 there. Therefore, intravenous transplantation of MSCs which protect dopaminergic neurons from MPTP toxicity may be engaged in anyone or a combination of these mechanisms: repair of the BBB, reduction of MBL in the brain, inhibition of microglial cytotoxicity, and direct protection of dopaminergic neurons.

  4. Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats.

    Directory of Open Access Journals (Sweden)

    Deyuan Li

    Full Text Available c-Jun N-terminal kinase (JNK plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI. In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.

  5. Evaluation of cardiac adrenergic neuronal damage in rats with doxorubicin-induced cardiomyopathy using iodine-131 MIBG autoradiography and PGP 9.5 immunohistochemistry

    International Nuclear Information System (INIS)

    Jeon, T.J.; Lee, J.D.; Ha, J.-W.; Yang, W.I.; Cho, S.H.

    2000-01-01

    Doxorubicin is one of the most useful anticancer agents, but its repeated administration can induce irreversible cardiomyopathy as a major complication. The purpose of this study was to investigate doxorubicin toxicity on cardiac sympathetic neurons using iodine-131-metaiodobenzylguanidine (MIBG) and protein gene product (PGP) 9.5 immunohistochemistry, which is a marker of cardiac innervation. Wistar rats were treated with doxorubicin (2 mg/kg, i.v.) once a week for 4 (n=5), 6 (n=6) or 8 (n=7) weeks consecutively. Left ventricular ejection fraction (LVEF), calculated by M-mode echocardiography, was used as an indicator of cardiac function. Plasma noradrenaline (NA) concentration was measured by high-performance liquid chromatography (HPLC). 131 I-MIBG uptake of the left ventricular wall (24 ROIs) was measured by autoradiography. 131 I-MIBG uptake pattern was compared with histopathological results, the neuronal population on PGP 9.5 immunohistochemistry and the degree of myocyte damage assessed using a visual scoring system on haematoxylin and eosin and Masson's trichrome staining. LVEF was significantly decreased in the 8-week group (P 131 I-MIBG uptake ratio of subepicardium to subendocardium were significantly increased (P<0.05) in the 8-week group as compared with the control group. It may be concluded that radioiodinated MIBG is a reliable marker for the detection of cardiac adrenergic neuronal damage in doxorubicin-induced cardiomyopathy; it detects such damage earlier than do other clinical parameters and in this study showed a good correlation with the reduction in the neuronal population on PGP 9.5 stain. The subendocardial layer appeared to be more vulnerable to doxorubicin than the subepicardium. (orig.)

  6. Effects of cryotherapy on muscle damage markers and perception of delayed onset muscle soreness after downhill running: A Pilot study

    Directory of Open Access Journals (Sweden)

    M. Rossato

    2015-06-01

    Conclusion: Use of cryotherapy after exercise with eccentric contractions was effective to reestablish the level of biochemical markers of muscle damage and reduce muscle soreness and pain perception in subjects submitted to downhill running.

  7. Lactation exposure to BDE-153 damages learning and memory, disrupts spontaneous behavior and induces hippocampus neuron death in adult rats.

    Science.gov (United States)

    Zhang, Hongmei; Li, Xin; Nie, Jisheng; Niu, Qiao

    2013-06-23

    -down test was significantly increased in the 10mg/kg BDE-153 group at 2 months after treatment (P<0.05), and the BDE-153-treated rats' swimming times and distances in the target quadrant were significantly decreased at 1 month and 2 months after treatment (P<0.05 or P<0.01). These parameters were also significantly increased in the opposite quadrant at 1 month after treatment (P<0.05 or P<0.01). The spontaneous behavior was significantly reduced in the treated groups compared to the controls (P<0.05 or P<0.01). The severity of neurobehavioral dysfunction was dependent on the exposure dose of BDE-153, and worsened with age. Under an optical microscope, the treated rats' neurons in the CA3 region of the hippocampus were observed to be reduced and disarranged, and the cell junctions were loosened and the intercellular spaces were enlarged. Under a transmission electron microscope, the cell nucleus was observed to shrink; the chromatin was condensed and gathered near the nuclear membrane, the Nissl bodies and other organelles in the perikaryon were reduced, and the vacuole was observed to degenerate and even disappear. Moreover, compared to the controls, the cell apoptosis rates were significantly increased in the 5 and 10mg/kg BDE-153 groups (P<0.05), and the LDH activity was significantly increased in the 10mg/kg BDE-153 groups (P<0.01). Lactation exposure to BDE-153 damaged adult rats' learning and memory abilities, disrupted their spontaneous behavior (hypoactivity) and induced hippocampus neuron apoptosis. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  8. Supplementation with a Polyphenol-Rich Extract, TensLess® , Attenuates Delayed Onset Muscle Soreness and Improves Muscle Recovery from Damages After Eccentric Exercise.

    Science.gov (United States)

    Romain, Cindy; Freitas, Tomás T; Martínez-Noguera, Francisco J; Laurent, Caroline; Gaillet, Sylvie; Chung, Linda H; Alcaraz, Pedro E; Cases, Julien

    2017-11-01

    High-intensity exercises are known to provoke delayed onset muscle soreness (DOMS). Delayed onset muscle soreness typically occurs within the first 24 h, peaks between 24 and 72 h, and can last as long as 5-7 days post-exercise. Delayed onset muscle soreness is a multifactorial process involving both mechanical and biochemical components, associated with clinical features that may limit range of motion, and athletes seek for effective recovery strategies to optimize future training sessions. TensLess ® is a food supplement developed to help manage post-exercise recovery. The supplement has been investigated on 13 recreationally active athletes of both sex, during a randomized, double-blind, and crossover clinical investigation, including a 3-week washout period. The clinical investigation was based on the study of TensLess ® effects for DOMS management and on the reduction of associated muscle damages following an eccentric exercise protocol. Supplementation with TensLess ® induced significant decrease in DOMS perception (-33%; p = 0.008) as of the first 24 h; this was significantly correlated with a lowered release of muscle damage-associated biomarkers, namely myoglobin, creatinine, and creatine kinase, for the whole length of the recovery period. Taken together, these positive results clearly indicate that post-exercise supplementation with TensLess ® may preserve myocytes and reduce soreness following eccentric exercise-induced damages, and, accordingly, significantly shorten muscle recovery. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  9. The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

    Directory of Open Access Journals (Sweden)

    Maria Florencia Angelo

    Full Text Available Sleep apnea (SA causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE and its downstream effector Nuclear Factor Kappa B (NF-κB have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

  10. A field guide to predict delayed mortality of fire-damaged ponderosa pine: application and validation of the Malheur model.

    Science.gov (United States)

    Walter G. Thies; Douglas J. Westlind; Mark Loewen; Greg. Brenner

    2008-01-01

    The Malheur model for fire-caused delayed mortality is presented as an easily interpreted graph (mortality-probability calculator) as part of a one-page field guide that allows the user to determine postfire probability of mortality for ponderosa pine (Pinus ponderosa Dougl. ex Laws.). Following both prescribed burns and wildfires, managers need...

  11. Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi

    Science.gov (United States)

    2013-01-01

    Background Ceramide accumulation is considered a contributing factor to neuronal dysfunction and damage. However, the underlying mechanisms that occur following ischemic insult are still unclear. Methods In the present study, we established cerebral ischemia models using four-vessel occlusion and oxygen-glucose deprivation methods. The hippocampus neural cells were subjected to immunohistochemistry and immunofluorescence staining for ceramide and neutral sphingomyelinase 2 (nSMase2) levels; immunoprecipitation and immunoblot analysis for nSMase2, receptor for activated C kinase 1 (RACK1), embryonic ectoderm development (EED), p38 mitogen-activated protein kinase (p38MAPK) and phosphorylated p38MAPK expression; SMase assay for nSMase and acid sphingomyelinase (aSMase) activity; real-time reverse transcription polymerase chain reaction for cytokine expression; and Nissl, microtubule-associated protein 2 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining. Results We found considerable production of ceramide in astrocytes, but not in neurons, during early cerebral ischemia. This was accompanied by the induction of nSMase (but not aSMase) activity in the rat hippocampi. The inhibition of nSMase2 activity effectively reduced ceramide accumulation in astrocytes and alleviated neuronal damage to some extent. Meanwhile, the expression levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6, were found to be upregulated, which may have played an import role in neuronal damage mediated by the nSMase2/ceramide pathway. Although enhanced binding of nSMase2 with RACK1 and EED were also observed after cerebral ischemia, nSMase2 activity was not blocked by the TNF-α receptor inhibitor through RACK1/EED signaling. p38MAPK, but not protein kinase Cζ or protein phosphatase 2B, was able to induce nSMase2 activation after ischemia. p38MAPK can be induced by A2B adenosine

  12. P2X7 receptor activation ameliorates CA3 neuronal damage via a tumor necrosis factor-α-mediated pathway in the rat hippocampus following status epilepticus

    Directory of Open Access Journals (Sweden)

    Ryu Hea Jin

    2011-06-01

    Full Text Available Abstract Background The release of tumor necrosis factor-α (TNF-α appears depend on the P2X7 receptor, a purinergic receptor. In the present study, we addressed the question of whether P2X7 receptor-mediated TNF-α regulation is involved in pathogenesis and outcome of status epilepticus (SE. Methods SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, 2',3'-O-(4-benzoylbenzoyl-adenosine 5'-triphosphate (BzATP, adenosine 5'-triphosphate-2',3'-dialdehyde (OxATP, A-438079, or A-740003 prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunit phosphorylations. Results Following SE, P2X7 receptor agonist (BzATP infusion increased TNF-α immunoreactivity in dentate granule cells as compared with that in saline-infused animals. In addition, TNF-α immunoreactivity was readily apparent in the mossy fibers, while TNF-α immunoreactivity in CA1-3 pyramidal cells was unaltered. However, P2X7 receptor antagonist (OxATP-, A-438079, and A-740003 infusion reduced SE-induced TNF-α expression in dentate granule cells. In the CA3 region, BzATP infusion attenuated SE-induced neuronal damage, accompanied by enhancement of p65-Ser276 and p65-Ser311 NF-κB subunit phosphorylations. In contrast, OxATP-, A-438079, and A-740003 infusions increased SE-induced neuronal death. Soluble TNF p55 receptor (sTNFp55R, and cotreatment with BzATP and sTNFp55R infusion also increased SE-induced neuronal damage in CA3 region. However, OxATP-, sTNFp55R or BzATP+sTNFp55R infusions could not exacerbate SE-induced neuronal damages in the dentate gyrus and the CA1 region, as compared to BzATP infusion. Conclusions These findings suggest that TNF-α induction by P2X7 receptor activation may ameliorate SE-induced CA3 neuronal damage via enhancing NF-κB p65-Ser276 and p65-Ser311 phosphorylations.

  13. Curcumin protects dopaminergic neurons against inflammation-mediated damage and improves motor dysfunction induced by single intranigral lipopolysaccharide injection.

    Science.gov (United States)

    Sharma, Neha; Sharma, Sheetal; Nehru, Bimla

    2017-06-01

    Various studies have indicated a lower incidence and prevalence of neurological conditions in people consuming curcumin. The ability of curcumin to target multiple cascades, simultaneously, could be held responsible for its neuroprotective effects. The present study was designed to investigate the potential of curcumin in minimizing microglia-mediated damage in lipopolysaccharide (LPS) induced model of PD. Altered microglial functions and increased inflammatory profile of the CNS have severe behavioral consequences. In the current investigation, a single injection of LPS (5 ug/5 µl PBS) was injected into the substantia nigra (SN) of rats, and curcumin [40 mg/kg b.wt (i.p.)] was administered daily for a period of 21 days. LPS triggered an inflammatory response characterized by glial activation [Iba-1 and glial fibrillary acidic protein (GFAP)] and pro-inflammatory cytokine production (TNF-α and IL-1β) leading to extensive dopaminergic loss and behavioral abnormality in rats. The behavioral observations, biochemical markers, quantification of dopamine and its metabolites (DOPAC and HVA) using HPLC followed by IHC of tyrosine hydroxylase (TH) were evaluated after 21 days of LPS injection. Curcumin supplementation prevented dopaminergic degeneration in LPS-treated animals by normalizing the altered levels of biomarkers. Also, a significant improvement in TH levels as well as behavioral parameters (actophotometer, rotarod, beam walking and grid walking tests) were seen in LPS injected rats. Curcumin shielded the dopaminergic neurons against LPS-induced inflammatory response, which was associated with suppression of glial activation (microglia and astrocytes) and transcription factor NF-κB as depicted from RT-PCR and EMSA assay. Curcumin also suppressed microglial NADPH oxidase activation as observed from NADPH oxidase activity. The results suggested that one of the important mechanisms by which curcumin mediates its protective effects in the LPS-induced PD

  14. Sensitivity of spiral ganglion neurons to damage caused by mobile phone electromagnetic radiation will increase in lipopolysaccharide-induced inflammation in vitro model.

    Science.gov (United States)

    Zuo, Wen-Qi; Hu, Yu-Juan; Yang, Yang; Zhao, Xue-Yan; Zhang, Yuan-Yuan; Kong, Wen; Kong, Wei-Jia

    2015-05-29

    With the increasing popularity of mobile phones, the potential hazards of radiofrequency electromagnetic radiation (RF-EMR) on the auditory system remain unclear. Apart from RF-EMR, humans are also exposed to various physical and chemical factors. We established a lipopolysaccharide (LPS)-induced inflammation in vitro model to investigate whether the possible sensitivity of spiral ganglion neurons to damage caused by mobile phone electromagnetic radiation (at specific absorption rates: 2, 4 W/kg) will increase. Spiral ganglion neurons (SGN) were obtained from neonatal (1- to 3-day-old) Sprague Dawley® (SD) rats. After the SGN were treated with different concentrations (0, 20, 40, 50, 100, 200, and 400 μg/ml) of LPS, the Cell Counting Kit-8 (CCK-8) and alkaline comet assay were used to quantify cellular activity and DNA damage, respectively. The SGN were treated with the moderate LPS concentrations before RF-EMR exposure. After 24 h intermittent exposure at an absorption rate of 2 and 4 W/kg, DNA damage was examined by alkaline comet assay, ultrastructure changes were detected by transmission electron microscopy, and expression of the autophagy markers LC3-II and Beclin1 were examined by immunofluorescence and confocal laser scanning microscopy. Reactive oxygen species (ROS) production was quantified by the dichlorofluorescin-diacetate assay. LPS (100 μg/ml) induced DNA damage and suppressed cellular activity (P 0.05); therefore, 40 μg/ml was used to pretreat the concentration before exposure to RF-EMR. RF-EMR could not directly induce DNA damage. However, the 4 W/kg combined with LPS (40 μg/ml) group showed mitochondria vacuoles, karyopyknosis, presence of lysosomes and autophagosome, and increasing expression of LC3-II and Beclin1. The ROS values significantly increased in the 4 W/kg exposure, 4 W/kg combined with LPS (40 μg/ml) exposure, and H2O2 groups (P spiral ganglion neurons, but it could cause the changes of cellular ultrastructure at special SAR 4

  15. Telomerase activity-independent function of telomerase reverse transcriptase is involved in acrylamide-induced neuron damage.

    Science.gov (United States)

    Zhang, P; Pan, H; Wang, J; Liu, X; Hu, X

    2014-07-01

    Polyacrylamide is used widely in industry, and its decomposition product, acrylamide (ACR), readily finds its way into commonly consumed cosmetics and baked and fried foods. ACR exerts potent neurotoxic effects in human and animal models. Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, traditionally has been considered to play an important role in maintaining telomere length. Emerging evidence has shown, however, that TERT plays an important role in neuroprotection by inhibiting apoptosis and excitotoxicity, and by promoting angiogenesis, neuronal survival and neurogenesis, which are closely related to the telomere-independent functions of TERT. We investigated whether and how the TERT pathway is involved in ACR induced neurotoxicity in rat cortical neurons. We found that ACR 1) significantly reduced the viability of cortical neurons as measured by MTT assay, 2) induced neuron apoptosis as revealed by FITC-conjugated Annexin V/PI double staining and flow cytometry (FACS) analysis, 3) elevated expression of cleaved caspase-3, and 4) decreased bcl-2 expression of cortical neurons. ACR also increased intracellular ROS levels in cortical neurons, increased MDA levels and reduced GSH, SOD and GSH-Px levels in mitochondria in a dose-dependent manner. We found that TERT expression in mitochondria was increased by ACR at concentrations of 2.5 and 5.0 mM, but TERT expression was decreased by 10 mM ACR. Telomerase activity, however, was undetectable in rat cortical neurons. Our results suggest that the TERT pathway is involved in ACR induced apoptosis of cortical neurons. TERT also may exert its neuroprotective role in a telomerase activity-independent way, especially in mitochondria.

  16. Diabetic microangiopathy: impact of impaired cerebral vasoreactivity and delayed angiogenesis after permanent middle cerebral artery occlusion on stroke damage and cerebral repair in mice.

    Science.gov (United States)

    Poittevin, Marine; Bonnin, Philippe; Pimpie, Cynthia; Rivière, Léa; Sebrié, Catherine; Dohan, Anthony; Pocard, Marc; Charriaut-Marlangue, Christiane; Kubis, Nathalie

    2015-03-01

    Diabetes increases the risk of stroke by three, increases related mortality, and delays recovery. We aimed to characterize functional and structural alterations in cerebral microvasculature before and after experimental cerebral ischemia in a mouse model of type 1 diabetes. We hypothesized that preexisting brain microvascular disease in patients with diabetes might partly explain increased stroke severity and impact on outcome. Diabetes was induced in 4-week-old C57Bl/6J mice by intraperitoneal injections of streptozotocin (60 mg/kg). After 8 weeks of diabetes, the vasoreactivity of the neurovascular network to CO2 was abolished and was not reversed by nitric oxide (NO) donor administration; endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) mRNA, phospho-eNOS protein, nNOS, and phospho-nNOS protein were significantly decreased; angiogenic and vessel maturation factors (vascular endothelial growth factor a [VEGFa], angiopoietin 1 (Ang1), Ang2, transforming growth factor-β [TGF-β], and platelet-derived growth factor-β [PDGF-β]) and blood-brain barrier (BBB) occludin and zona occludens 1 (ZO-1) expression were significantly decreased; and microvessel density was increased without changes in ultrastructural imaging. After permanent focal cerebral ischemia induction, infarct volume and neurological deficit were significantly increased at D1 and D7, and neuronal death (TUNEL+ / NeuN+ cells) and BBB permeability (extravasation of Evans blue) at D1. At D7, CD31+ / Ki67+ double-immunolabeled cells and VEGFa and Ang2 expression were significantly increased, indicating delayed angiogenesis. We show that cerebral microangiopathy thus partly explains stroke severity in diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  17. Diets containing salmon fillet delay development of high blood pressure and hyperfusion damage in kidneys in obese Zucker fa/fa rats.

    Science.gov (United States)

    Vikøren, Linn A; Drotningsvik, Aslaug; Mwakimonga, Angela; Leh, Sabine; Mellgren, Gunnar; Gudbrandsen, Oddrun A

    2018-04-01

    Hypertension is the leading risk factor for cardiovascular and chronic renal diseases, affecting more than 1 billion people. Fish intake is inversely correlated with the prevalence of hypertension in several, but not all, studies, and intake of fish oil and fish proteins has shown promising potential to delay development of high blood pressure in rats. The effects of baked and raw salmon fillet intake on blood pressure and renal function were investigated in obese Zucker fa/fa rats, which spontaneously develop hypertension with proteinuria and renal failure. Rats were fed diets containing baked or raw salmon fillet in an amount corresponding to 25% of total protein from salmon and 75% of protein from casein, or casein as the sole protein source (control group) for 4 weeks. Results show lower blood pressure and lower urine concentrations of albumin and cystatin C (relative to creatinine) in salmon diet groups when compared to control group. Morphological examinations revealed less prominent hyperfusion damage in podocytes from rats fed diets containing baked or raw salmon when compared to control rats. In conclusion, diets containing baked or raw salmon fillet delayed the development of hypertension and protected against podocyte damage in obese Zucker fa/fa rats. Copyright © 2018 American Heart Association. Published by Elsevier Inc. All rights reserved.

  18. Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins.

    Science.gov (United States)

    Colin, Didier J; Hain, Karolina O; Allan, Lindsey A; Clarke, Paul R

    2015-03-01

    Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-xL by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

  19. Xenon Reduces Neuronal Hippocampal Damage and Alters the Pattern of Microglial Activation after Experimental Subarachnoid Hemorrhage: A Randomized Controlled Animal Trial

    Directory of Open Access Journals (Sweden)

    Michael Veldeman

    2017-09-01

    Full Text Available ObjectiveThe neuroprotective properties of the noble gas xenon have already been demonstrated using a variety of injury models. Here, we examine for the first time xenon’s possible effect in attenuating early brain injury (EBI and its influence on posthemorrhagic microglial neuroinflammation in an in vivo rat model of subarachnoid hemorrhage (SAH.MethodsSprague-Dawley rats (n = 22 were randomly assigned to receive either Sham surgery (n = 9; divided into two groups or SAH induction via endovascular perforation (n = 13, divided into two groups. Of those randomized for SAH, 7 animals were postoperatively ventilated with 50 vol% oxygen/50 vol% xenon for 1 h and 6 received 50 vol% oxygen/50 vol% nitrogen (control. The animals were sacrificed 24 h after SAH. Of each animal, a cerebral coronal section (−3.60 mm from bregma was selected for assessment of histological damage 24 h after SAH. A 5-point neurohistopathological severity score was applied to assess neuronal cell damage in H&E and NeuN stained sections in a total of four predefined anatomical regions of interest. Microglial activation was evaluated by a software-assisted cell count of Iba-1 stained slices in three cortical regions of interest.ResultsA diffuse cellular damage was apparent in all regions of the ipsilateral hippocampus 24 h after SAH. Xenon-treated animals presented with a milder damage after SAH. This effect was found to be particularly pronounced in the medial regions of the hippocampus, CA3 (p = 0.040, and dentate gyrus (DG p = 0.040. However, for the CA1 and CA2 regions, there were no statistical differences in neuronal damage according to our histological scoring. A cell count of activated microglia was lower in the cortex of xenon-treated animals. This difference was especially apparent in the left piriform cortex (p = 0.017.ConclusionIn animals treated with 50 vol% xenon (for 1 h after SAH, a less pronounced neuronal damage was

  20. Study on CT changes in autistic children; Anatomical correlation of the damaged brain and delay of psychomotor development

    Energy Technology Data Exchange (ETDEWEB)

    Yaguchi, Katsumi [Juntendo Univ., Tokyo (Japan). School of Medicine

    1993-05-01

    Since 1979 we have performed CT examinations on 132 autistic children. Neurological diagnosis of the lesion was established by Dr. Segawa's group. On the CT of many autistic children, we found a small low density change located in the anterior wall of the temporal horn, or localized dilatation of the inferior horn near the damaged brain. We reviewed 96 of these patients who all had the obvious low density changes, or localized irregular dilatations in the anterior wall of the temporal horn. By measuring the distance of damage from the midline, we divided the 96 cases into two groups. Group 1 consisted of those with damage located laterally more than 30 mm line from the midline. Group 2 consisted of those with damage medially to the 30 mm line from the midline. Those cases with a large lesion both laterally and medially of the 30 mm line were categorized into group 1. In the adult brain the lateral border of the amygdaloid nucleus was never located laterally more than 30 mm from the midline. Laterally over the 30 mm line there were two marked fiber systems running near the anterior wall of the temporal horn: the fiber of the anterior commissure and the uncinate fascicle. Group 1 consisted of 62 patients and group 2 of 34 patients. The majority of the two group patients were pure autism children. This suggested that the main lesion in autism was in the amygdala. (author).

  1. Study on CT changes in autistic children; Anatomical correlation of the damaged brain and delay of psychomotor development

    Energy Technology Data Exchange (ETDEWEB)

    Yaguchi, Katsumi (Juntendo Univ., Tokyo (Japan). School of Medicine)

    1993-05-01

    Since 1979 we have performed CT examinations on 132 autistic children. Neurological diagnosis of the lesion was established by Dr. Segawa's group. On the CT of many autistic children, we found a small low density change located in the anterior wall of the temporal horn, or localized dilatation of the inferior horn near the damaged brain. We reviewed 96 of these patients who all had the obvious low density changes, or localized irregular dilatations in the anterior wall of the temporal horn. By measuring the distance of damage from the midline, we divided the 96 cases into two groups. Group 1 consisted of those with damage located laterally more than 30 mm line from the midline. Group 2 consisted of those with damage medially to the 30 mm line from the midline. Those cases with a large lesion both laterally and medially of the 30 mm line were categorized into group 1. In the adult brain the lateral border of the amygdaloid nucleus was never located laterally more than 30 mm from the midline. Laterally over the 30 mm line there were two marked fiber systems running near the anterior wall of the temporal horn: the fiber of the anterior commissure and the uncinate fascicle. Group 1 consisted of 62 patients and group 2 of 34 patients. The majority of the two group patients were pure autism children. This suggested that the main lesion in autism was in the amygdala. (author).

  2. Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons.

    Science.gov (United States)

    Tao, Ling-Xue; Huang, Xiao-Tian; Chen, Yu-Ting; Tang, Xi-Can; Zhang, Hai-Yan

    2016-11-01

    Iron dyshomeostasis is one of the primary causes of neuronal death in Alzheimer's disease (AD). Huperzine A (HupA), a natural inhibitor of acetylcholinesterase (AChE), is a licensed anti-AD drug in China and a nutraceutical in the United Sates. Here, we investigated the protective effects of HupA against iron overload-induced injury in neurons. Rat cortical neurons were treated with ferric ammonium citrate (FAC), and cell viability was assessed with MTT assays. Reactive oxygen species (ROS) assays and adenosine triphosphate (ATP) assays were performed to assess mitochondrial function. The labile iron pool (LIP) level, cytosolic-aconitase (c-aconitase) activity and iron uptake protein expression were measured to determine iron metabolism changes. The modified Ellman's method was used to evaluate AChE activity. HupA significantly attenuated the iron overload-induced decrease in neuronal cell viability. This neuroprotective effect of HupA occurred concurrently with a decrease in ROS and an increase in ATP. Moreover, HupA treatment significantly blocked the upregulation of the LIP level and other aberrant iron metabolism changes induced by iron overload. Additionally, another specific AChE inhibitor, donepezil (Don), at a concentration that caused AChE inhibition equivalent to that of HupA negatively, influenced the aberrant changes in ROS, ATP or LIP that were induced by excessive iron. We provide the first demonstration of the protective effects of HupA against iron overload-induced neuronal damage. This beneficial role of HupA may be attributed to its attenuation of oxidative stress and mitochondrial dysfunction and elevation of LIP, and these effects are not associated with its AChE-inhibiting effect.

  3. Ellagic acid protects against neuron damage in ischemic stroke through regulating the ratio of Bcl-2/Bax expression.

    Science.gov (United States)

    Liu, Qing-Shan; Deng, Ran; Li, Shuran; Li, Xu; Li, Keqin; Kebaituli, Gulibanumu; Li, Xueli; Liu, Rui

    2017-08-01

    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.

  4. Extension of knee immobilization delays recovery of histological damages in the anterior cruciate ligament insertion and articular cartilage in rabbits

    OpenAIRE

    Mutsuzaki,, Hirotaka; Nakajima,, Hiromi; Sakane,, Masataka

    2018-01-01

    [Purpose] To investigate the influence of knee immobilization period on recovery of histological damages in the anterior cruciate ligament (ACL) insertion and articular cartilage in rabbits. This knowledge is important for determining the appropriate rehabilitation approach for patients with ligament injuries, fracture, disuse atrophy, and degenerative joint disease. [Materials and Methods] Forty-eight male Japanese white rabbits were divided equally into the remobilization and control groups...

  5. Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABA(A) receptor δ subunit in cerebellar granule neurons and delays motor development in rats.

    Science.gov (United States)

    Diaz, Marvin R; Vollmer, Cyndel C; Zamudio-Bulcock, Paula A; Vollmer, William; Blomquist, Samantha L; Morton, Russell A; Everett, Julie C; Zurek, Agnieszka A; Yu, Jieying; Orser, Beverley A; Valenzuela, C Fernando

    2014-04-01

    Exposure to ethanol (EtOH) during fetal development can lead to long-lasting alterations, including deficits in fine motor skills and motor learning. Studies suggest that these are, in part, a consequence of cerebellar damage. Cerebellar granule neurons (CGNs) are the gateway of information into the cerebellar cortex. Functionally, CGNs are heavily regulated by phasic and tonic GABAergic inhibition from Golgi cell interneurons; however, the effect of EtOH exposure on the development of GABAergic transmission in immature CGNs has not been investigated. To model EtOH exposure during the 3rd trimester-equivalent of human pregnancy, neonatal pups were exposed intermittently to high levels of vaporized EtOH from postnatal day (P) 2 to P12. This exposure gradually increased pup serum EtOH concentrations (SECs) to ∼60 mM (∼0.28 g/dl) during the 4 h of exposure. EtOH levels gradually decreased to baseline 8 h after the end of exposure. Surprisingly, basal tonic and phasic GABAergic currents in CGNs were not significantly affected by postnatal alcohol exposure (PAE). However, PAE increased δ subunit expression at P28 as detected by immunohistochemical and western blot analyses. Also, electrophysiological studies with an agonist that is highly selective for δ-containing GABA(A) receptors, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP), showed an increase in THIP-induced tonic current. Behavioral studies of PAE rats did not reveal any deficits in motor coordination, except for a delay in the acquisition of the mid-air righting reflex that was apparent at P15 to P18. These findings demonstrate that repeated intermittent exposure to high levels of EtOH during the equivalent of the last trimester of human pregnancy has significant but relatively subtle effects on motor coordination and GABAergic transmission in CGNs in rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Additional effects of taurine on the benefits of BCAA intake for the delayed-onset muscle soreness and muscle damage induced by high-intensity eccentric exercise.

    Science.gov (United States)

    Ra, Song-Gyu; Miyazaki, Teruo; Ishikura, Keisuke; Nagayama, Hisashi; Suzuki, Takafumi; Maeda, Seiji; Ito, Masaharu; Matsuzaki, Yasushi; Ohmori, Hajime

    2013-01-01

    Taurine (TAU) has a lot of the biological, physiological, and pharmocological functions including anti-inflammatory and anti-oxidative stress. Although previous studies have appreciated the effectiveness of branched-chain amino acids (BCAA) on the delayed-onset muscle soreness (DOMS), consistent finding has not still convinced. The aim of this study was to examine the additional effect of TAU with BCAA on the DOMS and muscle damages after eccentric exercise. Thirty-six untrained male volunteers were equally divided into four groups, and ingested a combination with 2.0 g TAU (or placebo) and 3.2 g BCAA (or placebo), thrice a day, 2 weeks prior to and 4 days after elbow flexion eccentric exercise. Following the period after eccentric exercise, the physiological and blood biochemical markers for DOMS and muscle damage showed improvement in the combination of TAU and BCAA supplementation rather than in the single or placebo supplementations. In conclusion, additional supplement of TAU with BCAA would be a useful way to attenuate DOMS and muscle damages induced by high-intensity exercise.

  7. Inhibition of cytosolic Phospholipase A2 prevents prion peptide-induced neuronal damage and co-localisation with Beta III Tubulin

    Directory of Open Access Journals (Sweden)

    Last Victoria

    2012-08-01

    Full Text Available Abstract Background Activation of phospholipase A2 (PLA2 and the subsequent metabolism of arachidonic acid (AA to prostaglandins have been shown to play an important role in neuronal death in neurodegenerative disease. Here we report the effects of the prion peptide fragment HuPrP106-126 on the PLA2 cascade in primary cortical neurons and translocation of cPLA2 to neurites. Results Exposure of primary cortical neurons to HuPrP106-126 increased the levels of phosphorylated cPLA2 and caused phosphorylated cPLA2 to relocate from the cell body to the cellular neurite in a PrP-dependent manner, a previously unreported observation. HuPrP106-126 also induced significant AA release, an indicator of cPLA2 activation; this preceded synapse damage and subsequent cellular death. The novel translocation of p-cPLA2 postulated the potential for exposure to HuPrP106-126 to result in a re-arrangement of the cellular cytoskeleton. However p-cPLA2 did not colocalise significantly with F-actin, intermediate filaments, or microtubule-associated proteins. Conversely, p-cPLA2 did significantly colocalise with the cytoskeletal protein beta III tubulin. Pre-treatment with the PLA2 inhibitor, palmitoyl trifluoromethyl ketone (PACOCF3 reduced cPLA2 activation, AA release and damage to the neuronal synapse. Furthermore, PACOCF3 reduced expression of p-cPLA2 in neurites and inhibited colocalisation with beta III tubulin, resulting in protection against PrP-induced cell death. Conclusions Collectively, these findings suggest that cPLA2 plays a vital role in the action of HuPrP106-126 and that the colocalisation of p-cPLA2 with beta III tubulin could be central to the progress of neurodegeneration caused by prion peptides. Further work is needed to define exactly how PLA2 inhibitors protect neurons from peptide-induced toxicity and how this relates to intracellular structural changes occurring in neurodegeneration.

  8. Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage

    Institute of Scientific and Technical Information of China (English)

    Yifan He; Jihong Zhu; Fang Huang; Liu Qin; Wenguo Fan; Hongwen He

    2014-01-01

    The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory be-haviors and structural changes in related brain regions, in a mouse model of Alzheimer’s disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learn-ing and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltrans-ferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic ifbers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no signiifcant differences in histology or be-havior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present ifndings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer’s disease, and

  9. Elevated levels of plasminogen activators in the pathogenesis of delayed radiation damage in rat cervical spinal cord in vivo

    International Nuclear Information System (INIS)

    Sawaya, R.; Rayford, A.; Kono, S.; Rao, J.S.; Ang, K.K.; Feng, Y.; Stephens, L.C.

    1994-01-01

    The pathophysiology of the cellular basis of radiation-induced demyelination and white-matter necrosis of the central nervous system (CNS) is poorly understood. Preliminary data suggest that tissue damage is partly mediated through changes in the proteolytic enzymes. In this study, we irradiated rat cervical spinal cords with single doses of 24 Gy of 18 MV photons or 20 MeV electrons and measured the levels of plasminogen activators at days 2, 7, 30, 60, 90, 120, 130 and 145 after irradiation, using appropriate controls at each time. Fibrin zymography revealed fibrinolytic bands representing molecular weights of 68,000 and 48,000 in controls and irradiated samples; these bands increased significantly at days 120, 130 and 145 after irradiation. Inhibition of these enzymatic bands with specific antibodies against tissue-type plasminogen activator (tPA) and amiloride, an inhibitor for urokinase plasminogen activator (uPA), confirmed that these bands were tPA and uPA. Enzymatic levels quantified by densitometry showed a twofold elevation in the levels of tPA and more than a tenfold increase in uPA after 120 days' irradiation. Activity of uPA was increased threefold by day 2 and increased steadily with time compared to nonirradiated control samples. Enzyme-linked immunosorbent assay (ELISA) also showed a threefold increase in the tPA content in the extracts of irradiated rat cervical spinal cords at days 120, 130 and 145. This study adds additional information to the proposed role of plasminogen activators in the pathogenic pathways of radiation damage in the CNS. 38 refs., 6 figs

  10. Elevated levels of plasminogen activators in the pathogenesis of delayed radiation damage in rat cervical spinal cord in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Sawaya, R.; Rayford, A.; Kono, S.; Rao, J.S.; Ang, K.K.; Feng, Y.; Stephens, L.C. [Univ. of Texas, Houston, TX (United States)

    1994-06-01

    The pathophysiology of the cellular basis of radiation-induced demyelination and white-matter necrosis of the central nervous system (CNS) is poorly understood. Preliminary data suggest that tissue damage is partly mediated through changes in the proteolytic enzymes. In this study, we irradiated rat cervical spinal cords with single doses of 24 Gy of 18 MV photons or 20 MeV electrons and measured the levels of plasminogen activators at days 2, 7, 30, 60, 90, 120, 130 and 145 after irradiation, using appropriate controls at each time. Fibrin zymography revealed fibrinolytic bands representing molecular weights of 68,000 and 48,000 in controls and irradiated samples; these bands increased significantly at days 120, 130 and 145 after irradiation. Inhibition of these enzymatic bands with specific antibodies against tissue-type plasminogen activator (tPA) and amiloride, an inhibitor for urokinase plasminogen activator (uPA), confirmed that these bands were tPA and uPA. Enzymatic levels quantified by densitometry showed a twofold elevation in the levels of tPA and more than a tenfold increase in uPA after 120 days` irradiation. Activity of uPA was increased threefold by day 2 and increased steadily with time compared to nonirradiated control samples. Enzyme-linked immunosorbent assay (ELISA) also showed a threefold increase in the tPA content in the extracts of irradiated rat cervical spinal cords at days 120, 130 and 145. This study adds additional information to the proposed role of plasminogen activators in the pathogenic pathways of radiation damage in the CNS. 38 refs., 6 figs.

  11. Effect of endurance training on seizure susceptibility, behavioral changes and neuronal damage after kainate-induced status epilepticus in spontaneously hypertensive rats.

    Science.gov (United States)

    Tchekalarova, J; Shishmanova, M; Atanasova, D; Stefanova, M; Alova, L; Lazarov, N; Georgieva, K

    2015-11-02

    The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depression comorbidity has been confirmed previously. In the present study, we examined the effects of endurance training on susceptibility to kainate (KA)-induced status epilepticus (SE), behavioral changes and neuronal damage in spontaneously hypertensive rats (SHRs). Male SHRs were randomly divided into two groups. One group was exercised on a treadmill with submaximal loading for four weeks and the other group was sedentary. Immediately after the training period, SE was evoked in half of the sedentary and trained rats by KA, while the other half of the two groups received saline. Basal systolic (SP), diastolic (DP) and mean arterial pressure (MAP) of all rats were measured at the beginning and at the end of the training period. Anxiety, memory and depression-like behaviour were evaluated a month after SE. The release of 5-HT in the hippocampus was measured using a liquid scintillation method and neuronal damage was analyzed by hematoxylin and eosin staining. SP and MAP of exercised SHRs decreased in comparison with the initial values. The increased resistance of SHRs to KA-induced SE was accompanied by an elongated latent seizure-free period, improved object recognition memory and antidepressant effect after the training program. While the anticonvulsant and positive behavioral effects of endurance training were accompanied by an increase of 5-HT release in the hippocampus, it did not exert neuroprotective activity. Our results indicate that prior exercise is an effective means to attenuate KA-induced seizures and comorbid behavioral changes in a model of hypertension and epilepsy suggesting a potential influence of hippocampal 5-HT on a comorbid depression. However, this beneficial impact does not prevent the development of epilepsy and concomitant brain damage. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons.

    Science.gov (United States)

    Moruno-Manchon, Jose F; Koellhoffer, Edward C; Gopakumar, Jayakrishnan; Hambarde, Shashank; Kim, Nayun; McCullough, Louise D; Tsvetkov, Andrey S

    2017-09-12

    The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double-strand breaks (DSBs) in cultured neurons. We also found that pyridostatin downregulated transcription of the Brca1 gene, a gene that is critical for DSB repair. Importantly, in an in vitro gel shift assay, we discovered that an antibody specific to the G-quadruplex structure binds to a synthetic oligonucleotide, which corresponds to the first putative G-quadruplex in the Brca1 gene promoter. Our results suggest that the G-quadruplex complexes regulate transcription in neurons. Studying the G-quadruplexes could represent a new avenue for neurodegeneration and brain aging research.

  13. Effect of loperamide and delay of bowel motility on bile acid malabsorption caused by late radiation damage and ileal resection

    Energy Technology Data Exchange (ETDEWEB)

    Valdes Olmos, R. (Nederlands Kanker Inst., Amsterdam (Netherlands). Dept. of Nuclear Medicine); Hartog Jager, F. den; Hoefnagel, C.; Taal, B. (Nederlands Kanker Inst., Amsterdam (Netherlands). Dept. of Gastroenterology)

    1991-05-01

    Selenium-75 homocholic acid conjugated with taurine ({sup 75}Se-HCAT) was used during loperamide administration in seven patients suspected of having bile acid malabsorption due to late radiation damage and small-bowel resection in order to document the aetiology of ileal dysfunction and to adjust therapeutic mamagement. In two patients with ileal resection up to 50 cm and in one patient without resection, a reduction of bowel motility by loperamide resulted in marked normalization of the {sup 75}Se-HCAT retention measurements. Sequential scintigraphic {sup 75}Se-HCAT imaging demonstrated a significant improvement in the {sup 75}Se-HCAT reabsorption and recirculation, accompanied in one case by prolongation of colonic retention of the radiopharmaceutical. In four patients with more than 80 cm resection, the {sup 75}Se-HCAT test was abnormal during loperamide administration. In two of these patients for whom baseline values were available, no improvement in the pattern of {sup 75}Se-HCAT absorption was observed. In conclusion, the first results of loperamide {sup 75}Se-HCAT in patients suspected of having bile acid malabsorption and abnormal baseline {sup 75}Se-HCAT are promising. Intervention with loperamide is easy and seems to improve the clinical value of the test with direct therapeutic implications. Sequential {sup 75}Se-HCAT imaging is essential for interpreting changes in the {sup 75}Se-HCAT retention measurements. (orig.).

  14. Extension of knee immobilization delays recovery of histological damages in the anterior cruciate ligament insertion and articular cartilage in rabbits.

    Science.gov (United States)

    Mutsuzaki, Hirotaka; Nakajima, Hiromi; Sakane, Masataka

    2018-01-01

    [Purpose] To investigate the influence of knee immobilization period on recovery of histological damages in the anterior cruciate ligament (ACL) insertion and articular cartilage in rabbits. This knowledge is important for determining the appropriate rehabilitation approach for patients with ligament injuries, fracture, disuse atrophy, and degenerative joint disease. [Materials and Methods] Forty-eight male Japanese white rabbits were divided equally into the remobilization and control groups. The remobilization group had the right knee surgically immobilized, and was divided equally into four subgroups according to the duration of immobilization (1, 2, 4 and 8 weeks). After the immobilization was removed, the rabbits moved freely for 8 weeks. The control group underwent sham operation and followed the same time course as the remobilization group. The chondrocyte apoptosis rate and chondrocyte proliferation rate in the ACL insertion and articular cartilage were analyzed after remobilization. [Results] In the ACL insertion, the remobilization group had a higher chondrocyte apoptosis rate than the control group after 8 weeks of immobilization, and a lower chondrocyte proliferation rate than the control group after 4 and 8 weeks of immobilization. In the articular cartilage, the remobilization group had a lower chondrocyte proliferation rate than the control group after 8 weeks of immobilization. After 8 weeks of remobilization, the ACL insertion and articular cartilage are not completely recovered after 4 and 8 weeks of immobilization, respectively. [Conclusion] Our results suggest that 8 weeks of remobilization will result in recovery of the ACL insertion after 2 weeks of knee immobilization, and recovery of the articular cartilage after 4 weeks of knee immobilization. If 8 weeks of immobilization occurs, a remobilization duration of more than 8 weeks may be necessary.

  15. Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia.

    Science.gov (United States)

    Cameron, Stella H; Alwakeel, Amr J; Goddard, Liping; Hobbs, Catherine E; Gowing, Emma K; Barnett, Elizabeth R; Kohe, Sarah E; Sizemore, Rachel J; Oorschot, Dorothy E

    2015-09-01

    Perinatal hypoxia-ischemia is a major cause of striatal injury and may lead to cerebral palsy. This study investigated whether delayed administration of bone marrow-derived mesenchymal stem cells (MSCs), at one week after neonatal rat hypoxia-ischemia, was neurorestorative of striatal medium-spiny projection neurons and improved motor function. The effect of a subcutaneous injection of a high-dose, or a low-dose, of MSCs was investigated in stereological studies. Postnatal day (PN) 7 pups were subjected to hypoxia-ischemia. At PN14, pups received treatment with either MSCs or diluent. A subset of high-dose pups, and their diluent control pups, were also injected intraperitoneally with bromodeoxyuridine (BrdU), every 24h, on PN15, PN16 and PN17. This permitted tracking of the migration and survival of neuroblasts originating from the subventricular zone into the adjacent injured striatum. Pups were euthanized on PN21 and the absolute number of striatal medium-spiny projection neurons was measured after immunostaining for DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32), double immunostaining for BrdU and DARPP-32, and after cresyl violet staining alone. The absolute number of striatal immunostained calretinin interneurons was also measured. There was a statistically significant increase in the absolute number of DARPP-32-positive, BrdU/DARPP-32-positive, and cresyl violet-stained striatal medium-spiny projection neurons, and fewer striatal calretinin interneurons, in the high-dose mesenchymal stem cell (MSC) group compared to their diluent counterparts. A high-dose of MSCs restored the absolute number of these neurons to normal uninjured levels, when compared with previous stereological data on the absolute number of cresyl violet-stained striatal medium-spiny projection neurons in the normal uninjured brain. For the low-dose experiment, in which cresyl violet-stained striatal medium-spiny neurons alone were measured, there was a lower statistically

  16. High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats.

    Science.gov (United States)

    Brückner, Melanie; Lasarzik, Irina; Jahn-Eimermacher, Antje; Peetz, Dirk; Werner, Christian; Engelhard, Kristin; Thal, Serge C

    2013-09-13

    Recent studies demonstrated anticoagulatory, antiinflammatory, antiapoptotic, and neuroprotective properties of activated protein C (APC) in rodent models of acute neurodegenerative diseases, suggesting APC as promising broad acting therapeutic agent. Unfortunately, continuous infusion of recombinant human APC (rhAPC) failed to improve brain damage following cardiac arrest in rats. The present study was designed to investigate the neuroprotective effect after global cerebral ischemia (GI) with an optimized infusion protocol. Rats were subjected to bilateral clip occlusion of the common carotid arteries (BCAO) and controlled hemorrhagic hypotension to 40 mm Hg for 14 min and a subsequent 5h-infusion of rhAPC (2mg/kg bolus+6 mg/kg/h continuous IV) or vehicle (0.9% NaCl). The dosage was calculated to maintain plasma hAPC activity at 150%. Cerebral inflammation, apoptosis and neuronal survival was determined at day 10. rhAPC infusion did not influence cortical cerebral perfusion during reperfusion and failed to reduce neuronal cell loss, microglia activation, and caspase 3 activity. Even an optimized rhAPC infusion protocol designed to maintain a high level of APC plasma activity failed to improve the sequels following GI. Despite positive reports about protective effects of APC following, e.g., ischemic stroke, the present study supports the notion that infusion of APC during the early reperfusion phase does not result in sustained neuroprotection and fails to improve outcome after global cerebral ischemia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  17. Neuroprotective effects of the antioxidant action of 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride against ischemic neuronal damage in the brain

    Directory of Open Access Journals (Sweden)

    Soo Young Choi

    2013-07-01

    Full Text Available Ischemia is characterized by oxidative stress and changes in theantioxidant defense system. Our recent in vitro study showedthat 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochlorideprotects cortical astrocytes against oxidative stress. In the currentstudy, we examined the effects of 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride on ischemia-induced neuronaldamage in a gerbil ischemia/reperfusion models. Extensive neuronaldeath in the hippocampal CA1 area was observed 4 daysafter ischemia/reperfusion. Intraperitoneal injection of 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (0.3 mg/kgbody weight significantly prevented neuronal death in the CA1region of the hippocampus in response to transient forebrainischemia. 2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochlorideadministration reduced ischemia-induced increases inreactive oxygen species levels and malondialdehyde content. Italso attenuated the associated reductions in glutathione level andsuperoxide dismutase, catalase, and glutathione peroxidaseactivities. Taken together, our results suggest that 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride protects againstischemia-induced neuronal damage by reducing oxidative stressthrough its antioxidant actions. [BMB Reports 2013; 46(7:370-375

  18. Lycium barbarum polysaccharides reduce neuronal damage, blood-retinal barrier disruption and oxidative stress in retinal ischemia/reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Suk-Yee Li

    Full Text Available Neuronal cell death, glial cell activation, retinal swelling and oxidative injury are complications in retinal ischemia/reperfusion (I/R injuries. Lycium barbarum polysaccharides (LBP, extracts from the wolfberries, are good for "eye health" according to Chinese medicine. The aim of our present study is to explore the use of LBP in retinal I/R injury. Retinal I/R injury was induced by surgical occlusion of the internal carotid artery. Prior to induction of ischemia, mice were treated orally with either vehicle (PBS or LBP (1 mg/kg once a day for 1 week. Paraffin-embedded retinal sections were prepared. Viable cells were counted; apoptosis was assessed using TUNEL assay. Expression levels of glial fibrillary acidic protein (GFAP, aquaporin-4 (AQP4, poly(ADP-ribose (PAR and nitrotyrosine (NT were investigated by immunohistochemistry. The integrity of blood-retinal barrier (BRB was examined by IgG extravasations. Apoptosis and decreased viable cell count were found in the ganglion cell layer (GCL and the inner nuclear layer (INL of the vehicle-treated I/R retina. Additionally, increased retinal thickness, GFAP activation, AQP4 up-regulation, IgG extravasations and PAR expression levels were observed in the vehicle-treated I/R retina. Many of these changes were diminished or abolished in the LBP-treated I/R retina. Pre-treatment with LBP for 1 week effectively protected the retina from neuronal death, apoptosis, glial cell activation, aquaporin water channel up-regulation, disruption of BRB and oxidative stress. The present study suggests that LBP may have a neuroprotective role to play in ocular diseases for which I/R is a feature.

  19. Heavy Chronic Ethanol Exposure From Adolescence to Adulthood Induces Cerebellar Neuronal Loss and Motor Function Damage in Female Rats

    Directory of Open Access Journals (Sweden)

    Fernando B. R. da Silva

    2018-05-01

    Full Text Available Over the last years, heavy ethanol consumption by teenagers/younger adults has increased considerably among females. However, few studies have addressed the long-term impact on brain structures’ morphology and function of chronic exposure to high ethanol doses from adolescence to adulthood in females. In line with this idea, in the current study we investigated whether heavy chronic ethanol exposure during adolescence to adulthood may induce motor impairments and morphological and cellular alterations in the cerebellum of female rats. Adolescent female Wistar rats (35 days old were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v during 55 days by gavage. At 90 days of age, motor function of animals was assessed using open field (OF, pole, beam walking and rotarod tests. Following completion of behavioral tests, morphological and immunohistochemical analyses of the cerebellum were performed. Chronic ethanol exposure impaired significantly motor performance of female rats, inducing spontaneous locomotor activity deficits, bradykinesia, incoordination and motor learning disruption. Moreover, histological analysis revealed that ethanol exposure induced atrophy and neuronal loss in the cerebellum. These findings indicate that heavy ethanol exposure during adolescence is associated with long-lasting cerebellar degeneration and motor impairments in female rats.

  20. The subacute damage of the dorsal root ganglion induced by collagenase in rats: a study on the ultrastructure of neurons

    International Nuclear Information System (INIS)

    Li Heping; Zhuang Wenquan; Yang Jianyong; Chen Wei

    2005-01-01

    Objective: To study the effects of collagenase on the ultrastructure of dorsal root ganglion (DRG) in rats. The safety of collagenase on nerve tissue was investigated. Additionally, the safety of percutaneous collagenase chemonucleolysis (PCCN) on nerve tissue was evaluated. Methods: In total 27 male, healthy SD rats were enrolled. All rats were randomized into 3 groups: normal group (9 rats), subacute damage of collagenase group (9 rats), subacute intervention-analogue group (9 rats). The left L5 DRG was exposed in each rat. One milliliter of the collagenase solution (300 units) was carefully applied to the exposed DRG in collagenase group, and one milliliter of the isotonic saline was applied to the exposed DRG in intervention-analogue group. The morphology of the DRG under electron microscope were analyzed 7-9 days after the procedures. Results: The types, number, and morphology of cells; the membrane of neutrons; the nerve fibers and blood vessels in DRG had not been changed in all groups observed under optic microscope. The difference of the ultrastructure of neutrons in DRG among the normal groups, intervention-analogue group and collagenase group was significant: 1) The eccentric nucleolus were revealed; 2) Swelling mitochondria and absence of mitochondria crests and vesicles. Cytoclasis and apoptosis of neutrons had not been observed under electron microscope. Conclusion: The collagenase used in PCCN dose have a certain damage to the neutreons in DRG. In the procedure of PCCN, the volume and dosage of collagenase should be carefully selected and the intervention should be precisely performed by experienced hands. (authors)

  1. ApoB100/LDLR-/- hypercholesterolaemic mice as a model for mild cognitive impairment and neuronal damage.

    Directory of Open Access Journals (Sweden)

    Carlos Ramírez

    Full Text Available Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD. Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR] of human familial hypercholesterolaemia (FH. From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100 levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing and impairment of the episodic-like memory (determined by the integrated memory test. This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.

  2. Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis

    Directory of Open Access Journals (Sweden)

    Henry James L

    2009-09-01

    Full Text Available Abstract Background Clinical data on osteoarthritis (OA suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons. Results At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis. Conclusion These data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.

  3. Enteric Neuronal Damage, Intramuscular Denervation and Smooth Muscle Phenotype Changes as Mechanisms of Chagasic Megacolon: Evidence from a Long-Term Murine Model of Trypanosoma cruzi Infection.

    Directory of Open Access Journals (Sweden)

    Camila França Campos

    Full Text Available We developed a novel murine model of long-term infection with Trypanosoma cruzi with the aim to elucidate the pathogenesis of megacolon and the associated adaptive and neuromuscular intestinal disorders. Our intent was to produce a chronic stage of the disease since the early treatment should avoid 100% mortality of untreated animals at acute phase. Treatment allowed animals to be kept infected and alive in order to develop the chronic phase of infection with low parasitism as in human disease. A group of Swiss mice was infected with the Y strain of T. cruzi. At the 11th day after infection, a sub-group was euthanized (acute-phase group and another sub-group was treated with benznidazole and euthanized 15 months after infection (chronic-phase group. Whole colon samples were harvested and used for studying the histopathology of the intestinal smooth muscle and the plasticity of the enteric nerves. In the acute phase, all animals presented inflammatory lesions associated with intense and diffuse parasitism of the muscular and submucosa layers, which were enlarged when compared with the controls. The occurrence of intense degenerative inflammatory changes and increased reticular fibers suggests inflammatory-induced necrosis of muscle cells. In the chronic phase, parasitism was insignificant; however, the architecture of Aüerbach plexuses was focally affected in the inflamed areas, and a significant decrease in the number of neurons and in the density of intramuscular nerve bundles was detected. Other changes observed included increased thickness of the colon wall, diffuse muscle cell hypertrophy, and increased collagen deposition, indicating early fibrosis in the damaged areas. Mast cell count significantly increased in the muscular layers. We propose a model for studying the long-term (15 months pathogenesis of Chagasic megacolon in mice that mimics the human disease, which persists for several years and has not been fully elucidated. We

  4. New Insights in the Pathogenesis of Multiple Sclerosis—Role of Acrolein in Neuronal and Myelin Damage

    Directory of Open Access Journals (Sweden)

    Riyi Shi

    2013-10-01

    Full Text Available Multiple sclerosis (MS is an autoimmune disease of the central nervous system (CNS characterized by an inappropriate inflammatory reaction resulting in widespread myelin injury along white matter tracts. Neurological impairment as a result of the disease can be attributed to immune-mediated injury to myelin, axons and mitochondria, but the molecular mechanisms underlying the neuropathy remain incompletely understood. Incomplete mechanistic knowledge hinders the development of therapies capable of alleviating symptoms and slowing disease progression in the long-term. Recently, oxidative stress has been implicated as a key component of neural tissue damage prompting investigation of reactive oxygen species (ROS scavengers as a potential therapeutic option. Despite the establishment of oxidative stress as a crucial process in MS development and progression, ROS scavengers have had limited success in animal studies which has prompted pursuit of an alternative target capable of curtailing oxidative stress. Acrolein, a toxic β-unsaturated aldehyde capable of initiating and perpetuating oxidative stress, has been suggested as a viable point of intervention to guide the development of new treatments. Sequestering acrolein using an FDA-approved compound, hydralazine, offers neuroprotection resulting in dampened symptom severity and slowed disease progression in experimental autoimmune encephalomyelitis (EAE mice. These results provide promise for therapeutic development, indicating the possible utility of neutralizing acrolein to preserve and improve neurological function in MS patients.

  5. Early intervention with human albumin to reduce the tissue plasminogen activator-mediated blood-brain barrier permeability damaged by delayed reperfusion: an experimental study in rats

    International Nuclear Information System (INIS)

    Lu Haitao; Zhao Jungong; Li Minghua; Li Yongdong; Zhang Peilei

    2011-01-01

    Objective: To clarify whether early use of high-dose human albumin can reduce the permeability of blood-brain barrier (BBB) damaged by delayed thrombolysis or not, and, in tun, reduce the vasogenic brain edema. Methods: A total of 138 male SD rats weighing 320-380 grams were randomly divided into 4 groups: sham operation group (n=3), control group (n=45), albumin group (n=45) and albumin+rt-PA group (n=45). According to the reperfusion time after the onset of middle cerebral artery occlusion (MCAO), each group, except sham operation group, was divided into three subgroups of 2 h, 3 h and 4 h with 15 rats in each subgroup. Rats in albumin group and albumin+rt-PA group received an intravenous infusion of 20% human albumin (2.5 g/kg) 2 hours after the onset of MCAO, and rats in albumin+rt-PA group received an intravenous infusion of rt-PA (10 mg/kg) at all points of reperfusion time via the rat's femoral vein immediately after the reperfusion. All rats were sacrificed 24 hours after MCAO, the infarct volume of the brain was determined with TTC dye method, the leakage extent of BBB was quantitatively estimated by using Evans blue method, and the matrix metalloproteinase-9 (MMP-9) expression was assessed with immunohistochemistry technique. Results: Early intervention with the use of high-dose human albumin could significantly improve the neurological score at 24 h. In MCAO 3 h albumin group, MCAO 4 h albumin group and MCAO 3 h albumin+rt-PA group, neurological score was significantly better than that in the control group (P 0.05). The volume of the infarct tissue was also significantly smaller in all the treated groups with high-dose human albumin groups (P<0.05) when compared with the control group. The infarct volume of the MCAO 4 h in albumin group and albumin+rt-PA group was reduced by 23% and by 17.3%, respectively. Cerebral hemorrhage transformation occurred in two rats of MCAO 4 h control group, in one rat of MCAO 4 h albumin group and in one rat of MCAO 4 h

  6. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis.

    Science.gov (United States)

    Chen, Liuji; Hambright, William Sealy; Na, Ren; Ran, Qitao

    2015-11-20

    Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degeneration of motor neurons in the spinal cord but had no overt neuron degeneration in the cerebral cortex. Consistent with the role of GPX4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis, including no caspase-3 activation, no TUNEL staining, activation of ERKs, and elevated spinal inflammation. Supplementation with vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Gpx4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Gpx4 ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Effect of hyperbaric oxygenation on mitochondrial function of neuronal cells in the cortex of neonatal rats after hypoxic-ischemic brain damage

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    L. Yang

    2016-01-01

    Full Text Available The timing and mechanisms of protection by hyperbaric oxygenation (HBO in hypoxic-ischemic brain damage (HIBD have only been partially elucidated. We monitored the effect of HBO on the mitochondrial function of neuronal cells in the cerebral cortex of neonatal rats after HIBD. Neonatal Sprague-Dawley rats (total of 360 of both genders were randomly divided into normal control, HIBD, and HIBD+HBO groups. The HBO treatment began immediately after hypoxia-ischemia (HI and continued once a day for 7 consecutive days. Animals were euthanized 0, 2, 4, 6, and 12 h post-HI to monitor the changes in mitochondrial membrane potential (ΔΨm occurring soon after a single dose of HBO treatment, as well as 2, 3, 4, 5, 6, and 7 days post-HI to study ΔΨm changes after a series of HBO treatments. Fluctuations in ΔΨm were observed in the ipsilateral cortex in both HIBD and HIBD+HBO groups. Within 2 to 12 h after HI insult, the ΔΨm of the HIBD and HIBD+HBO groups recovered to some extent. A secondary drop in ΔΨm was observed in both groups during the 1-4 days post-HI period, but was more severe in the HIBD+HBO group. There was a secondary recovery of ΔΨm observed in the HIBD+HBO group, but not in the HIBD group, during the 5-7 days period after HI insult. HBO therapy may not lead to improvement of neural cell mitochondrial function in the cerebral cortex in the early stage post-HI, but may improve it in the sub-acute stage post-HI.

  8. Characterization of the of the Pathological and Biochemical Markers That Correlate to the Clinical Features of Autism. Subproject 2. Contribution of Significant Delay of Neuronal Development and Metabolic Shift of Neurons to Clinical Phenotype of Autism

    Science.gov (United States)

    2013-04-01

    4:e4415 11. Bruce S, Nyberg F, Melén E et al (2009) The protective effect of farm animal exposure on childhood allergy is modified by NPSR1...Rabbit monoclonal (R-m) or polyclonal (R-p), Goat polyclonal (G-p). Immunocytochemistry (ICH), Confocal microscopy (CM), Western blots (WB). doi:10.1371...immunostained with a goat anti-GFAP polyclonal antibody. Projections of the raphe nuclei serotonergic neurons were identified by using mouse mAb ST51-2

  9. Selective lesion of septal cholinergic neurons in rats impairs acquisition of a delayed matching to position T-maze task by delaying the shift from a response to a place strategy.

    Science.gov (United States)

    Fitz, Nicholas F; Gibbs, Robert B; Johnson, David A

    2008-12-16

    This study tested the hypothesis that septal cholinergic lesions impair acquisition of a delayed matching to position (DMP) T-maze task in male rats by affecting learning strategy. Rats received either the selective cholinergic immunotoxin, 192 IgG-saporin (SAP) or artificial cerebrospinal fluid directly into the medial septum. Two weeks later, animals were trained to acquire the DMP task. SAP-treated rats took significantly longer to acquire the task than corresponding controls. Both SAP-treated and control rats adopted a persistent turn and utilized a response strategy during early periods of training. By the time rats reached criterion the persistent turn was no longer evident, and all rats had shifted to an allocentric strategy, i.e., were relying on extramaze cues to a significant degree. During the acquisition period, SAP-treated rats spent significantly more days showing a persistent turn and using a response strategy than corresponding controls. The added time spent using a response strategy accounted entirely for the added days required to reach criterion among the SAP-treated rats. This suggests that the principal mechanism by which septal cholinergic lesions impair DMP acquisition in male rats is by increasing the predisposition to use a response vs. a place strategy, thereby affecting the ability to switch from one strategy to another.

  10. Ibuprofen or piroxicam protects nigral neurons and delays the development of l-dopa induced dyskinesia in rats with experimental Parkinsonism: Influence on angiogenesis.

    Science.gov (United States)

    Teema, Asmaa M; Zaitone, Sawsan A; Moustafa, Yasser M

    2016-08-01

    Neuroinflammation and angiogenesis have been involved in the pathogenesis of Parkinson's disease (PD). This study investigated the effect of ibuprofen or piroxicam on the motor response to l-dopa and development of dyskinesia in Parkinsonian rats focusing on the anti-angiogenic role of the two non-steroidal anti-inflammatory drugs (NSAIDs). Rats were divided into nine groups as follows: Group I: the vehicle group, Group II: rotenone group, rats were injected with nine doses of rotenone (1 mg/kg/48 h), group III&IV: rats received rotenone + ibuprofen (10 or 30 mg/kg), Group V-VI: rats received rotenone + piroxicam (1 or 3 mg/kg), Group VII: rats received rotenone + l-dopa/carbidopa (100/10 mg/kg), Group VIII-IX: rats received rotenone + l-dopa/carbidopa + ibuprofen (30 mg/kg) or piroxicam (3 mg/kg). In general, drugs were administered daily for ten weeks. Rotenone-treated rats showed motor dysfunction, lower striatal dopamine, lower staining for nigral tyrosine hydroxylase but higher level of striatal cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) compared to vehicle-treated rats (P piroxicam in combination with l-dopa preserved the effect of l-dopa at the end of week 10, delayed the development of dyskinesia and decreased striatal COX-2 and VEGF levels. In conclusion, the current study suggests that ibuprofen and piroxicam are promising candidates for neuroprotection in PD and may have utility in conjunction with l-dopa in order to ensure the longevity of its action and to delay the development of dyskinesia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. The neurobiology of thalamic amnesia: Contributions of medial thalamus and prefrontal cortex to delayed conditional discrimination.

    Science.gov (United States)

    Mair, Robert G; Miller, Rikki L A; Wormwood, Benjamin A; Francoeur, Miranda J; Onos, Kristen D; Gibson, Brett M

    2015-07-01

    Although medial thalamus is well established as a site of pathology associated with global amnesia, there is uncertainty about which structures are critical and how they affect memory function. Evidence from human and animal research suggests that damage to the mammillothalamic tract and the anterior, mediodorsal (MD), midline (M), and intralaminar (IL) nuclei contribute to different signs of thalamic amnesia. Here we focus on MD and the adjacent M and IL nuclei, structures identified in animal studies as critical nodes in prefrontal cortex (PFC)-related pathways that are necessary for delayed conditional discrimination. Recordings of PFC neurons in rats performing a dynamic delayed non-matching-to position (DNMTP) task revealed discrete populations encoding information related to planning, execution, and outcome of DNMTP-related actions and delay-related activity signaling previous reinforcement. Parallel studies recording the activity of MD and IL neurons and examining the effects of unilateral thalamic inactivation on the responses of PFC neurons demonstrated a close coupling of central thalamic and PFC neurons responding to diverse aspects of DNMTP and provide evidence that thalamus interacts with PFC neurons to give rise to complex goal-directed behavior exemplified by the DNMTP task. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. The co-repressor SMRT delays DNA damage-induced caspase activation by repressing pro-apoptotic genes and modulating the dynamics of checkpoint kinase 2 activation.

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    Claudio Scafoglio

    Full Text Available Checkpoint kinase 2 (Chk2 is a major regulator of DNA damage response and can induce alternative cellular responses: cell cycle arrest and DNA repair or programmed cell death. Here, we report the identification of a new role of Chk2 in transcriptional regulation that also contributes to modulating the balance between survival and apoptosis following DNA damage. We found that Chk2 interacts with members of the NCoR/SMRT transcriptional co-regulator complexes and serves as a functional component of the repressor complex, being required for recruitment of SMRT on the promoter of pro-apoptotic genes upon DNA damage. Thus, the co-repressor SMRT exerts a critical protective action against genotoxic stress-induced caspase activation, repressing a functionally important cohort of pro-apoptotic genes. Amongst them, SMRT is responsible for basal repression of Wip1, a phosphatase that de-phosphorylates and inactivates Chk2, thus affecting a feedback loop responsible for licensing the correct timing of Chk2 activation and the proper execution of the DNA repair process.

  13. Inhibition of Myeloperoxidase by N-Acetyl Lysyltyrosylcysteine Amide Reduces Oxidative Stress-Mediated Inflammation, Neuronal Damage, and Neural Stem Cell Injury in a Murine Model of Stroke.

    Science.gov (United States)

    Yu, Guoliang; Liang, Ye; Zheng, Shikan; Zhang, Hao

    2018-02-01

    Recent studies suggest that myeloperoxidase (MPO)-dependent oxidative stress plays a significant role in brain injury in stroke patients. We previously showed that N -acetyl lysyltyrosylcysteine amide (KYC), a novel MPO inhibitor, significantly decreased infarct size, blood-brain barrier leakage, infiltration of myeloid cells, loss of neurons, and apoptosis in the brains of middle cerebral artery occlusion (MCAO) mice. Inhibition of MPO also noticeably reduced neurologic severity scores of MCAO mice. Thus, our data support the idea that MPO-dependent oxidative stress plays a detrimental role in tissue injury in ischemic stroke. However, the mechanisms of MPO-induced injury in stroke are still largely unknown. Here, we present new evidence showing that KYC treatment greatly reduced inflammation by decreasing the number of proinflammatory M1 microglial cells and N1 neutrophils in the brains of MCAO mice. KYC also markedly reduced the expression of high-mobility group box 1, receptor for advanced glycation end products, and nuclear factor- κ B in the brains of MCAO mice. Both neurons and neural stem cells (NSCs) were oxidatively injured by MPO-dependent oxidative stress in MCAO mice. Inhibiting MPO-dependent oxidative stress with KYC significantly reduced oxidative injury and apoptosis in neurons and NSCs. KYC treatment also protected transplanted exogenous NSCs in the brains of MCAO mice. Thus, our studies suggest that MPO-dependent oxidative stress directly injures brain tissues by oxidizing neurons and NSCs and increasing inflammation during stroke. Inhibition of MPO activity with KYC preserves neuronal function and helps the brain recover from injury after stroke. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Ginseng Rb fraction protects glia, neurons and cognitive function in a rat model of neurodegeneration.

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    Kangning Xu

    Full Text Available The loss and injury of neurons play an important role in the onset of various neurodegenerative diseases, while both microgliosis and astrocyte loss or dysfunction are significant causes of neuronal degeneration. Previous studies have suggested that an extract enriched panaxadiol saponins from ginseng has more neuroprotective potential than the total saponins of ginseng. The present study investigated whether a fraction of highly purified panaxadiol saponins (termed as Rb fraction was protective for both glia and neurons, especially GABAergic interneurons, against kainic acid (KA-induced excitotoxicity in rats. Rats received Rb fraction at 30 mg/kg (i.p., 40 mg/kg (i.p. or saline followed 40 min later by an intracerebroventricular injection of KA. Acute hippocampal injury was determined at 48 h after KA, and impairment of hippocampus-dependent learning and memory as well as delayed neuronal injury was determined 16 to 21 days later. KA injection produced significant acute hippocampal injuries, including GAD67-positive GABAergic interneuron loss in CA1, paralbumin (PV-positive GABAergic interneuron loss, pyramidal neuron degeneration and astrocyte damage accompanied with reactive microglia in both CA1 and CA3 regions of the hippocampus. There was also a delayed loss of GAD67-positive interneurons in CA1, CA3, hilus and dentate gyrus. Microgliosis also became more severe 21 days later. Accordingly, KA injection resulted in hippocampus-dependent spatial memory impairment. Interestingly, the pretreatment with Rb fraction at 30 or 40 mg/kg significantly protected the pyramidal neurons and GABAergic interneurons against KA-induced acute excitotoxicity and delayed injury. Rb fraction also prevented memory impairments and protected astrocytes from KA-induced acute excitotoxicity. Additionally, microglial activation, especially the delayed microgliosis, was inhibited by Rb fraction. Overall, this study demonstrated that Rb fraction protected both

  15. Reward acts as a signal to control delay-period activity in delayed-response tasks.

    Science.gov (United States)

    Ichihara-Takeda, Satoe; Takeda, Kazuyoshi; Funahashi, Shintaro

    2010-03-31

    Prefrontal delay-period activity represents a neural mechanism for the active maintenance of information and needs to be controlled by some signal to appropriately operate working memory. To examine whether reward-delivery acts as this signal, the effects of delay-period activity in response to unexpected reward-delivery were examined by analyzing single-neuron activity recorded in the primate dorsolateral prefrontal cortex. Among neurons that showed delay-period activity, 34% showed inhibition of this activity in response to unexpected reward-delivery. The delay-period activity of these neurons was affected by the expectation of reward-delivery. The strength of the reward signal in controlling the delay-period activity is related to the strength of the effect of reward information on the delay-period activity. These results indicate that reward-delivery acts as a signal to control delay-period activity.

  16. Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons

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    Shanshan Sun

    2017-04-01

    Full Text Available Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury. In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD, a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen–glucose-deprivation/reperfusion (OGD/R model in a mouse hippocampal neuronal cell line. CBD supplementation during reperfusion rescued OGD/R-induced cell death, attenuated intracellular ROS generation and lipid peroxidation, and simultaneously reversed the abnormal changes in antioxidant biomarkers. Using the Seahorse XFe24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons. The activation of glucose 6-phosphate dehydrogenase and the preservation of the NADPH/NADP+ ratio implies that the pentose-phosphate pathway is stimulated by CBD, thus protecting hippocampal neurons from OGD/R injury. This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance.

  17. Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons.

    Science.gov (United States)

    Sun, Shanshan; Hu, Fangyuan; Wu, Jihong; Zhang, Shenghai

    2017-04-01

    Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury. In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD), a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen-glucose-deprivation/reperfusion (OGD/R) model in a mouse hippocampal neuronal cell line. CBD supplementation during reperfusion rescued OGD/R-induced cell death, attenuated intracellular ROS generation and lipid peroxidation, and simultaneously reversed the abnormal changes in antioxidant biomarkers. Using the Seahorse XF e 24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons. The activation of glucose 6-phosphate dehydrogenase and the preservation of the NADPH/NADP + ratio implies that the pentose-phosphate pathway is stimulated by CBD, thus protecting hippocampal neurons from OGD/R injury. This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  18. An insert-based enzymatic cell culture system to rapidly and reversibly induce hypoxia: investigations of hypoxia-induced cell damage, protein expression and phosphorylation in neuronal IMR-32 cells

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    Ying Huang

    2013-11-01

    Ischemia-reperfusion injury and tissue hypoxia are of high clinical relevance because they are associated with various pathophysiological conditions such as myocardial infarction and stroke. Nevertheless, the underlying mechanisms causing cell damage are still not fully understood, which is at least partially due to the lack of cell culture systems for the induction of rapid and transient hypoxic conditions. The aim of the study was to establish a model that is suitable for the investigation of cellular and molecular effects associated with transient and long-term hypoxia and to gain insights into hypoxia-mediated mechanisms employing a neuronal culture system. A semipermeable membrane insert system in combination with the hypoxia-inducing enzymes glucose oxidase and catalase was employed to rapidly and reversibly generate hypoxic conditions in the culture medium. Hydrogen peroxide assays, glucose measurements and western blotting were performed to validate the system and to evaluate the effects of the generated hypoxia on neuronal IMR-32 cells. Using the insert-based two-enzyme model, hypoxic conditions were rapidly induced in the culture medium. Glucose concentrations gradually decreased, whereas levels of hydrogen peroxide were not altered. Moreover, a rapid and reversible (onoff generation of hypoxia could be performed by the addition and subsequent removal of the enzyme-containing inserts. Employing neuronal IMR-32 cells, we showed that 3 hours of hypoxia led to morphological signs of cellular damage and significantly increased levels of lactate dehydrogenase (a biochemical marker of cell damage. Hypoxic conditions also increased the amounts of cellular procaspase-3 and catalase as well as phosphorylation of the pro-survival kinase Akt, but not Erk1/2 or STAT5. In summary, we present a novel framework for investigating hypoxia-mediated mechanisms at the cellular level. We claim that the model, the first of its kind, enables researchers to rapidly and

  19. Peculiarities of reaction of HIF-1α protein of the hippocampus neurons in rats with experimental diabetes mellitus in the dynamics of ischemic-reperfusion damage of the brain

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    T. M. Boychuk

    2016-12-01

    Higher State Educational Establishment of Ukraine “Bukovinian State medical University”, Chernivtsi, Ukraine   Abstract Introduction. The role of the transcriptional factor Hif-1α in pathogenesis of hypoxic damages and diabetes mellitus (DM is proved, although molecular mechanisms underlying the basis of this factor dysfunction in association with DM with ischemic-reperfusion damage of the brain remain unknown. Objective. The objective of this investigation was to study the content of Hif-1α protein in the hippocampus neurons of rats with experimental DM in the dynamics of ischemic-reperfusion damage of the brain. Results. In rats without DM 20 minute ischemia with one hour reperfusion increases the content of Hif-1α protein in all the fields of the hippocampus. On the 12th day of ischemic-reperfusion period in the hippocampus CA2-CA4 fields the values of certain examined indices of the activity of Hif-1α transcriptional factor continue to increase, and in СА1field they normalize or approach to the values of animals in the control group.  In rats with DM during early post-ischemic period there are no changes of Hif-1α protein content in CA1 field, in CA2 field there are signs of its reduced activity, in CA3 field they are limited by the reaction of one index, in CA4 field they are of a similar character with those of the control rats under experimental conditions.  On the 12th day of ischemic-reperfusion period in CA1 field all the indices of activity of Hif-1α transcriptional factor increase exceeding corresponding indices by absolute values in animals of the control group under the same experimental conditions, in СА2 and СА3 fields changes of the examined parameters are limited as compared to the same ones in animals from the control group, in CA4 field values that were increased in the control group decrease. Conclusions. Diabetes mellitus restricts reaction of Hif-1α protein on ischemia-reperfusion inn the neurons of СА1-СА3 fields in

  20. Dimethyl Fumarate Protects Neural Stem/Progenitor Cells and Neurons from Oxidative Damage through Nrf2-ERK1/2 MAPK Pathway

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    Qin Wang

    2015-06-01

    Full Text Available Multiple sclerosis (MS is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS. Due to the progressive neurodegenerative nature of MS, developing treatments that exhibit direct neuroprotective effects are needed. Tecfidera™ (BG-12 is an oral formulation of the fumaric acid esters (FAE, containing the active metabolite dimethyl fumarate (DMF. Although BG-12 showed remarkable efficacy in lowering relapse rates in clinical trials, its mechanism of action in MS is not yet well understood. In this study, we reported the potential neuroprotective effects of dimethyl fumarate (DMF on mouse and rat neural stem/progenitor cells (NPCs and neurons. We found that DMF increased the frequency of the multipotent neurospheres and the survival of NPCs following oxidative stress with hydrogen peroxide (H2O2 treatment. In addition, utilizing the reactive oxygen species (ROS assay, we showed that DMF reduced ROS production induced by H2O2. DMF also decreased oxidative stress-induced apoptosis. Using motor neuron survival assay, DMF significantly promoted survival of motor neurons under oxidative stress. We further analyzed the expression of oxidative stress-induced genes in the NPC cultures and showed that DMF increased the expression of transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2 at both levels of RNA and protein. Furthermore, we demonstrated the involvement of Nrf2-ERK1/2 MAPK pathway in DMF-mediated neuroprotection. Finally, we utilized SuperArray gene screen technology to identify additional anti-oxidative stress genes (Gstp1, Sod2, Nqo1, Srxn1, Fth1. Our data suggests that analysis of anti-oxidative stress mechanisms may yield further insights into new targets for treatment of multiple sclerosis (MS.

  1. Mutant APP and Amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease.

    Science.gov (United States)

    Reddy, P Hemachandra; Yin, XiangLin; Manczak, Maria; Kumar, Subodh; Jangampalli Adi, Pradeepkiran; Vijayan, Murali; Reddy, Arubala P

    2018-04-25

    The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Aβ) in human mutant APP (mAPP) cDNA transfected with primary mouse hippocampal neurons (HT22). Hippocampal tissues are the best source of studying learning and memory functions in patients with Alzheimer's disease (AD) and healthy controls. However, investigating immortalized hippocampal neurons that express AD proteins provide an excellent opportunity for drug testing. Using quantitative RT-PCR, immunoblotting & immunofluorescence, and transmission electron microscopy, we assessed mRNA and protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2, and assessed mitochondrial number and length in mAPP-HT22 cells that express Swedish/Indiana mutations. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial ATP. Increased levels of mRNA and protein levels of mitochondrial fission genes, Drp1 and Fis1 and decreased levels fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1α, NRF1, NRF2 & TFAM), autophagy (ATG5 & LC3BI, LC3BII), mitophagy (PINK1 & TERT, BCL2 & BNIPBL), synaptic (synaptophysin & PSD95) and dendritic (MAP2) genes were found in mAPP-HT22 cells relative to WT-HT22 cells. Cell survival was significantly reduced mAPP-HT22 cells. GTPase-Dp1 enzymatic activity was increased in mAPP-HT22 cells. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells. These findings suggest that hippocampal accumulation of mutant APP and Aβ is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins & reduced dendritic spines and mitochondrial structural and functional changes in mutant APP hippocampal cells. These observations strongly suggest that accumulation of mAPP and A

  2. Delayed fission

    Energy Technology Data Exchange (ETDEWEB)

    Hatsukawa, Yuichi [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment

    1997-07-01

    Delayed fission is a nuclear decay process that couples {beta} decay and fission. In the delayed fission process, a parent nucleus undergoes {beta} decay and thereby populates excited states in the daughter. If these states are of energies comparable to or greater than the fission barrier of the daughter, then fission may compete with other decay modes of the excited states in the daughter. In this paper, mechanism and some experiments of the delayed fission will be discussed. (author)

  3. Superpulsed low-level laser therapy protects skeletal muscle of mdx mice against damage, inflammation and morphological changes delaying dystrophy progression.

    Science.gov (United States)

    Leal-Junior, Ernesto Cesar Pinto; de Almeida, Patrícia; Tomazoni, Shaiane Silva; de Carvalho, Paulo de Tarso Camillo; Lopes-Martins, Rodrigo Álvaro Brandão; Frigo, Lucio; Joensen, Jon; Johnson, Mark I; Bjordal, Jan Magnus

    2014-01-01

    To evaluate the effects of preventive treatment with low-level laser therapy (LLLT) on progression of dystrophy in mdx mice. Ten animals were randomly divided into 2 experimental groups treated with superpulsed LLLT (904 nm, 15 mW, 700 Hz, 1 J) or placebo-LLLT at one point overlying the tibialis anterior muscle (bilaterally) 5 times per week for 14 weeks (from 6th to 20th week of age). Morphological changes, creatine kinase (CK) activity and mRNA gene expression were assessed in animals at 20th week of age. Animals treated with LLLT showed very few morphological changes in skeletal muscle, with less atrophy and fibrosis than animals treated with placebo-LLLT. CK was significantly lower (p=0.0203) in animals treated with LLLT (864.70 U.l-1, SEM 226.10) than placebo (1708.00 U.l-1, SEM 184.60). mRNA gene expression of inflammatory markers was significantly decreased by treatment with LLLT (pmuscle damage and inflammation in mdx mice. This indicates that LLLT has potential to decrease progression of Duchenne muscular dystrophy.

  4. Long-term streptozotocin-induced diabetes in rats leads to severe damage of brain blood vessels and neurons via enhanced oxidative stress.

    Science.gov (United States)

    Yang, Hongying; Fan, Shourui; Song, Dianping; Wang, Zhuo; Ma, Shungao; Li, Shuqing; Li, Xiaohong; Xu, Mian; Xu, Min; Wang, Xianmo

    2013-02-01

    The aim of this study was to investigate pathophysiological alterations and oxidative stress in various stages of streptozotocin (STZ)‑induced diabetes mellitus (DM) in rats. Male Sprague-Dawley rats (120) were randomized into DM and control groups. Body mass, plasma glucose, glycated hemoglobin (HbA1c), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels, as well as aldose reductase (AR) activities, in brain tissue and serum were determined. Electron microscopy was used to observe neuron and vessel changes in the brain. In STZ‑treated rats, blood glucose, low density lipoproteins, triglycerides and total cholesterol levels increased 1.43‑3.0‑fold and high density lipoprotein, HbA1c and insulin sensitivity index increased 1.1‑1.23‑fold compared with control. At week 16 following treatment, DM rat serum H2O2 concentration was increased, indicating oxidative stress and mRNA levels of GPx and SOD were 2‑fold higher than the control. Protein GPx and SOD levels were reduced (PNeuron cells and blood vessels in the DM rat brains became increasingly abnormal over time with altered Golgi bodies, mitochondria and endoplasmic reticulum cisterns, concurrent with SOD inactivation and AR protein accumulation. Disease progression in rats with STZ‑induced DM included brain pathologies with vascular and neuron cell abnormalities, associated with the reduction of SOD, CAT and GPx activities and also AR accumulation.

  5. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

    2017-06-01

    Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

  6. Kalopanacis Cortex extract-capped gold nanoparticles activate NRF2 signaling and ameliorate damage in human neuronal SH-SY5Y cells exposed to oxygen–glucose deprivation and reoxygenation

    Directory of Open Access Journals (Sweden)

    Park SY

    2017-06-01

    Full Text Available Sun Young Park,1 Seon Yeong Chae,1,2 Jin Oh Park,2 Kyu Jin Lee,2 Geuntae Park1,2 1Bio-IT Fusion Technology Research Institute, 2Department of Nanofusion Technology, Graduate School, Pusan National University, Busan, Republic of Korea Abstract: Recently, environment-friendly synthesis of gold nanoparticles (GNPs has been extensively explored by biologists and chemists. However, significant research is still required to determine whether “eco-friendly” GNPs are beneficial to human health and to elucidate the molecular mechanisms of their effects on human cells. We used human neuronal SH-SY5Y cells to show that treatment with Kalopanacis Cortex extract-capped GNPs (KC-GNs, prepared via an eco-friendly, fast, one-pot synthetic route, protected neuronal cells against oxygen–glucose deprivation/reoxygenation (OGD/R-induced damage. To prepare GNPs, Kalopanacis Cortex was used without any chemical reducing and stabilizing agents. Ultraviolet–visible spectroscopy showed maximum absorbance at 526 nm owing to KC-GN surface plasmon resonance. Hydrodynamic size (54.02±2.19 nm and zeta potential (-20.3±0.04 mV were determined by dynamic light scattering. The average diameter (41.07±3.05 nm was determined by high-resolution transmission electron microscopy. Energy-dispersive X-ray diffraction spectroscopy and X-ray diffraction confirmed the presence of assembled GNPs. Fourier transform infrared analysis suggested that functional groups such as O–H, C–C, and C–N participated in KC-GN formation. Cell viability assays indicated that KC-GNs restored the viability of OGD/R-treated SH-SY5Y cells. Flow cytometry demonstrated that KC-GNs inhibited the OGD/R-induced reactive oxygen species production and mitochondrial membrane potential disruption. KC-GNs also inhibited the apoptosis of OGD/R-exposed cells. Western blot analysis indicated that the OGD/R-induced cellular apoptosis and simultaneous increases in the expression of cleaved caspase-3, p

  7. Curcumin protects microglia and primary rat cortical neurons against HIV-1 gp120-mediated inflammation and apoptosis.

    Directory of Open Access Journals (Sweden)

    Luyan Guo

    Full Text Available Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. To explore whether curcumin is able to ameliorate HIV-1-associated neurotoxicity, we treated a murine microglial cell line (N9 and primary rat cortical neurons with curcumin in the presence or absence of neurotoxic HIV-1 gp120 (V3 loop protein. We found that HIV-1 gp120 profoundly induced N9 cells to produce reactive oxygen species (ROS, tumor necrosis factor-α (TNF-α and monocyte chemoattractant protein-1 (MCP-1. HIV-1 gp120 also induced apoptosis of primary rat cortical neurons. Curcumin exerted a powerful inhibitory effect against HIV-1 gp120-induced neuronal damage, reducing the production of ROS, TNF-α and MCP-1 by N9 cells and inhibiting apoptosis of primary rat cortical neurons. Curcumin may exert its biological activities through inhibition of the delayed rectification and transient outward potassium (K(+ current, as curcumin effectively reduced HIV-1 gp120-mediated elevation of the delayed rectification and transient outward K(+ channel current in neurons. We conclude that HIV-1 gp120 increases ROS, TNF-α and MCP-1 production in microglia, and induces cortical neuron apoptosis by affecting the delayed rectification and transient outward K(+ channel current. Curcumin reduces production of ROS and inflammatory mediators in HIV-1-gp120-stimulated microglia, and protects cortical neurons against HIV-1-mediated apoptosis, most likely through inhibition of HIV-1 gp120-induced elevation of the delayed rectification and transient outward K(+ current.

  8. Delayed Ejaculation

    Science.gov (United States)

    ... cases, it is due to a combination of physical and psychological concerns. Psychological causes of delayed ejaculation include: Depression, anxiety or other mental health conditions Relationship problems due to stress, poor communication ...

  9. Delayed growth

    Science.gov (United States)

    ... Slow rate of growth; Retarded growth and development; Growth delay Images Toddler development References Cooke DW, Divall SA, Radovick S. Normal and aberrant growth in children. In: Melmed S, Polonsky KS, Larsen PR, ...

  10. Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: Case-control Study with a Pair of Identical Twins.

    Science.gov (United States)

    Ferraresi, Cleber; Bertucci, Danilo; Schiavinato, Josiane; Reiff, Rodrigo; Araújo, Amélia; Panepucci, Rodrigo; Matheucci, Euclides; Cunha, Anderson Ferreira; Arakelian, Vivian Maria; Hamblin, Michael R; Parizotto, Nivaldo; Bagnato, Vanderlei

    2016-10-01

    The aim of this study was to verify how a pair of monozygotic twins would respond to light-emitting diode therapy (LEDT) or placebo combined with a strength-training program during 12 weeks. This case-control study enrolled a pair of male monozygotic twins, allocated randomly to LEDT or placebo therapies. Light-emitting diode therapy or placebo was applied from a flexible light-emitting diode array (λ = 850 nm, total energy = 75 J, t = 15 seconds) to both quadriceps femoris muscles of each twin immediately after each strength training session (3 times/wk for 12 weeks) consisting of leg press and leg extension exercises with load of 80% and 50% of the 1-repetition maximum test, respectively. Muscle biopsies, magnetic resonance imaging, maximal load, and fatigue resistance tests were conducted before and after the training program to assess gene expression, muscle hypertrophy and performance, respectively. Creatine kinase levels in blood and visual analog scale assessed muscle damage and delayed-onset muscle soreness, respectively, during the training program. Compared with placebo, LEDT increased the maximal load in exercise and reduced fatigue, creatine kinase, and visual analog scale. Gene expression analyses showed decreases in markers of inflammation (interleukin 1β) and muscle atrophy (myostatin) with LEDT. Protein synthesis (mammalian target of rapamycin) and oxidative stress defense (SOD2 [mitochondrial superoxide dismutase]) were up-regulated with LEDT, together with increases in thigh muscle hypertrophy. Light-emitting diode therapy can be useful to reduce muscle damage, pain, and atrophy, as well as to increase muscle mass, recovery, and athletic performance in rehabilitation programs and sports medicine.

  11. Synchronization in networks with heterogeneous coupling delays

    Science.gov (United States)

    Otto, Andreas; Radons, Günter; Bachrathy, Dániel; Orosz, Gábor

    2018-01-01

    Synchronization in networks of identical oscillators with heterogeneous coupling delays is studied. A decomposition of the network dynamics is obtained by block diagonalizing a newly introduced adjacency lag operator which contains the topology of the network as well as the corresponding coupling delays. This generalizes the master stability function approach, which was developed for homogenous delays. As a result the network dynamics can be analyzed by delay differential equations with distributed delay, where different delay distributions emerge for different network modes. Frequency domain methods are used for the stability analysis of synchronized equilibria and synchronized periodic orbits. As an example, the synchronization behavior in a system of delay-coupled Hodgkin-Huxley neurons is investigated. It is shown that the parameter regions where synchronized periodic spiking is unstable expand when increasing the delay heterogeneity.

  12. Mechanism of mesenchymal stem cell-induced neuron recovery and anti-inflammation.

    Science.gov (United States)

    Huang, Peng; Gebhart, Nichole; Richelson, Elliott; Brott, Thomas G; Meschia, James F; Zubair, Abba C

    2014-10-01

    After ischemic or hemorrhagic stroke, neurons in the penumbra surrounding regions of irreversible injury are vulnerable to delayed but progressive damage as a result of ischemia and hemin-induced neurotoxicity. There is no effective treatment to rescue such dying neurons. Mesenchymal stem cells (MSCs) hold promise for rescue of these damaged neurons. In this study, we evaluated the efficacy and mechanism of MSC-induced neuro-regeneration and immune modulation. Oxygen-glucose deprivation (OGD) was used in our study. M17 neuronal cells were subjected to OGD stress then followed by co-culture with MSCs. Rescue effects were evaluated using proliferation and apoptosis assays. Cytokine assay and quantitative polymerase chain reaction were used to explore the underlying mechanism. Antibody and small molecule blocking experiments were also performed to further understand the mechanism. We showed that M17 proliferation was significantly decreased and the rate of apoptosis increased after exposure to OGD. These effects could be alleviated via co-culture with MSCs. Tumor necrosis factor-α was found elevated after OGD stress and was back to normal levels after co-culture with MSCs. We believe these effects involve interleukin-6 and vascular endothelial growth factor signaling pathways. Our studies have shown that MSCs have anti-inflammatory properties and the capacity to rescue injured neurons. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  13. Analysis of the immunological biomarker profile during acute Zika virus infection reveals the overexpression of CXCL10, a chemokine linked to neuronal damage

    Directory of Open Access Journals (Sweden)

    Felipe Gomes Naveca

    2018-05-01

    Full Text Available BACKGROUND Infection with Zika virus (ZIKV manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications and little is known about Zika immunopathogenesis. OBJECTIVES To define the immunologic biomarkers that correlate with acute ZIKV infection. METHODS We characterized the levels of circulating cytokines, chemokines, and growth factors in 54 infected patients of both genders at five different time points after symptom onset using microbeads multiplex immunoassay; comparison to 100 age-matched controls was performed for statistical analysis and data mining. FINDINGS ZIKV-infected patients present a striking systemic inflammatory response with high levels of pro-inflammatory mediators. Despite the strong inflammatory pattern, IL-1Ra and IL-4 are also induced during the acute infection. Interestingly, the inflammatory cytokines IL-1β, IL-13, IL-17, TNF-α, and IFN-γ; chemokines CXCL8, CCL2, CCL5; and the growth factor G-CSF, displayed a bimodal distribution accompanying viremia. While this is the first manuscript to document bimodal distributions of viremia in ZIKV infection, this has been documented in other viral infections, with a primary viremia peak during mild systemic disease and a secondary peak associated with distribution of the virus to organs and tissues. MAIN CONCLUSIONS Biomarker network analysis demonstrated distinct dynamics in concurrence with the bimodal viremia profiles at different time points during ZIKV infection. Such a robust cytokine and chemokine response has been associated with blood-brain barrier permeability and neuroinvasiveness in other flaviviral infections. High-dimensional data analysis further identified CXCL10, a chemokine involved in foetal neuron apoptosis and Guillain-Barré syndrome, as the most promising biomarker of acute ZIKV infection for potential clinical application.

  14. Synchronization of Coupled Neurons Controlled by a Pacemaker

    International Nuclear Information System (INIS)

    Li Mei-Sheng; Zhang Hong-Hui; Zhao Yong; Shi Xia

    2011-01-01

    We investigate synchronization of Hindmarsh—Rose neurons with gap junctions under the control of a pacemaker. In a ring Hindmarsh—Rose neuronal network, the coupled neurons with the pacemaker can occur in synchronization more easily than those without the pacemaker. Furthermore, the pacemaker can induce phase synchronization or nearly-complete synchronization of nonidentical neurons. This synchronization can occur more easily when time delay is considered. Theses results can be helpful to understand the activities of the real neuronal system. (general)

  15. Tempol moderately extends survival in a hSOD1(G93A ALS rat model by inhibiting neuronal cell loss, oxidative damage and levels of non-native hSOD1(G93A forms.

    Directory of Open Access Journals (Sweden)

    Edlaine Linares

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease characterized by the progressive dysfunction and death of motor neurons by mechanisms that remain unclear. Evidence indicates that oxidative mechanisms contribute to ALS pathology, but classical antioxidants have not performed well in clinical trials. Cyclic nitroxides are an alternative worth exploring because they are multifunctional antioxidants that display low toxicity in vivo. Here, we examine the effects of the cyclic nitroxide tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl on ALS onset and progression in transgenic female rats over-expressing the mutant hSOD1(G93A . Starting at 7 weeks of age, a high dose of tempol (155 mg/day/rat in the rat´s drinking water had marginal effects on the disease onset but decelerated disease progression and extended survival by 9 days. In addition, tempol protected spinal cord tissues as monitored by the number of neuronal cells, and the reducing capability and levels of carbonylated proteins and non-native hSOD1 forms in spinal cord homogenates. Intraperitoneal tempol (26 mg/rat, 3 times/week extended survival by 17 days. This group of rats, however, diverted to a decelerated disease progression. Therefore, it was inconclusive whether the higher protective effect of the lower i.p. dose was due to higher tempol bioavailability, decelerated disease development or both. Collectively, the results show that tempol moderately extends the survival of ALS rats while protecting their cellular and molecular structures against damage. Thus, the results provide proof that cyclic nitroxides are alternatives worth to be further tested in animal models of ALS.

  16. KB-R7943 reduces 4-aminopyridine-induced epileptiform activity in adult rats after neuronal damage induced by neonatal monosodium glutamate treatment.

    Science.gov (United States)

    Hernandez-Ojeda, Mariana; Ureña-Guerrero, Monica E; Gutierrez-Barajas, Paola E; Cardenas-Castillo, Jazmin A; Camins, Antoni; Beas-Zarate, Carlos

    2017-05-09

    Neonatal monosodium glutamate (MSG) treatment triggers excitotoxicity and induces a degenerative process that affects several brain regions in a way that could lead to epileptogenesis. Na + /Ca 2+ exchangers (NCX1-3) are implicated in Ca 2+ brain homeostasis; normally, they extrude Ca 2+ to control cell inflammation, but after damage and in epilepsy, they introduce Ca 2+ by acting in the reverse mode, amplifying the damage. Changes in NCX3 expression in the hippocampus have been reported immediately after neonatal MSG treatment. In this study, the expression level of NCX1-3 in the entorhinal cortex (EC) and hippocampus (Hp); and the effects of blockade of NCXs on the seizures induced by 4-Aminopyridine (4-AP) were analysed in adult rats after neonatal MSG treatment. KB-R7943 was applied as NCXs blocker, but is more selective to NCX3 in reverse mode. Neonatal MSG treatment was applied to newborn male rats at postnatal days (PD) 1, 3, 5, and 7 (4 g/kg of body weight, s.c.). Western blot analysis was performed on total protein extracts from the EC and Hp to estimate the expression level of NCX1-3 proteins in relative way to the expression of β-actin, as constitutive protein. Electrographic activity of the EC and Hp were acquired before and after intracerebroventricular (i.c.v.) infusion of 4-AP (3 nmol) and KB-R7943 (62.5 pmol), alone or in combination. All experiments were performed at PD60. Behavioural alterations were also recorder. Neonatal MSG treatment significantly increased the expression of NCX3 protein in both studied regions, and NCX1 protein only in the EC. The 4-AP-induced epileptiform activity was significantly higher in MSG-treated rats than in controls, and KB-R7943 co-administered with 4-AP reduced the epileptiform activity in more prominent way in MSG-treated rats than in controls. The long-term effects of neonatal MSG treatment include increases on functional expression of NCXs (mainly of NCX3) in the EC and Hp, which seems to contribute to

  17. Rich-Club Organization in Effective Connectivity among Cortical Neurons.

    Science.gov (United States)

    Nigam, Sunny; Shimono, Masanori; Ito, Shinya; Yeh, Fang-Chin; Timme, Nicholas; Myroshnychenko, Maxym; Lapish, Christopher C; Tosi, Zachary; Hottowy, Pawel; Smith, Wesley C; Masmanidis, Sotiris C; Litke, Alan M; Sporns, Olaf; Beggs, John M

    2016-01-20

    The performance of complex networks, like the brain, depends on how effectively their elements communicate. Despite the importance of communication, it is virtually unknown how information is transferred in local cortical networks, consisting of hundreds of closely spaced neurons. To address this, it is important to record simultaneously from hundreds of neurons at a spacing that matches typical axonal connection distances, and at a temporal resolution that matches synaptic delays. We used a 512-electrode array (60 μm spacing) to record spontaneous activity at 20 kHz from up to 500 neurons simultaneously in slice cultures of mouse somatosensory cortex for 1 h at a time. We applied a previously validated version of transfer entropy to quantify information transfer. Similar to in vivo reports, we found an approximately lognormal distribution of firing rates. Pairwise information transfer strengths also were nearly lognormally distributed, similar to reports of synaptic strengths. Some neurons transferred and received much more information than others, which is consistent with previous predictions. Neurons with the highest outgoing and incoming information transfer were more strongly connected to each other than chance, thus forming a "rich club." We found similar results in networks recorded in vivo from rodent cortex, suggesting the generality of these findings. A rich-club structure has been found previously in large-scale human brain networks and is thought to facilitate communication between cortical regions. The discovery of a small, but information-rich, subset of neurons within cortical regions suggests that this population will play a vital role in communication, learning, and memory. Significance statement: Many studies have focused on communication networks between cortical brain regions. In contrast, very few studies have examined communication networks within a cortical region. This is the first study to combine such a large number of neurons (several

  18. Rich-Club Organization in Effective Connectivity among Cortical Neurons

    Science.gov (United States)

    Shimono, Masanori; Ito, Shinya; Yeh, Fang-Chin; Timme, Nicholas; Myroshnychenko, Maxym; Lapish, Christopher C.; Tosi, Zachary; Hottowy, Pawel; Smith, Wesley C.; Masmanidis, Sotiris C.; Litke, Alan M.; Sporns, Olaf; Beggs, John M.

    2016-01-01

    The performance of complex networks, like the brain, depends on how effectively their elements communicate. Despite the importance of communication, it is virtually unknown how information is transferred in local cortical networks, consisting of hundreds of closely spaced neurons. To address this, it is important to record simultaneously from hundreds of neurons at a spacing that matches typical axonal connection distances, and at a temporal resolution that matches synaptic delays. We used a 512-electrode array (60 μm spacing) to record spontaneous activity at 20 kHz from up to 500 neurons simultaneously in slice cultures of mouse somatosensory cortex for 1 h at a time. We applied a previously validated version of transfer entropy to quantify information transfer. Similar to in vivo reports, we found an approximately lognormal distribution of firing rates. Pairwise information transfer strengths also were nearly lognormally distributed, similar to reports of synaptic strengths. Some neurons transferred and received much more information than others, which is consistent with previous predictions. Neurons with the highest outgoing and incoming information transfer were more strongly connected to each other than chance, thus forming a “rich club.” We found similar results in networks recorded in vivo from rodent cortex, suggesting the generality of these findings. A rich-club structure has been found previously in large-scale human brain networks and is thought to facilitate communication between cortical regions. The discovery of a small, but information-rich, subset of neurons within cortical regions suggests that this population will play a vital role in communication, learning, and memory. SIGNIFICANCE STATEMENT Many studies have focused on communication networks between cortical brain regions. In contrast, very few studies have examined communication networks within a cortical region. This is the first study to combine such a large number of neurons (several

  19. Developmental delay

    Science.gov (United States)

    Nutrition support is essential for the care of the child with developmental delay. After a thorough evaluation, an individualized intervention plan that accounts for the child’s nutrition status, feeding ability, and medical condition may be determined. Nutrition assessments may be performed at leas...

  20. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles

    NARCIS (Netherlands)

    de Jong, Eiko K.; Vinet, Jonathan; Stanulovic, Vesna S.; Meijer, Michel; Wesseling, Evelyn; Sjollema, Klaas; Boddeke, Hendrikus W. G. M.; Biber, Knut

    2008-01-01

    Neurons are highly polarized cells, and neuron-neuron communication is based on directed transport and release of neurotransmitters, neuropeptides, and neurotrophins. Directed communication may also be attributed to neuron-microglia signaling, since neuronal damage can induce a microglia reaction at

  1. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles.

    NARCIS (Netherlands)

    Jong, E.K. de; Vinet, J.; Stanulovic, V.S.; Meijer, M.; Wesseling, E.; Sjollema, K.; Boddeke, H.W.; Biber, K.

    2008-01-01

    Neurons are highly polarized cells, and neuron-neuron communication is based on directed transport and release of neurotransmitters, neuropeptides, and neurotrophins. Directed communication may also be attributed to neuron-microglia signaling, since neuronal damage can induce a microglia reaction at

  2. Diagnostic Delay in Rheumatoid Arthritis

    DEFF Research Database (Denmark)

    Mølbaek, Karen; Hørslev-Petersen, Kim; Primdahl, Jette

    2016-01-01

    BACKGROUND: To prevent joint damage among patients with rheumatoid arthritis (RA), there is a need to minimize delays from the onset of symptoms until the initiation of appropriate therapy. The present study explored the factors that have an impact on the time it takes for Danish patients with RA...

  3. Design flaw could delay collider

    CERN Multimedia

    Cho, Adrian

    2007-01-01

    "A magnet for the Large Hadron Collider (LHC) failed during a key test at the European particle physics laboratory CERN last week. Physicists and engineers will have to repair the damaged magnet and retrofit others to correct the underlynig design flaw, which could delay the start-up of the mammouth subterranean machine." (1,5 page)

  4. Concurrent Delay in Construction Disputes

    DEFF Research Database (Denmark)

    Cavaleri, Sylvie Cécile

    the delay is contractually defined as a contractor's risk, the contractor is liable to pay liquidated damages to the employer; if it is not, the contractor can under certain circumstances claim an extension of time and in some cases also economic compensation from the employer. The situation where a given...

  5. Firing dynamics of an autaptic neuron

    International Nuclear Information System (INIS)

    Wang Heng-Tong; Chen Yong

    2015-01-01

    Autapses are synapses that connect a neuron to itself in the nervous system. Previously, both experimental and theoretical studies have demonstrated that autaptic connections in the nervous system have a significant physiological function. Autapses in nature provide self-delayed feedback, thus introducing an additional timescale to neuronal activities and causing many dynamic behaviors in neurons. Recently, theoretical studies have revealed that an autapse provides a control option for adjusting the response of a neuron: e.g., an autaptic connection can cause the electrical activities of the Hindmarsh–Rose neuron to switch between quiescent, periodic, and chaotic firing patterns; an autapse can enhance or suppress the mode-locking status of a neuron injected with sinusoidal current; and the firing frequency and interspike interval distributions of the response spike train can also be modified by the autapse. In this paper, we review recent studies that showed how an autapse affects the response of a single neuron. (topical review)

  6. Contribution of sleep to the repair of neuronal DNA double-strand breaks: evidence from flies and mice.

    Science.gov (United States)

    Bellesi, Michele; Bushey, Daniel; Chini, Mattia; Tononi, Giulio; Cirelli, Chiara

    2016-11-10

    Exploration of a novel environment leads to neuronal DNA double-strand breaks (DSBs). These DSBs are generated by type 2 topoisomerase to relieve topological constrains that limit transcription of plasticity-related immediate early genes. If not promptly repaired, however, DSBs may lead to cell death. Since the induction of plasticity-related genes is higher in wake than in sleep, we asked whether it is specifically wake associated with synaptic plasticity that leads to DSBs, and whether sleep provides any selective advantage over wake in their repair. In flies and mice, we find that enriched wake, more than simply time spent awake, induces DSBs, and their repair in mice is delayed or prevented by subsequent wake. In both species the repair of irradiation-induced neuronal DSBs is also quicker during sleep, and mouse genes mediating the response to DNA damage are upregulated in sleep. Thus, sleep facilitates the repair of neuronal DSBs.

  7. Delayed Puberty

    DEFF Research Database (Denmark)

    Kolby, Nanna; Busch, Alexander Siegfried; Juul, Anders

    2017-01-01

    . The underlying reasons for the large variation in the age at pubertal onset are not fully established; however, nutritional status and socioeconomic and environmental factors are known to be influencing, and a significant amount of influencing genetic factors have also been identified. The challenges...... optimal in discriminating especially CDGP from HH. Management of the delayed puberty depends on the etiology. For boys with CDGP an observational period will often reveal imminent puberty. If puberty is not progressing spontaneously, sex steroid replacement is effective in stimulating the development...

  8. Neuronal damage and memory deficits after seizures are reversed by ascorbic acid? O dano neuronal e o déficit de memória após convulsões são revertidos pelo ácido ascórbico?

    Directory of Open Access Journals (Sweden)

    Adriana da Rocha Tomé

    2010-08-01

    Full Text Available The objective of the present study was to evaluate the neuroprotective effects of ascorbic acid (AA in rats, against the neuronal damage and memory deficit caused by seizures. Wistar rats were treated with 0.9% saline (i.p., control group, ascorbic acid (500 mg/kg, i.p., AA group, pilocarpine (400 mg/kg, i.p., pilocarpine group, and the association of ascorbic acid (500 mg/kg, i.p. plus pilocarpine (400 mg/kg, i.p., 30 min before of administration of ascorbic acid (AA plus pilocarpine group. After the treatments all groups were observed for 24 h. Pilocarpine group presented seizures which progressed to status epilepticus in 75% of the animals. Pretreatment with AA led to a reduction of 50% of this rate. Results showed that pretreatment with AA did not alter reference memory when compared to a control group. In the working memory task, we observed a significant day's effect with important differences between control, pilocarpine and AA plus pilocarpine groups. Pilocarpine and AA plus pilocarpine groups had 81 and 16% of animals with brain injury, respectively. In the hippocampus of pilocarpine animals, it was detected an injury of 60%. As for the animals tested with AA plus pilocarpine, the hippocampal region of the group had a reduction of 43% in hippocampal lesion. Our findings suggest that seizures caused cognitive dysfunction and neuronal damage that might be related, at least in part, to the neurological problems presented by epileptic patients. AA can reverse cognitive dysfunction observed in rats with seizures as well as decrease neuronal injury in rat hippocampus.O objetivo do presente estudo foi avaliar o efeito neuroprotetor do ácido ascórbico (AA, contra o dano neuronal e o déficit de memória em ratos causados pelas convulsões. Ratos Wistar foram tratados com solução salina a 0,9% (i.p., grupo controle, ácido ascórbico (500 mg/kg, i.p., grupo AA, pilocarpina (400 mg/kg, i.p., grupo pilocarpina, e a associação de ácido asc

  9. Motor Neurons

    DEFF Research Database (Denmark)

    Hounsgaard, Jorn

    2017-01-01

    Motor neurons translate synaptic input from widely distributed premotor networks into patterns of action potentials that orchestrate motor unit force and motor behavior. Intercalated between the CNS and muscles, motor neurons add to and adjust the final motor command. The identity and functional...... in in vitro preparations is far from complete. Nevertheless, a foundation has been provided for pursuing functional significance of intrinsic response properties in motoneurons in vivo during motor behavior at levels from molecules to systems....

  10. Inhibition of Notch Signaling in Human Embryonic Stem Cell-Derived Neural Stem Cells Delays G1/S Phase Transition and Accelerates Neuronal Differentiation In Vitro and In Vivo

    Czech Academy of Sciences Publication Activity Database

    Borghese, L.; Doležalová, Dáša; Opitz, T.; Haupt, S.; Leinhaas, A.; Steinfarz, B.; Koch, P.; Edenhofer, F.; Hampl, Aleš; Brüstle, O.

    2010-01-01

    Roč. 28, č. 5 (2010), s. 955-964 ISSN 1066-5099 Grant - others:GA MŠk(CZ) 1M0538; EC FP6 project ESTOOLS(XE) LSHG-CT-2006-018739; EC FP7 project NeuroStemcell(XE) HEALTH-2007-B-22943 Program:1M Institutional research plan: CEZ:AV0Z50390703 Keywords : neural stem cells * notch * neuron Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.871, year: 2010

  11. Autapse-induced synchronization in a coupled neuronal network

    International Nuclear Information System (INIS)

    Ma, Jun; Song, Xinlin; Jin, Wuyin; Wang, Chuni

    2015-01-01

    Highlights: • The functional effect of autapse on neuronal activity is detected. • Autapse driving plays active role in regulating electrical activities as pacemaker. • It confirms biological experimental results for rhythm synchronization between heterogeneous cells. - Abstract: The effect of autapse on coupled neuronal network is detected. In our studies, three identical neurons are connected with ring type and autapse connected to one neuron of the network. The autapse connected to neuron can impose time-delayed feedback in close loop on the neuron thus the dynamics of membrane potentials can be changed. Firstly, the effect of autapse driving on single neuron is confirmed that negative feedback can calm down the neuronal activity while positive feedback can excite the neuronal activity. Secondly, the collective electrical behaviors of neurons are regulated by a pacemaker, which associated with the autapse forcing. By using appropriate gain and time delay in the autapse, the neurons can reach synchronization and the membrane potentials of all neurons can oscillate with the same rhythm under mutual coupling. It indicates that autapse forcing plays an important role in changing the collective electric activities of neuronal network, and appropriate electric modes can be selected due to the switch of feedback type(positive or negative) in autapse. And the autapse-induced synchronization in network is also consistent with some biological experiments about synchronization between nonidentical neurons.

  12. Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage.

    Science.gov (United States)

    Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Cavaliere, Fabio; Magnus, Tim; Koch-Nolte, Friederich; Scemes, Eliana; Pérez-Samartín, Alberto; Matute, Carlos

    2015-05-01

    The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to ~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise.

  13. [Mirror neurons].

    Science.gov (United States)

    Rubia Vila, Francisco José

    2011-01-01

    Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal. Some of them also respond to the emotional expression of other animals of the same species. These mirror neurons have also been found in humans. They respond to or "reflect" actions of other individuals in the brain and are thought to represent the basis for imitation and empathy and hence the neurobiological substrate for "theory of mind", the potential origin of language and the so-called moral instinct.

  14. Delayed switching applied to memristor neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Frank Z.; Yang Xiao; Lim Guan [Future Computing Group, School of Computing, University of Kent, Canterbury (United Kingdom); Helian Na [School of Computer Science, University of Hertfordshire, Hatfield (United Kingdom); Wu Sining [Xyratex, Havant (United Kingdom); Guo Yike [Department of Computing, Imperial College, London (United Kingdom); Rashid, Md Mamunur [CERN, Geneva (Switzerland)

    2012-04-01

    Magnetic flux and electric charge are linked in a memristor. We reported recently that a memristor has a peculiar effect in which the switching takes place with a time delay because a memristor possesses a certain inertia. This effect was named the ''delayed switching effect.'' In this work, we elaborate on the importance of delayed switching in a brain-like computer using memristor neural networks. The effect is used to control the switching of a memristor synapse between two neurons that fire together (the Hebbian rule). A theoretical formula is found, and the design is verified by a simulation. We have also built an experimental setup consisting of electronic memristive synapses and electronic neurons.

  15. Delayed switching applied to memristor neural networks

    International Nuclear Information System (INIS)

    Wang, Frank Z.; Yang Xiao; Lim Guan; Helian Na; Wu Sining; Guo Yike; Rashid, Md Mamunur

    2012-01-01

    Magnetic flux and electric charge are linked in a memristor. We reported recently that a memristor has a peculiar effect in which the switching takes place with a time delay because a memristor possesses a certain inertia. This effect was named the ''delayed switching effect.'' In this work, we elaborate on the importance of delayed switching in a brain-like computer using memristor neural networks. The effect is used to control the switching of a memristor synapse between two neurons that fire together (the Hebbian rule). A theoretical formula is found, and the design is verified by a simulation. We have also built an experimental setup consisting of electronic memristive synapses and electronic neurons.

  16. Mini Review: Biomaterials for Enhancing Neuronal Repair

    Science.gov (United States)

    Cangellaris, Olivia V.; Gillette, Martha U.

    2018-04-01

    As they differentiate from neuroblasts, nascent neurons become highly polarized and elongate. Neurons extend and elaborate fine and fragile cellular extensions that form circuits enabling long-distance communication and signal integration within the body. While other organ systems are developing, projections of differentiating neurons find paths to distant targets. Subsequent post-developmental neuronal damage is catastrophic because the cues for reinnervation are no longer active. Advances in biomaterials are enabling fabrication of micro-environments that encourage neuronal regrowth and restoration of function by recreating these developmental cues. This mini-review considers new materials that employ topographical, chemical, electrical, and/or mechanical cues for use in neuronal repair. Manipulating and integrating these elements in different combinations will generate new technologies to enhance neural repair.

  17. Layer 5 Callosal Parvalbumin-Expressing Neurons: A Distinct Functional Group of GABAergic Neurons.

    Science.gov (United States)

    Zurita, Hector; Feyen, Paul L C; Apicella, Alfonso Junior

    2018-01-01

    Previous studies have shown that parvalbumin-expressing neurons (CC-Parv neurons) connect the two hemispheres of motor and sensory areas via the corpus callosum, and are a functional part of the cortical circuit. Here we test the hypothesis that layer 5 CC-Parv neurons possess anatomical and molecular mechanisms which dampen excitability and modulate the gating of interhemispheric inhibition. In order to investigate this hypothesis we use viral tracing to determine the anatomical and electrophysiological properties of layer 5 CC-Parv and parvalbumin-expressing (Parv) neurons of the mouse auditory cortex (AC). Here we show that layer 5 CC-Parv neurons had larger dendritic fields characterized by longer dendrites that branched farther from the soma, whereas layer 5 Parv neurons had smaller dendritic fields characterized by shorter dendrites that branched nearer to the soma. The layer 5 CC-Parv neurons are characterized by delayed action potential (AP) responses to threshold currents, lower firing rates, and lower instantaneous frequencies compared to the layer 5 Parv neurons. Kv1.1 containing K + channels are the main source of the AP repolarization of the layer 5 CC-Parv and have a major role in determining both the spike delayed response, firing rate and instantaneous frequency of these neurons.

  18. Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats.

    Science.gov (United States)

    Mucio-Ramírez, Samuel; Makeyev, Oleksandr

    2017-01-01

    Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats ( n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals ( p  = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses ( p  = 0.71) nor due to the delay after the last stimulation dose ( p  = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200  μ s, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

  19. Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats

    Directory of Open Access Journals (Sweden)

    Samuel Mucio-Ramírez

    2017-01-01

    Full Text Available Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats (n=36 due to the single dose or five doses (given every 24 hours of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals (p = 0.71. Moreover, it showed no statistically significant differences due to the number of stimulation doses (p = 0.71 nor due to the delay after the last stimulation dose (p = 0.96. Obtained results suggest that stimulation at current parameters (50 mA, 200 μs, 300 Hz, biphasic, charge-balanced pulses for 2 minutes does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

  20. Delay-slope-dependent stability results of recurrent neural networks.

    Science.gov (United States)

    Li, Tao; Zheng, Wei Xing; Lin, Chong

    2011-12-01

    By using the fact that the neuron activation functions are sector bounded and nondecreasing, this brief presents a new method, named the delay-slope-dependent method, for stability analysis of a class of recurrent neural networks with time-varying delays. This method includes more information on the slope of neuron activation functions and fewer matrix variables in the constructed Lyapunov-Krasovskii functional. Then some improved delay-dependent stability criteria with less computational burden and conservatism are obtained. Numerical examples are given to illustrate the effectiveness and the benefits of the proposed method.

  1. Essential roles of mitochondrial depolarization in neuron loss through microglial activation and attraction toward neurons.

    Science.gov (United States)

    Nam, Min-Kyung; Shin, Hyun-Ah; Han, Ji-Hye; Park, Dae-Wook; Rhim, Hyangshuk

    2013-04-10

    As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron-microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Delayed puberty in girls

    Science.gov (United States)

    ... sexual development - girls; Pubertal delay - girls; Constitutional delayed puberty ... In most cases of delayed puberty, growth changes just begin later than usual, sometimes called a late bloomer. Once puberty begins, it progresses normally. This pattern runs ...

  3. Delayed Puberty (For Teens)

    Science.gov (United States)

    ... Safe Videos for Educators Search English Español Delayed Puberty KidsHealth / For Teens / Delayed Puberty What's in this ... wonder if there's anything wrong. What Is Delayed Puberty? Puberty is the time when your body grows ...

  4. Spiking neuron devices consisting of single-flux-quantum circuits

    International Nuclear Information System (INIS)

    Hirose, Tetsuya; Asai, Tetsuya; Amemiya, Yoshihito

    2006-01-01

    Single-flux-quantum (SFQ) circuits can be used for making spiking neuron devices, which are useful elements for constructing intelligent, brain-like computers. The device we propose is based on the leaky integrate-and-fire neuron (IFN) model and uses a SFQ pulse as an action signal or a spike of neurons. The operation of the neuron device is confirmed by computer simulator. It can operate with a short delay of 100 ps or less and is the highest-speed neuron device ever reported

  5. Neurons other than motor neurons in motor neuron disease.

    Science.gov (United States)

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  6. ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury.

    Science.gov (United States)

    Mazzone, Graciela L; Veeraraghavan, Priyadharishini; Gonzalez-Inchauspe, Carlota; Nistri, Andrea; Uchitel, Osvaldo D

    2017-02-20

    In the spinal cord high extracellular glutamate evokes excitotoxic damage with neuronal loss and severe locomotor impairment. During the cell dysfunction process, extracellular pH becomes acid and may activate acid-sensing ion channels (ASICs) which could be important contributors to neurodegenerative pathologies. Our previous studies have shown that transient application of the glutamate analog kainate (KA) evokes delayed excitotoxic death of spinal neurons, while white matter is mainly spared. The present goal was to enquire if ASIC channels modulated KA damage in relation to locomotor network function and cell death. Mouse spinal cord slices were treated with KA (0.01 or 0.1mM) for 1h, and then washed out for 24h prior to analysis. RT-PCR results showed that KA (at 0.01mM concentration that is near-threshold for damage) increased mRNA expression of ASIC1a, ASIC1b, ASIC2 and ASIC3, an effect reversed by the ASIC inhibitor 4',6-diamidino-2-phenylindole (DAPI). A KA neurotoxic dose (0.1mM) reduced ASIC1a and ASIC2 expression. Cell viability assays demonstrated KA-induced large damage in spinal slices from mice with ASIC1a gene ablation. Likewise, immunohistochemistry indicated significant neuronal loss when KA was followed by the ASIC inhibitors DAPI or amiloride. Electrophysiological recording from ventral roots of isolated spinal cords showed that alternating oscillatory cycles were slowed down by 0.01mMKA, and intensely inhibited by subsequently applied DAPI or amiloride. Our data suggest that early rise in ASIC expression and function counteracted deleterious effects on spinal networks by raising the excitotoxicity threshold, a result with potential implications for improving neuroprotection. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. White matter damage impairs access to consciousness in multiple sclerosis.

    Science.gov (United States)

    Reuter, Françoise; Del Cul, Antoine; Malikova, Irina; Naccache, Lionel; Confort-Gouny, Sylviane; Cohen, Laurent; Cherif, André Ali; Cozzone, Patrick J; Pelletier, Jean; Ranjeva, Jean-Philippe; Dehaene, Stanislas; Audoin, Bertrand

    2009-01-15

    Global neuronal workspace theory predicts that damage to long-distance white matter (WM) tracts should impair access to consciousness during the perception of brief stimuli. To address this issue, we studied visual backward masking in 18 patients at the very first clinical stage of multiple sclerosis (MS), a neurological disease characterized by extensive WM damage, and in 18 matched healthy subjects. In our masking paradigm, the visibility of a digit stimulus increases non-linearly as a function of the interval duration between this target and a subsequent mask. In order to characterize quantitatively, for each subject, the transition between non-conscious and conscious perception of the stimulus, we used non-linear regression to fit a sigmoid curve to objective performance and subjective visibility reports as a function of target-mask delay. The delay corresponding to the inflexion point of the sigmoid, where visibility suddenly increases, was termed the "non-linear transition threshold" and used as a summary measure of masking efficiency. Objective and subjective non-linear transition thresholds were highly correlated across subjects in both groups, and were higher in patients compared to controls. In patients, variations in the non-linear transition threshold were inversely correlated to the Magnetization transfer ratio (MTR) values inside the right dorsolateral prefrontal WM, the right occipito-frontal fasciculus and the left cerebellum. This study provides clinical evidence of a relationship between impairments of conscious access and integrity of large WM bundles, particularly involving prefrontal cortex, as predicted by global neuronal workspace theory.

  8. Optimal compensation for neuron loss

    Science.gov (United States)

    Barrett, David GT; Denève, Sophie; Machens, Christian K

    2016-01-01

    The brain has an impressive ability to withstand neural damage. Diseases that kill neurons can go unnoticed for years, and incomplete brain lesions or silencing of neurons often fail to produce any behavioral effect. How does the brain compensate for such damage, and what are the limits of this compensation? We propose that neural circuits instantly compensate for neuron loss, thereby preserving their function as much as possible. We show that this compensation can explain changes in tuning curves induced by neuron silencing across a variety of systems, including the primary visual cortex. We find that compensatory mechanisms can be implemented through the dynamics of networks with a tight balance of excitation and inhibition, without requiring synaptic plasticity. The limits of this compensatory mechanism are reached when excitation and inhibition become unbalanced, thereby demarcating a recovery boundary, where signal representation fails and where diseases may become symptomatic. DOI: http://dx.doi.org/10.7554/eLife.12454.001 PMID:27935480

  9. Review Paper: Polyphenolic Antioxidants and Neuronal Regeneration

    Directory of Open Access Journals (Sweden)

    Amin Ataie

    2016-05-01

    Full Text Available Many studies indicate that oxidative stress is involved in the pathophysiology of neurodegenerative diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling and ultimately leads to neuronal death by apoptosis or necrosis. To review antioxidants preventive effects on oxidative stress and neurodegenerative diseases we accumulated data from international medical journals and academic informations' sites. According to many studies, antioxidants could reduce toxic neuronal damages and many studies confirmed the efficacy of polyphenol antioxidants in fruits and vegetables to reduce neuronal death and to diminish oxidative stress. This systematic review showed the antioxidant activities of phytochemicals which play as natural neuroprotectives with low adverse effects against some neurodegenerative diseases as Parkinson or Alzheimer diseases.

  10. Review Paper: Polyphenolic Antioxidants and Neuronal Regeneration

    Directory of Open Access Journals (Sweden)

    Amin Ataie

    2016-04-01

    Full Text Available Many studies indicate that oxidative stress is involved in the pathophysiology of neurodegenerative diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling and ultimately leads to neuronal death by apoptosis or necrosis. To review antioxidants preventive effects on oxidative stress and neurodegenerative diseases we accumulated data from international medical journals and academic informations' sites. According to many studies, antioxidants could reduce toxic neuronal damages and many studies confirmed the efficacy of polyphenol antioxidants in fruits and vegetables to reduce neuronal death and to diminish oxidative stress. This systematic review showed the antioxidant activities of phytochemicals which play as natural neuroprotectives with low adverse effects against some neurodegenerative diseases as Parkinson or Alzheimer diseases.

  11. Speech and Language Delay

    Science.gov (United States)

    ... OTC Relief for Diarrhea Home Diseases and Conditions Speech and Language Delay Condition Speech and Language Delay Share Print Table of Contents1. ... Treatment6. Everyday Life7. Questions8. Resources What is a speech and language delay? A speech and language delay ...

  12. Detecting dependencies between spike trains of pairs of neurons through copulas

    DEFF Research Database (Denmark)

    Sacerdote, Laura; Tamborrino, Massimiliano; Zucca, Cristina

    2011-01-01

    The dynamics of a neuron are influenced by the connections with the network where it lies. Recorded spike trains exhibit patterns due to the interactions between neurons. However, the structure of the network is not known. A challenging task is to investigate it from the analysis of simultaneously...... the two neurons. Furthermore, the method recognizes the presence of delays in the spike propagation....

  13. Dynamics in a delayed-neural network

    International Nuclear Information System (INIS)

    Yuan Yuan

    2007-01-01

    In this paper, we consider a neural network of four identical neurons with time-delayed connections. Some parameter regions are given for global, local stability and synchronization using the theory of functional differential equations. The root distributions in the corresponding characteristic transcendental equation are analyzed, Pitchfork bifurcation, Hopf and equivariant Hopf bifurcations are investigated by revealing the center manifolds and normal forms. Numerical simulations are shown the agreements with the theoretical results

  14. Determination of the rate constant for neuronal and extra-neuronal monoamine oxidase

    International Nuclear Information System (INIS)

    Cassis, L.; Ludwig, J.; Trendelenburg, U.

    1986-01-01

    In the rat vas deferens, neuronal deamination of 3 H-(-) noradrenaline ( 3 H-NA) to 3 H-dihydroxyphenethylglycol ( 3 HDOPEG) cannot be inhibited by pretreatment with a monoamine oxidase (MAO) inhibitor. However, in the extraneuronal compartment of the rat heart, inhibition of MAO abolishes the formation of 3 HDOPEG. To clarify this discrepancy, the authors determined the rate constant for MAO (/sup k/mao/) neuronally (rat vas deferens) and extraneuronally (rat heart). For neuronal /sup k/mao, vasa deferentia were incubated with 3 HNA for 300 minutes, and the cumulative formation of 3 HDOPEG measured. The delay in time before 3 HDOPEG achieves steady state (/sup tau/system), is inversely proportional to /sup k/mao. Because /sup tau/system is very short for neuronal MAO, an appreciable delay was only achieved after partial inhibition of MAO with various parglyline concentrations. To relate to the uninhibited enzyme, the percentage inhibition by pargyline was then determined in homogenate preparations. For extraneuronal MAO, a similar procedure was performed in perfused rat hearts. Results show a significantly greater /sup k/mao of neuronal origin, (/sup k/mao = .57min - 1) which when related to the fractional size of the neuronal compartment suggests a very high activity of neuronal MAO

  15. Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2

    Directory of Open Access Journals (Sweden)

    Little Morgan R

    2010-06-01

    Full Text Available Abstract Background Using a murine model of herpes simplex virus (HSV-1 encephalitis, our laboratory has determined that induction of proinflammatory mediators in response to viral infection is largely mediated through a Toll-like receptor-2 (TLR2-dependent mechanism. Published studies have shown that, like other inflammatory mediators, reactive oxygen species (ROS are generated during viral brain infection. It is increasingly clear that ROS are responsible for facilitating secondary tissue damage during central nervous system infection and may contribute to neurotoxicity associated with herpes encephalitis. Methods Purified microglial cell and mixed neural cell cultures were prepared from C57B/6 and TLR2-/- mice. Intracellular ROS production in cultured murine microglia was measured via 2', 7'-Dichlorofluorescin diacetate (DCFH-DA oxidation. An assay for 8-isoprostane, a marker of lipid peroxidation, was utilized to measure free radical-associated cellular damage. Mixed neural cultures obtained from β-actin promoter-luciferase transgenic mice were used to detect neurotoxicity induced by HSV-infected microglia. Results Stimulation with HSV-1 elevated intracellular ROS in wild-type microglial cell cultures, while TLR2-/- microglia displayed delayed and attenuated ROS production following viral infection. HSV-infected TLR2-/- microglia produced less neuronal oxidative damage to mixed neural cell cultures in comparison to HSV-infected wild-type microglia. Further, HSV-infected TLR2-/- microglia were found to be less cytotoxic to cultured neurons compared to HSV-infected wild-type microglia. These effects were associated with decreased activation of p38 MAPK and p42/p44 ERK in TLR2-/- mice. Conclusions These studies demonstrate the importance of microglial cell TLR2 in inducing oxidative stress and neuronal damage in response to viral infection.

  16. Secondary damage in the spinal cord after motor cortex injury in rats.

    Science.gov (United States)

    Weishaupt, Nina; Silasi, Gergely; Colbourne, Frederick; Fouad, Karim

    2010-08-01

    When neurons within the motor cortex are fatally injured, their axons, many of which project into the spinal cord, undergo wallerian degeneration. Pathological processes occurring downstream of the cortical damage have not been extensively studied. We created a focal forelimb motor cortex injury in rats and found that axons from cell bodies located in the hindlimb motor cortex (spared by the cortical injury) become secondarily damaged in the spinal cord. To assess axonal degeneration in the spinal cord, we quantified silver staining in the corticospinal tract (CST) at 1 week and 4 weeks after the injury. We found a significant increase in silver deposition at the thoracic spinal cord level at 4 weeks compared to 1 week post-injury. At both time points, no degenerating neurons could be found in the hindlimb motor cortex. In a separate experiment, we showed that direct injury of neurons within the hindlimb motor cortex caused marked silver deposition in the thoracic CST at 1 week post-injury, and declined thereafter. Therefore, delayed axonal degeneration in the thoracic spinal cord after a focal forelimb motor cortex injury is indicative of secondary damage at the spinal cord level. Furthermore, immunolabeling of spinal cord sections showed that a local inflammatory response dominated by partially activated Iba-1-positive microglia is mounted in the CST, a viable mechanism to cause the observed secondary degeneration of fibers. In conclusion, we demonstrate that following motor cortex injury, wallerian degeneration of axons in the spinal cord leads to secondary damage, which is likely mediated by inflammatory processes.

  17. Astrocytic gap junctional networks suppress cellular damage in an in vitro model of ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Shinotsuka, Takanori; Yasui, Masato; Nuriya, Mutsuo, E-mail: mnuriya@z2.keio.jp

    2014-02-07

    Highlights: • Astrocytes exhibit characteristic changes in [Ca{sup 2+}]{sub i} under OGD. • Astrocytic [Ca{sup 2+}]{sub i} increase is synchronized with a neuronal anoxic depolarization. • Gap junctional couplings protect neurons as well as astrocytes during OGD. - Abstract: Astrocytes play pivotal roles in both the physiology and the pathophysiology of the brain. They communicate with each other via extracellular messengers as well as through gap junctions, which may exacerbate or protect against pathological processes in the brain. However, their roles during the acute phase of ischemia and the underlying cellular mechanisms remain largely unknown. To address this issue, we imaged changes in the intracellular calcium concentration ([Ca{sup 2+}]{sub i}) in astrocytes in mouse cortical slices under oxygen/glucose deprivation (OGD) condition using two-photon microscopy. Under OGD, astrocytes showed [Ca{sup 2+}]{sub i} oscillations followed by larger and sustained [Ca{sup 2+}]{sub i} increases. While the pharmacological blockades of astrocytic receptors for glutamate and ATP had no effect, the inhibitions of gap junctional intercellular coupling between astrocytes significantly advanced the onset of the sustained [Ca{sup 2+}]{sub i} increase after OGD exposure. Interestingly, the simultaneous recording of the neuronal membrane potential revealed that the onset of the sustained [Ca{sup 2+}]{sub i} increase in astrocytes was synchronized with the appearance of neuronal anoxic depolarization. Furthermore, the blockade of gap junctional coupling resulted in a concurrent faster appearance of neuronal depolarizations, which remain synchronized with the sustained [Ca{sup 2+}]{sub i} increase in astrocytes. These results indicate that astrocytes delay the appearance of the pathological responses of astrocytes and neurons through their gap junction-mediated intercellular network under OGD. Thus, astrocytic gap junctional networks provide protection against tissue damage

  18. Astrocytic gap junctional networks suppress cellular damage in an in vitro model of ischemia

    International Nuclear Information System (INIS)

    Shinotsuka, Takanori; Yasui, Masato; Nuriya, Mutsuo

    2014-01-01

    Highlights: • Astrocytes exhibit characteristic changes in [Ca 2+ ] i under OGD. • Astrocytic [Ca 2+ ] i increase is synchronized with a neuronal anoxic depolarization. • Gap junctional couplings protect neurons as well as astrocytes during OGD. - Abstract: Astrocytes play pivotal roles in both the physiology and the pathophysiology of the brain. They communicate with each other via extracellular messengers as well as through gap junctions, which may exacerbate or protect against pathological processes in the brain. However, their roles during the acute phase of ischemia and the underlying cellular mechanisms remain largely unknown. To address this issue, we imaged changes in the intracellular calcium concentration ([Ca 2+ ] i ) in astrocytes in mouse cortical slices under oxygen/glucose deprivation (OGD) condition using two-photon microscopy. Under OGD, astrocytes showed [Ca 2+ ] i oscillations followed by larger and sustained [Ca 2+ ] i increases. While the pharmacological blockades of astrocytic receptors for glutamate and ATP had no effect, the inhibitions of gap junctional intercellular coupling between astrocytes significantly advanced the onset of the sustained [Ca 2+ ] i increase after OGD exposure. Interestingly, the simultaneous recording of the neuronal membrane potential revealed that the onset of the sustained [Ca 2+ ] i increase in astrocytes was synchronized with the appearance of neuronal anoxic depolarization. Furthermore, the blockade of gap junctional coupling resulted in a concurrent faster appearance of neuronal depolarizations, which remain synchronized with the sustained [Ca 2+ ] i increase in astrocytes. These results indicate that astrocytes delay the appearance of the pathological responses of astrocytes and neurons through their gap junction-mediated intercellular network under OGD. Thus, astrocytic gap junctional networks provide protection against tissue damage during the acute phase of ischemia

  19. UAVs and Control Delays

    National Research Council Canada - National Science Library

    de Vries, S. C

    2005-01-01

    .... Delays of about 250-300 ms often lead to unacceptable airplane handling qualities. Techniques such as filtering and predictive displays may extend the range of acceptable delays up to about 400 ms...

  20. Delayed puberty in boys

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/007695.htm Delayed puberty in boys To use the sharing features on this page, please enable JavaScript. Delayed puberty in boys is when puberty does not begin ...

  1. Role of Inflammation in MPTP-Induced Dopaminergic Neuronal Death

    Science.gov (United States)

    2008-12-01

    of MPTP to MPP+ and MPP+ entry into dopaminergic neurons are key to the neurotoxic effects of MPTP and interference in any of these processes...presented at the Society for Neuroscience Meetings in 2006 Figure 1. Tempol Structure 29 Figure 2. Tempol protects dopaminergic neurons...in PD. Dopaminergic neurons in the SNpc were protected to a significant degree against the damaging effects of MPTP by M40401 whereas its isoforms

  2. Spiking Neurons for Analysis of Patterns

    Science.gov (United States)

    Huntsberger, Terrance

    2008-01-01

    Artificial neural networks comprising spiking neurons of a novel type have been conceived as improved pattern-analysis and pattern-recognition computational systems. These neurons are represented by a mathematical model denoted the state-variable model (SVM), which among other things, exploits a computational parallelism inherent in spiking-neuron geometry. Networks of SVM neurons offer advantages of speed and computational efficiency, relative to traditional artificial neural networks. The SVM also overcomes some of the limitations of prior spiking-neuron models. There are numerous potential pattern-recognition, tracking, and data-reduction (data preprocessing) applications for these SVM neural networks on Earth and in exploration of remote planets. Spiking neurons imitate biological neurons more closely than do the neurons of traditional artificial neural networks. A spiking neuron includes a central cell body (soma) surrounded by a tree-like interconnection network (dendrites). Spiking neurons are so named because they generate trains of output pulses (spikes) in response to inputs received from sensors or from other neurons. They gain their speed advantage over traditional neural networks by using the timing of individual spikes for computation, whereas traditional artificial neurons use averages of activity levels over time. Moreover, spiking neurons use the delays inherent in dendritic processing in order to efficiently encode the information content of incoming signals. Because traditional artificial neurons fail to capture this encoding, they have less processing capability, and so it is necessary to use more gates when implementing traditional artificial neurons in electronic circuitry. Such higher-order functions as dynamic tasking are effected by use of pools (collections) of spiking neurons interconnected by spike-transmitting fibers. The SVM includes adaptive thresholds and submodels of transport of ions (in imitation of such transport in biological

  3. Delayed Orgasm and Anorgasmia

    OpenAIRE

    Jenkins, Lawrence C.; Mulhall, John P.

    2015-01-01

    Delayed orgasm/anorgasmia defined as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Delayed orgasm and anorgasmia are associated with significant sexual dissatisfaction. A focused medical history can shed light on the potential etiologies; which include: medications, penile sensation loss, endocrinopathies, penile hyperstimulation and psychological etiologies, amongst others. Unfortunately, ...

  4. Regenerative memory in time-delayed neuromorphic photonic resonators

    Science.gov (United States)

    Romeira, B.; Avó, R.; Figueiredo, José M. L.; Barland, S.; Javaloyes, J.

    2016-01-01

    We investigate a photonic regenerative memory based upon a neuromorphic oscillator with a delayed self-feedback (autaptic) connection. We disclose the existence of a unique temporal response characteristic of localized structures enabling an ideal support for bits in an optical buffer memory for storage and reshaping of data information. We link our experimental implementation, based upon a nanoscale nonlinear resonant tunneling diode driving a laser, to the paradigm of neuronal activity, the FitzHugh-Nagumo model with delayed feedback. This proof-of-concept photonic regenerative memory might constitute a building block for a new class of neuron-inspired photonic memories that can handle high bit-rate optical signals.

  5. Neuronal growth on L- and D-cysteine self-assembled monolayers reveals neuronal chiral sensitivity.

    Science.gov (United States)

    Baranes, Koby; Moshe, Hagay; Alon, Noa; Schwartz, Shmulik; Shefi, Orit

    2014-05-21

    Studying the interaction between neuronal cells and chiral molecules is fundamental for the design of novel biomaterials and drugs. Chirality influences all biological processes that involve intermolecular interaction. One common method used to study cellular interactions with different enantiomeric targets is the use of chiral surfaces. Based on previous studies that demonstrated the importance of cysteine in the nervous system, we studied the effect of L- and D-cysteine on single neuronal growth. L-Cysteine, which normally functions as a neuromodulator or a neuroprotective antioxidant, causes damage at elevated levels, which may occur post trauma. In this study, we grew adult neurons in culture enriched with L- and D-cysteine as free compounds or as self-assembled monolayers of chiral surfaces and examined the effect on the neuronal morphology and adhesion. Notably, we have found that exposure to the L-cysteine enantiomer inhibited, and even prevented, neuronal attachment more severely than exposure to the D-cysteine enantiomer. Atop the L-cysteine surfaces, neuronal growth was reduced and degenerated. Since the cysteine molecules were attached to the surface via the thiol groups, the neuronal membrane was exposed to the molecular chiral site. Thus, our results have demonstrated high neuronal chiral sensitivity, revealing chiral surfaces as indirect regulators of neuronal cells and providing a reference for studying chiral drugs.

  6. Frontal eye field sends delay activity related to movement, memory, and vision to the superior colliculus.

    Science.gov (United States)

    Sommer, M A; Wurtz, R H

    2001-04-01

    Many neurons within prefrontal cortex exhibit a tonic discharge between visual stimulation and motor response. This delay activity may contribute to movement, memory, and vision. We studied delay activity sent from the frontal eye field (FEF) in prefrontal cortex to the superior colliculus (SC). We evaluated whether this efferent delay activity was related to movement, memory, or vision, to establish its possible functions. Using antidromic stimulation, we identified 66 FEF neurons projecting to the SC and we recorded from them while monkeys performed a Go/Nogo task. Early in every trial, a monkey was instructed as to whether it would have to make a saccade (Go) or not (Nogo) to a target location, which permitted identification of delay activity related to movement. In half of the trials (memory trials), the target disappeared, which permitted identification of delay activity related to memory. In the remaining trials (visual trials), the target remained visible, which permitted identification of delay activity related to vision. We found that 77% (51/66) of the FEF output neurons had delay activity. In 53% (27/51) of these neurons, delay activity was modulated by Go/Nogo instructions. The modulation preceded saccades made into only part of the visual field, indicating that the modulation was movement-related. In some neurons, delay activity was modulated by Go/Nogo instructions in both memory and visual trials and seemed to represent where to move in general. In other neurons, delay activity was modulated by Go/Nogo instructions only in memory trials, which suggested that it was a correlate of working memory, or only in visual trials, which suggested that it was a correlate of visual attention. In 47% (24/51) of FEF output neurons, delay activity was unaffected by Go/Nogo instructions, which indicated that the activity was related to the visual stimulus. In some of these neurons, delay activity occurred in both memory and visual trials and seemed to represent a

  7. Delayed minocycline but not delayed mild hypothermia protects against embolic stroke

    Directory of Open Access Journals (Sweden)

    Noor Raza

    2002-04-01

    Full Text Available Abstract Background Inflammatory reactions occurring in the brain after ischemia may contribute to secondary damage. In the present study, effects of minocycline, an anti-inflammatory agent, alone or in combination with mild hypothermia on focal embolic cerebral ischemia have been examined. Methods Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery (MCA. Infarction volume was measured at 48 h after the injury. Mortality was also recorded. Results Delayed administration of minocycline alone or delayed minocycline plus delayed mild hypothermia reduced the infarction volume significantly. However, delayed mild hypothermia alone was not protective and delayed mild hypothermia in combination with minocycline did not show any additive effect. Conclusions These results suggest that minocycline is beneficial in focal ischemic brain injury, and the lack of the enhanced neuroprotection may be due to the brief exposure to hypothermia.

  8. Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function.

    Science.gov (United States)

    Zuure, Wieteke A; Roberts, Amy L; Quennell, Janette H; Anderson, Greg M

    2013-11-06

    The adipocyte-derived hormone leptin acts in the brain to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect, as GnRH neurons do not express leptin receptors (LEPRs). Here we test whether GABAergic or glutamatergic neurons provide the intermediate pathway between the site of leptin action and the GnRH neurons. Leptin receptors were deleted from GABA and glutamate neurons using Cre-Lox transgenics, and the downstream effects on puberty onset and reproduction were examined. Both mouse lines displayed the expected increase in body weight and region-specific loss of leptin signaling in the hypothalamus. The GABA neuron-specific LEPR knock-out females and males showed significantly delayed puberty onset. Adult fertility observations revealed that these knock-out animals have decreased fecundity. In contrast, glutamate neuron-specific LEPR knock-out mice displayed normal fertility. Assessment of the estrogenic hypothalamic-pituitary-gonadal axis regulation in females showed that leptin action on GABA neurons is not necessary for estradiol-mediated suppression of tonic luteinizing hormone secretion (an indirect measure of GnRH neuron activity) but is required for regulation of a full preovulatory-like luteinizing hormone surge. In conclusion, leptin signaling in GABAergic (but not glutamatergic neurons) plays a critical role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These results form an important step in explaining the role of central leptin signaling in the reproductive system. Limiting the leptin-to-GnRH mediators to GABAergic cells will enable future research to focus on a few specific types of neurons.

  9. Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration.

    Science.gov (United States)

    Kaplan, Artem; Spiller, Krista J; Towne, Christopher; Kanning, Kevin C; Choe, Ginn T; Geber, Adam; Akay, Turgay; Aebischer, Patrick; Henderson, Christopher E

    2014-01-22

    Selective neuronal loss is the hallmark of neurodegenerative diseases. In patients with amyotrophic lateral sclerosis (ALS), most motor neurons die but those innervating extraocular, pelvic sphincter, and slow limb muscles exhibit selective resistance. We identified 18 genes that show >10-fold differential expression between resistant and vulnerable motor neurons. One of these, matrix metalloproteinase-9 (MMP-9), is expressed only by fast motor neurons, which are selectively vulnerable. In ALS model mice expressing mutant superoxide dismutase (SOD1), reduction of MMP-9 function using gene ablation, viral gene therapy, or pharmacological inhibition significantly delayed muscle denervation. In the presence of mutant SOD1, MMP-9 expressed by fast motor neurons themselves enhances activation of ER stress and is sufficient to trigger axonal die-back. These findings define MMP-9 as a candidate therapeutic target for ALS. The molecular basis of neuronal diversity thus provides significant insights into mechanisms of selective vulnerability to neurodegeneration. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Development of rat telencephalic neurons after prenatal x-irradiation

    International Nuclear Information System (INIS)

    Norton, S.

    1979-01-01

    Telencephalic neurons of rats, irradiated at day 15 of gestation with 125 R, develop synaptic connections on dendrites during maturation which appear to be normal spines in Golgi-stained light microscope preparations. At six weeks of postnatal age both control and irradiated rats have spiny dendritic processes on cortical pyramidal cells and caudate Golgi type II neurons. However, when the rats are 6 months old the irradiated rats have more neurons with beaded dendritic processes that lack spines or neurons and are likely to be degenerating neurons. The apparently normal development of the neurons followed by degeneration in the irradiated rat has a parallel in previous reports of the delayed hyperactivity which develops in rats irradiated on the fifteenth gestational day

  11. Delayed behavioral dysfunctions following exposure to ionising radiation: role of neurogenesis

    International Nuclear Information System (INIS)

    Haridas, Seenu; Kumar, Mayank; Manda, Kailash

    2014-01-01

    Being a terminally differentiated organ, the brain has been considered to be a radioresistant one. Traditionally, delayed radiation-induced CNS damage was hypothesized as chiefly attributable to impaired vascular endothelial system and neuroinflammatory glial cell populations. In the recent decades, preclinical studies have focused on the hippocampal dentate gyrus, one of two discrete sites of the brain where adult neurogenesis takes place. Neurogenesis, in such area of the brain takes place throughout the adulthood and makes the brain highly vulnerable to the radiation. Recent investigations, including our own reports indicated that radiation ablates hippocampal neurogenesis, alters neuronal function, and induces neuroinflammation. Since the hippocampus is involved in learning and memory, behavioral adaptation and HPA axis regulation, damage by radiation leads to severe behavioral and cognitive dysfunctions. The present study aimed at evaluating the delayed effects of gamma-irradiation on the cognitive and affective functions, which were further corroborated to changes in neurogenesis. C57BL/6J mice were exposed to whole body irradiation as well as cranial irradiation by gamma-rays at different sub-lethal doses. The behavioral tests, consisting spontaneous motor activity, open field test, novel object recognition test, forced swim test and Morris water maze were performed at 1 month and 5 months post-exposure. Neurogenic potential was evaluated using flow-cytometry (FC) and immuno-histo-chemistry (IHC). The results indicated the significant changes in the affective and cognitive functions at delayed time points of radiation exposure. Profound alteration in the anxiety and depressive phenotype was observed following irradiation. Additionally, both long term and short term memory functions were disrupted, which were attributable to changes in the neurogenic potential as reported in the terms of BrdU positive cells using FC and IHC. Present investigation clearly

  12. Delayed orgasm and anorgasmia.

    Science.gov (United States)

    Jenkins, Lawrence C; Mulhall, John P

    2015-11-01

    Delayed orgasm/anorgasmia defined as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Delayed orgasm and anorgasmia are associated with significant sexual dissatisfaction. A focused medical history can shed light on the potential etiologies, which include medications, penile sensation loss, endocrinopathies, penile hyperstimulation, and psychological etiologies. Unfortunately, there are no excellent pharmacotherapies for delayed orgasm/anorgasmia, and treatment revolves largely around addressing potential causative factors and psychotherapy. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  13. Delayed dermal burns caused by dimethyl acetylenedicarboxylate

    Energy Technology Data Exchange (ETDEWEB)

    Slovak, A J; Payne, A R

    1984-07-01

    A chemical operator handling dimethyl acetylenedicarboxylate (DMAD) developed delayed and pain-free burns on one of his feet 2 days after a supposed spillage of DMAD. The injuries were confirmed to be associated with DMAD by chemical analysis of the operator's safety boot and patch tests. DMAD easily penetrates some protective clothing and dilute solutions can still be hazardous: the toxic effect is compounded by being delayed and painless. The lachrymatory irritant properties of undiluted DMAD are not adequate warning of its presence or spillage in quantities sufficient to cause significant skin damage.

  14. Study of ATM Phosphorylation by Cdk5 in Neuronal Cells.

    Science.gov (United States)

    She, Hua; Mao, Zixu

    2017-01-01

    The phosphatidylinositol-3-kinase-like kinase ATM (ataxia-telangiectasia mutated) plays a central role in coordinating the DNA damage responses including cell cycle checkpoint control, DNA repair, and apoptosis. Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition. We previously showed that Cdk5 (cyclin-dependent kinase 5) is activated by DNA damage and directly phosphorylates ATM at serine 794 in postmitotic neurons. Phosphorylation at serine 794 precedes and is required for ATM autophosphorylation at serine 1981, and activates ATM kinase activity. Cdk5-ATM pathway plays a crucial role in DNA damage-induced neuronal injury. This chapter describes protocols used in analyzing ATM phosphorylation by Cdk5 in CGNs (cerebellar granule neurons) and its effects on neuronal survival.

  15. Radiation damage

    CERN Document Server

    Heijne, Erik H M; CERN. Geneva

    1998-01-01

    a) Radiation damage in organic materials. This series of lectures will give an overview of radiation effects on materials and components frequently used in accelerator engineering and experiments. Basic degradation phenomena will be presented for organic materials with comprehensive damage threshold doses for commonly used rubbers, thermoplastics, thermosets and composite materials. Some indications will be given for glass, scintillators and optical fibres. b) Radiation effects in semiconductor materials and devices. The major part of the time will be devoted to treat radiation effects in semiconductor sensors and the associated electronics, in particular displacement damage, interface and single event phenomena. Evaluation methods and practical aspects will be shown. Strategies will be developed for the survival of the materials under the expected environmental conditions of the LHC machine and detectors. I will describe profound revolution in our understanding of black holes and their relation to quantum me...

  16. DNA damage in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Coppedè, Fabio, E-mail: fabio.coppede@med.unipi.it; Migliore, Lucia, E-mail: lucia.migliore@med.unipi.it

    2015-06-15

    Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

  17. DNA damage in neurodegenerative diseases

    International Nuclear Information System (INIS)

    Coppedè, Fabio; Migliore, Lucia

    2015-01-01

    Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

  18. Neuronal Migration Disorders

    Science.gov (United States)

    ... Understanding Sleep The Life and Death of a Neuron Genes At Work In The Brain Order Publications ... birth defects caused by the abnormal migration of neurons in the developing brain and nervous system. In ...

  19. Motor Neuron Diseases

    Science.gov (United States)

    ... and other neurodegenerative diseases to better understand the function of neurons and other support cells and identify candidate therapeutic ... and other neurodegenerative diseases to better understand the function of neurons and other support cells and identify candidate therapeutic ...

  20. Editorial Commentary: "Defer No Time, Delays Have Dangerous Ends" (Henry VI, Shakespeare): Delayed Anterior Cruciate Ligament Reconstruction Has Consequences.

    Science.gov (United States)

    Siegel, Mark G

    2018-06-01

    There continues to be controversy over the timing of anterior cruciate ligament (ACL) surgery. Early or delayed intervention after ACL injury is a topic that has not been settled. The issue is whether ACL tears should have surgery performed in an expedient manner. Or is delay an option with no repercussions to the health of the knee? My associates in nonsurgical specialties wave the New England Journal of Medicine to support their view that surgery is not needed. I routinely espouse the literature confirming that delay of surgery may cause future damage. It is now established that a failure to intervene in a timely manner does cause additional damage. I stand vindicated and can affirm to my colleagues that I have found the answer. There is no longer any doubt or equivocation. Delay in reconstructing an unstable knee does cause damage. Copyright © 2018 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

  1. Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant hSOD1 mouse models.

    Directory of Open Access Journals (Sweden)

    Marcelo R Vargas

    Full Text Available The nuclear factor erythroid 2-related factor 2 (Nrf2 governs the expression of antioxidant and phase II detoxifying enzymes. Nrf2 activation can prevent or reduce cellular damage associated with several types of injury in many different tissues and organs. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1 cause familial forms of amyotrophic lateral sclerosis (ALS, a fatal disorder characterized by the progressive loss of motor neurons and subsequent muscular atrophy. We have previously shown that Nrf2 activation in astrocytes delays neurodegeneration in ALS mouse models. To further investigate the role of Nrf2 in ALS we determined the effect of absence of Nrf2 or its restricted overexpression in neurons or type II skeletal muscle fibers on symptoms onset and survival in mutant hSOD1 expressing mice. We did not observe any detrimental effect associated with the lack of Nrf2 in two different mutant hSOD1 animal models of ALS. However, restricted Nrf2 overexpression in neurons or type II skeletal muscle fibers delayed disease onset but failed to extend survival in hSOD1(G93A mice. These results highlight the concept that not only the pharmacological target but also the cell type targeted may be relevant when considering a Nrf2-mediated therapeutic approach for ALS.

  2. American Dream Delayed

    DEFF Research Database (Denmark)

    Khorunzhina, Natalia; Miller, Robert A.

    This paper investigates the delay in homeownership and a subsequent reduction in homeownership rate observed over the past decades. We focus on the delay in giving birth to children and increased labor market participation as contributing factors to homeownership dynamics for prime-age female hou...

  3. Mutations in KPTN Cause Macrocephaly, Neurodevelopmental Delay, and Seizures

    Science.gov (United States)

    Baple, Emma L.; Maroofian, Reza; Chioza, Barry A.; Izadi, Maryam; Cross, Harold E.; Al-Turki, Saeed; Barwick, Katy; Skrzypiec, Anna; Pawlak, Robert; Wagner, Karin; Coblentz, Roselyn; Zainy, Tala; Patton, Michael A.; Mansour, Sahar; Rich, Phillip; Qualmann, Britta; Hurles, Matt E.; Kessels, Michael M.; Crosby, Andrew H.

    2014-01-01

    The proper development of neuronal circuits during neuromorphogenesis and neuronal-network formation is critically dependent on a coordinated and intricate series of molecular and cellular cues and responses. Although the cortical actin cytoskeleton is known to play a key role in neuromorphogenesis, relatively little is known about the specific molecules important for this process. Using linkage analysis and whole-exome sequencing on samples from families from the Amish community of Ohio, we have demonstrated that mutations in KPTN, encoding kaptin, cause a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures. Our immunofluorescence analyses in primary neuronal cell cultures showed that endogenous and GFP-tagged kaptin associates with dynamic actin cytoskeletal structures and that this association is lost upon introduction of the identified mutations. Taken together, our studies have identified kaptin alterations responsible for macrocephaly and neurodevelopmental delay and define kaptin as a molecule crucial for normal human neuromorphogenesis. PMID:24239382

  4. MR imaging of neuronal migration anomaly

    International Nuclear Information System (INIS)

    Hong, Hyun Sook; Choi, Eun Wan; Kim, Dae Ho; Chung, Moo Chan; Kwon, Kuy Hyang; Kim, Ki Jung

    1991-01-01

    Abnormalities of neuronal migration are characterized by anectopic location of neurons in the cerebral cortex. This broad group of anomalies includes agyria, pachygyria, schizencephaly, unilateral megalencephaly, and gray matter heterotopia. Patients with this anomaly present clinically with a variety of symptoms which are proportional to the extent of the brain involved. These abnormalities have characterized pathologically in vivo by sonography and CT scan. MR appears to be an imaging technique of choice in evaluating these anomalies because it is capable of exceptionally good differentiation between gray and white matter, high contrast resolution, multiplanar display of the anatomy, and lack of overlying bone artifac. The purpose of this paper is to describe the MR findings of neuronal migration anomaly. The results of our study support that MR appears to be the imaging method of choice for diagnosing migration anomalies and the primary screening method for infants or children who have seisure/and delayed development

  5. Tort Damages

    NARCIS (Netherlands)

    L.T. Visscher (Louis)

    2008-01-01

    textabstractAbstract: In this Chapter, I provide an overview of Law and Economics literature regarding tort damages. Where necessary, attention is also spent to rules of tort liability. Both types of rules provide behavioral incentives to both injurers and victims, with respect to their level of

  6. Nuclear size and cell division delay

    International Nuclear Information System (INIS)

    Bird, R.P.

    1986-01-01

    Radiation-induced division delay has been linked to damage at the nuclear envelope. Further, cells in G 2 phase are drastically arrested by high LET radiation such that single particles traversing cell nuclei may produce measurable division delay. A modest effort was initiated using two related cell lines of different size, near-diploid cells and near-tetraploid cells of Chinese hamster origin, to compare their sensitivity for radiation-induced division delay. If the nuclear surface is the critical target, then a larger nuclear cross-section presented to an alpha-particle beam should exhibit delay induced by a lesser particle fluence. Preliminary estimates of the extent of delay in asynchronous cultures following low doses of gamma-irradiation or of alpha-irradiation were made by in-situ observation of the time of onset of mitosis and by fixation and staining of cultures to determine the mitotic index as a function of time after irradiation. The basic approach to evaluating division delay will be to use Colecemid to accumulate mitotic cells over a period of time

  7. Global Hopf bifurcation analysis on a BAM neural network with delays

    Science.gov (United States)

    Sun, Chengjun; Han, Maoan; Pang, Xiaoming

    2007-01-01

    A delayed differential equation that models a bidirectional associative memory (BAM) neural network with four neurons is considered. By using a global Hopf bifurcation theorem for FDE and a Bendixon's criterion for high-dimensional ODE, a group of sufficient conditions for the system to have multiple periodic solutions are obtained when the sum of delays is sufficiently large.

  8. Global Hopf bifurcation analysis on a BAM neural network with delays

    International Nuclear Information System (INIS)

    Sun Chengjun; Han Maoan; Pang Xiaoming

    2007-01-01

    A delayed differential equation that models a bidirectional associative memory (BAM) neural network with four neurons is considered. By using a global Hopf bifurcation theorem for FDE and a Bendixon's criterion for high-dimensional ODE, a group of sufficient conditions for the system to have multiple periodic solutions are obtained when the sum of delays is sufficiently large

  9. The synchronization of asymmetric-structured electric coupling neuronal system

    Science.gov (United States)

    Wang, Guanping; Jin, Wuyin; Liu, Hao; Sun, Wei

    2018-02-01

    Based on the Hindmarsh-Rose (HR) model, the synchronization dynamics of asymmetric-structured electric coupling two neuronal system is investigated in this paper. It is discovered that when the time-delay scope and coupling strength for the synchronization are correlated positively under unequal time delay, the time-delay difference does not make a clear distinction between the two individual inter-spike intervals (ISI) bifurcation diagrams of the two coupled neurons. Therefore, the superficial difference of the system synchronization dynamics is not obvious for the unequal time-delay feedback. In the asymmetrical current incentives under asymmetric electric coupled system, the two neurons can only be almost completely synchronized in specific area of the interval which end-pointed with two discharge modes for a single neuron under different stimuli currents before coupling, but the intervention of time-delay feedback, together with the change of the coupling strength, can make the coupled system not only almost completely synchronized within anywhere in the front area, but also outside of it.

  10. Delayed power analysis

    International Nuclear Information System (INIS)

    Adamovich, L.A.; Azarov, V.V.

    1999-01-01

    Time dependent core power behavior in a nuclear reactor is described with well-known neutron kinetics equations. At the same time, two portions are distinguished in energy released from uranium nuclei fission; one released directly at fission and another delayed (residual) portion produced during radioactive decay of fission products. While prompt power is definitely described with kinetics equations, the delayed power presentation still remains outstanding. Since in operation the delayed power part is relatively small (about 6%) operation, it can be neglected for small reactivity disturbances assuming that entire power obeys neutron kinetics equations. In case of a high negative reactivity rapidly inserted in core (e.g. reactor scram initiation) the prompt and delayed components can be calculated separately with practically no impact on each other, employing kinetics equations for prompt power and known approximation formulas for delayed portion, named residual in this specific case. Under substantial disturbances the prompt component in the dynamic process becomes commensurable with delayed portion, thus making necessary to take into account their cross impact. A system of differential equations to describe time-dependent behavior of delayed power is presented. Specific NPP analysis shows a way to significantly simplify the task formulation. (author)

  11. Focal neuronal gigantism: a rare complication of therapeutic radiation.

    Science.gov (United States)

    Gaughen, J R; Bourne, T D; Aregawi, D; Shah, L M; Schiff, D

    2009-11-01

    Radiation therapy, a mainstay in the treatment of many brain tumors, results in a variety of well-documented acute and chronic complications. Isolated cortical damage following irradiation represents an extremely rare delayed therapeutic complication, described only twice in the medical literature. We report this rare delayed complication in a patient following treatment of a right frontal anaplastic oligodendroglioma.

  12. Convergent dynamics for multistable delayed neural networks

    International Nuclear Information System (INIS)

    Shih, Chih-Wen; Tseng, Jui-Pin

    2008-01-01

    This investigation aims at developing a methodology to establish convergence of dynamics for delayed neural network systems with multiple stable equilibria. The present approach is general and can be applied to several network models. We take the Hopfield-type neural networks with both instantaneous and delayed feedbacks to illustrate the idea. We shall construct the complete dynamical scenario which comprises exactly 2 n stable equilibria and exactly (3 n − 2 n ) unstable equilibria for the n-neuron network. In addition, it is shown that every solution of the system converges to one of the equilibria as time tends to infinity. The approach is based on employing the geometrical structure of the network system. Positively invariant sets and componentwise dynamical properties are derived under the geometrical configuration. An iteration scheme is subsequently designed to confirm the convergence of dynamics for the system. Two examples with numerical simulations are arranged to illustrate the present theory

  13. Endogenous sulfur dioxide regulates hippocampal neuron apoptosis in developing epileptic rats and is associated with the PERK signaling pathway.

    Science.gov (United States)

    Niu, Manman; Han, Ying; Li, Qinrui; Zhang, Jing

    2018-02-05

    Epilepsy is among the most common neurological diseases in children. Recurrent seizures can result in hippocampal damage and seriously impair learning and memory functions in children. However, the mechanisms underlying epilepsy-related brain injury are unclear. Neuronal apoptosis is among the most common neuropathological manifestations of brain injury. Endogenous sulfur dioxide (SO 2 ) has been shown to be involved in seizures and related neuron apoptosis. However, the role of endogenous SO 2 in epilepsy remains unclear. This study assessed whether endogenous SO 2 is involved in epilepsy and its underlying mechanisms. Using a rat epilepsy model induced by an intraperitoneal injection of kainic acid (KA), we found that hippocampal neuron apoptosis was induced in epileptic rats, and the SO 2 content and aspartate aminotransferase (AAT) activity in the plasma were increased compared to those in the control group. However, the inhibition of SO 2 production by l-aspartate-β-hydroxamate (HDX) can subvert this response 72h after an epileptic seizure. No difference in apoptosis was observed 7 d after the epileptic seizure in the KA and KA+HDX groups. The protein expression levels of AAT2, glucose-regulated protein 78 (GRP78), pancreatic eIF2 kinase-like ER kinase (PERK) and phospho-PERK (p-PERK) were remarkably elevated in the hippocampi of the epileptic rats, while the HDX treatment was capable of reversing this process 7 d after the epileptic seizure. These results indicate that the inhibition of endogenous SO 2 production can alleviate neuronal apoptosis and is associated with the PERK signaling pathway during the initial stages after epileptic seizure, but inhibiting SO 2 production only delayed the occurrence of apoptosis and did not prevent neuronal apoptosis in the epileptic rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Suppression of immunodeficiency virus-associated neural damage by the p75 neurotrophin receptor ligand, LM11A-31, in an in vitro feline model.

    Science.gov (United States)

    Meeker, Rick B; Poulton, Winona; Feng, Wen-hai; Hudson, Lola; Longo, Frank M

    2012-06-01

    Feline immunodeficiency virus (FIV) infection like human immunodeficiency virus (HIV), produces systemic and central nervous system disease in its natural host, the domestic cat, that parallels the pathogenesis seen in HIV-infected humans. The ability to culture feline nervous system tissue affords the unique opportunity to directly examine interactions of infectious virus with CNS cells for the development of models and treatments that can then be translated to a natural infectious model. To explore the therapeutic potential of a new p75 neurotrophin receptor ligand, LM11A-31, we evaluated neuronal survival, neuronal damage and calcium homeostasis in cultured feline neurons following inoculation with FIV. FIV resulted in the gradual appearance of dendritic beading, pruning of processes and shrinkage of neuronal perikarya in the neurons. Astrocytes developed a more activated appearance and there was an enhanced accumulation of microglia, particularly at longer times post-inoculation. Addition of 10 nM LM11A-31, to the cultures greatly reduced or eliminated the neuronal pathology as well as the FIV effects on astrocytes and microglia. LM11A-31 also, prevented the development of delayed calcium deregulation in feline neurons exposed to conditioned medium from FIV treated macrophages. The suppression of calcium accumulation prevented the development of foci of calcium accumulation and beading in the dendrites. FIV replication was unaffected by LM11A-31. The strong neuroprotection afforded by LM11A-31 in an infectious in vitro model indicates that LM11A-31 may have excellent potential for the treatment of HIV-associated neurodegeneration.

  15. Neutron delayed choice experiments

    International Nuclear Information System (INIS)

    Bernstein, H.J.

    1986-01-01

    Delayed choice experiments for neutrons can help extend the interpretation of quantum mechanical phenomena. They may also rule out alternative explanations which static interference experiments allow. A simple example of a feasible neutron test is presented and discussed. (orig.)

  16. Quad nanosecond delay module

    International Nuclear Information System (INIS)

    McDonald, R.J.; Hunter, J.B.; Wozniak, G.J.

    1986-04-01

    Four nanosecond (ns) delay units have been designed to fit in a single-width NIM module. This module is particularly suited for use in conjunction with quad constant fraction timing discriminators (CFTDs) since it has four delay units that can be placed adjacent to the four units of the CFTD. A series of different length cables connected via DIP toggle switches provide delays of 0.60 ns in 4 ns increments. Thus, the CFTD delay can be optimized for pulses of different rise times from approx.10-100 ns. Design work for the PC board and silkscreening of the front panel were done with the MacDraw program on the Apple Mackintosh computer and printed with the Lasewriter printer. 6 refs

  17. Delayed rule following

    OpenAIRE

    Schmitt, David R.

    2001-01-01

    Although the elements of a fully stated rule (discriminative stimulus [SD], some behavior, and a consequence) can occur nearly contemporaneously with the statement of the rule, there is often a delay between the rule statement and the SD. The effects of this delay on rule following have not been studied in behavior analysis, but they have been investigated in rule-like settings in the areas of prospective memory (remembering to do something in the future) and goal pursuit. Discriminative even...

  18. Vernier Delay Unit

    International Nuclear Information System (INIS)

    Pierce, W.B.

    1984-10-01

    This module will accept differential ECL pulses from the auxiliary rear panel or NIM level pulses from the front panel. The pulses are produced at the output with a fixed delay that is software programmable in steps of 0.1 ns over the range of 0.1 to 10.5 ns. Multiple outputs are available at the front panel. Minimum delay through the module is 9 ns

  19. Quad precision delay generator

    International Nuclear Information System (INIS)

    Krishnan, Shanti; Gopalakrishnan, K.R.; Marballi, K.R.

    1997-01-01

    A Quad Precision Delay Generator delays a digital edge by a programmed amount of time, varying from nanoseconds to microseconds. The output of this generator has an amplitude of the order of tens of volts and rise time of the order of nanoseconds. This was specifically designed and developed to meet the stringent requirements of the plasma focus experiments. Plasma focus is a laboratory device for producing and studying nuclear fusion reactions in hot deuterium plasma. 3 figs

  20. Delayed radiation-induced damage to the brachial plexus

    Energy Technology Data Exchange (ETDEWEB)

    Burns, R J

    1978-01-01

    Three patients are described who developed a brachial plexus neuropathy following radiation treatment for cancer of the breast. The clinical features consisted of a painless, slowly progressive sensory motor disturbance, affecting especially the hand. The latent period between the radiation therapy and the onset of the neuropathy was exceptionally long, being 8, 15 and 15 years respectively. Two patients were initially incorrectly diagnosed as having a carpal tunnel syndrome. The possible mechanisms of the insidious neuropathy are discussed.

  1. Modelling delays in pharmacokinetics

    International Nuclear Information System (INIS)

    Farooqi, Z.H.; Lambrecht, R.M.

    1990-01-01

    Linear system analysis has come to form the backbone of pharmacokinetics. Natural systems usually involve time delays, thus models incorporating them would be an order closer approximation to the real world compared to those that do not. Delays may be modelled in several ways. The approach considered in this study is to have a discrete-time delay dependent rate with the delay respresenting the duration between the entry of a drug into a compartment and its release in some form (may be as a metabolite) from the compartment. Such a delay may be because of one or more of several physiological reasons, like, formation of a reservoir, slow metabolism, or receptor binding. The mathematical structure this gives rise to is a system of delay-differential equations. Examples are given of simple one and two compartment systems with drugs like bumetanide, carbamazepine, and quinolone-caffeine interaction. In these examples generally a good fit is obtained and the suggested models form a good approximation. 21 refs., 6 figs

  2. Resveratrol stimulates AMP kinase activity in neurons.

    Science.gov (United States)

    Dasgupta, Biplab; Milbrandt, Jeffrey

    2007-04-24

    Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.

  3. Bax regulates neuronal Ca2+ homeostasis.

    Science.gov (United States)

    D'Orsi, Beatrice; Kilbride, Seán M; Chen, Gang; Perez Alvarez, Sergio; Bonner, Helena P; Pfeiffer, Shona; Plesnila, Nikolaus; Engel, Tobias; Henshall, David C; Düssmann, Heiko; Prehn, Jochen H M

    2015-01-28

    Excessive Ca(2+) entry during glutamate receptor overactivation ("excitotoxicity") induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation. Copyright © 2015 the authors 0270-6474/15/351706-17$15.00/0.

  4. Delayed habituation in Behcet's disease.

    Science.gov (United States)

    Gulturk, Sefa; Akyol, Melih; Kececi, Hulusi; Ozcelik, Sedat; Cinar, Ziynet; Demirkazik, Ayse

    2008-01-01

    The autonomic nervous system in Behcet's patients may be affected due to various reasons. This entity may be detected with the measurement of the electrodermal activities, heart rate variability and pupillometric methods. Habituation is one of the implicit forms of learning and memory and the loss of habituation can reveal pathological changes in the synaptic regions. To determine whether there is a functional decrease in the synaptic effectiveness (habituation) of the pathways to sympathetic neurons that had been repeatedly activated in Behcet's. Twelve patients with Behcet's disease and 12 healthy controls were included in the study. Sympathetic skin potential (SSP) records were taken at normal room temperature in a quiet place within a Faraday cage. Sixteen square wave single shock impulses (duration: 1200 ms, strength: 5 mA) were applied on each case. After the 1st stimulus, the SSP amplitudes were lower in the patients compared to the controls (P0.05). Whereas there was no significant differences among the SSP amplitudes after the 9th impulse in the controls (P>0.05). The habituation rate of the SSP after consecutive impulses was slowest in the patients compared to controls (P<0.001, t value=12.39). There is a delayed habituation in Behcet's disease and that may due to pathologic changes with vasculitis through their peripheral nerves.

  5. Toward heterogeneity in feedforward network with synaptic delays based on FitzHugh-Nagumo model

    Science.gov (United States)

    Qin, Ying-Mei; Men, Cong; Zhao, Jia; Han, Chun-Xiao; Che, Yan-Qiu

    2018-01-01

    We focus on the role of heterogeneity on the propagation of firing patterns in feedforward network (FFN). Effects of heterogeneities both in parameters of neuronal excitability and synaptic delays are investigated systematically. Neuronal heterogeneity is found to modulate firing rates and spiking regularity by changing the excitability of the network. Synaptic delays are strongly related with desynchronized and synchronized firing patterns of the FFN, which indicate that synaptic delays may play a significant role in bridging rate coding and temporal coding. Furthermore, quasi-coherence resonance (quasi-CR) phenomenon is observed in the parameter domain of connection probability and delay-heterogeneity. All these phenomena above enable a detailed characterization of neuronal heterogeneity in FFN, which may play an indispensable role in reproducing the important properties of in vivo experiments.

  6. Single or multiple synchronization transitions in scale-free neuronal networks with electrical or chemical coupling

    International Nuclear Information System (INIS)

    Hao Yinghang; Gong, Yubing; Wang Li; Ma Xiaoguang; Yang Chuanlu

    2011-01-01

    Research highlights: → Single synchronization transition for gap-junctional coupling. → Multiple synchronization transitions for chemical synaptic coupling. → Gap junctions and chemical synapses have different impacts on synchronization transition. → Chemical synapses may play a dominant role in neurons' information processing. - Abstract: In this paper, we have studied time delay- and coupling strength-induced synchronization transitions in scale-free modified Hodgkin-Huxley (MHH) neuron networks with gap-junctions and chemical synaptic coupling. It is shown that the synchronization transitions are much different for these two coupling types. For gap-junctions, the neurons exhibit a single synchronization transition with time delay and coupling strength, while for chemical synapses, there are multiple synchronization transitions with time delay, and the synchronization transition with coupling strength is dependent on the time delay lengths. For short delays we observe a single synchronization transition, whereas for long delays the neurons exhibit multiple synchronization transitions as the coupling strength is varied. These results show that gap junctions and chemical synapses have different impacts on the pattern formation and synchronization transitions of the scale-free MHH neuronal networks, and chemical synapses, compared to gap junctions, may play a dominant and more active function in the firing activity of the networks. These findings would be helpful for further understanding the roles of gap junctions and chemical synapses in the firing dynamics of neuronal networks.

  7. Single or multiple synchronization transitions in scale-free neuronal networks with electrical or chemical coupling

    Energy Technology Data Exchange (ETDEWEB)

    Hao Yinghang [School of Physics, Ludong University, Yantai 264025 (China); Gong, Yubing, E-mail: gongyubing09@hotmail.co [School of Physics, Ludong University, Yantai 264025 (China); Wang Li; Ma Xiaoguang; Yang Chuanlu [School of Physics, Ludong University, Yantai 264025 (China)

    2011-04-15

    Research highlights: Single synchronization transition for gap-junctional coupling. Multiple synchronization transitions for chemical synaptic coupling. Gap junctions and chemical synapses have different impacts on synchronization transition. Chemical synapses may play a dominant role in neurons' information processing. - Abstract: In this paper, we have studied time delay- and coupling strength-induced synchronization transitions in scale-free modified Hodgkin-Huxley (MHH) neuron networks with gap-junctions and chemical synaptic coupling. It is shown that the synchronization transitions are much different for these two coupling types. For gap-junctions, the neurons exhibit a single synchronization transition with time delay and coupling strength, while for chemical synapses, there are multiple synchronization transitions with time delay, and the synchronization transition with coupling strength is dependent on the time delay lengths. For short delays we observe a single synchronization transition, whereas for long delays the neurons exhibit multiple synchronization transitions as the coupling strength is varied. These results show that gap junctions and chemical synapses have different impacts on the pattern formation and synchronization transitions of the scale-free MHH neuronal networks, and chemical synapses, compared to gap junctions, may play a dominant and more active function in the firing activity of the networks. These findings would be helpful for further understanding the roles of gap junctions and chemical synapses in the firing dynamics of neuronal networks.

  8. The role of 12/15-lipoxygenases in ROS-mediated neuronal cell death

    OpenAIRE

    Tobaben, Svenja

    2011-01-01

    Oxidative stress has been established as a key trigger of neuronal dysfunction and death in age-related neurodegenerative diseases and in delayed neuronal death after acute brain injury by ischemic stroke or brain trauma. Despite increasing knowledge on the toxicity of reactive oxygen species (ROS) and oxidized reaction products that may further accelerate neuronal cell death, the major sources of ROS formation and the mechanisms ...

  9. Differential Receptive Field Properties of Parvalbumin and Somatostatin Inhibitory Neurons in Mouse Auditory Cortex.

    Science.gov (United States)

    Li, Ling-Yun; Xiong, Xiaorui R; Ibrahim, Leena A; Yuan, Wei; Tao, Huizhong W; Zhang, Li I

    2015-07-01

    Cortical inhibitory circuits play important roles in shaping sensory processing. In auditory cortex, however, functional properties of genetically identified inhibitory neurons are poorly characterized. By two-photon imaging-guided recordings, we specifically targeted 2 major types of cortical inhibitory neuron, parvalbumin (PV) and somatostatin (SOM) expressing neurons, in superficial layers of mouse auditory cortex. We found that PV cells exhibited broader tonal receptive fields with lower intensity thresholds and stronger tone-evoked spike responses compared with SOM neurons. The latter exhibited similar frequency selectivity as excitatory neurons. The broader/weaker frequency tuning of PV neurons was attributed to a broader range of synaptic inputs and stronger subthreshold responses elicited, which resulted in a higher efficiency in the conversion of input to output. In addition, onsets of both the input and spike responses of SOM neurons were significantly delayed compared with PV and excitatory cells. Our results suggest that PV and SOM neurons engage in auditory cortical circuits in different manners: while PV neurons may provide broadly tuned feedforward inhibition for a rapid control of ascending inputs to excitatory neurons, the delayed and more selective inhibition from SOM neurons may provide a specific modulation of feedback inputs on their distal dendrites. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Learning Recruits Neurons Representing Previously Established Associations in the Corvid Endbrain.

    Science.gov (United States)

    Veit, Lena; Pidpruzhnykova, Galyna; Nieder, Andreas

    2017-10-01

    Crows quickly learn arbitrary associations. As a neuronal correlate of this behavior, single neurons in the corvid endbrain area nidopallium caudolaterale (NCL) change their response properties during association learning. In crows performing a delayed association task that required them to map both familiar and novel sample pictures to the same two choice pictures, NCL neurons established a common, prospective code for associations. Here, we report that neuronal tuning changes during learning were not distributed equally in the recorded population of NCL neurons. Instead, such learning-related changes relied almost exclusively on neurons which were already encoding familiar associations. Only in such neurons did behavioral improvements during learning of novel associations coincide with increasing selectivity over the learning process. The size and direction of selectivity for familiar and newly learned associations were highly correlated. These increases in selectivity for novel associations occurred only late in the delay period. Moreover, NCL neurons discriminated correct from erroneous trial outcome based on feedback signals at the end of the trial, particularly in newly learned associations. Our results indicate that task-relevant changes during association learning are not distributed within the population of corvid NCL neurons but rather are restricted to a specific group of association-selective neurons. Such association neurons in the multimodal cognitive integration area NCL likely play an important role during highly flexible behavior in corvids.

  11. Delayed xenon post-conditioning mitigates spinal cord ischemia/reperfusion injury in rabbits by regulating microglial activation and inflammatory factors.

    Science.gov (United States)

    Yang, Yan-Wei; Wang, Yun-Lu; Lu, Jia-Kai; Tian, Lei; Jin, Mu; Cheng, Wei-Ping

    2018-03-01

    The neuroprotective effect against spinal cord ischemia/reperfusion injury in rats exerted by delayed xenon post-conditioning is stronger than that produced by immediate xenon post-conditioning. However, the mechanisms underlying this process remain unclear. Activated microglia are the main inflammatory cell type in the nervous system. The release of pro-inflammatory factors following microglial activation can lead to spinal cord damage, and inhibition of microglial activation can relieve spinal cord ischemia/reperfusion injury. To investigate how xenon regulates microglial activation and the release of inflammatory factors, a rabbit model of spinal cord ischemia/reperfusion injury was induced by balloon occlusion of the infrarenal aorta. After establishment of the model, two interventions were given: (1) immediate xenon post-conditioning-after reperfusion, inhalation of 50% xenon for 1 hour, 50% N 2 /50%O 2 for 2 hours; (2) delayed xenon post-conditioning-after reperfusion, inhalation of 50% N 2 /50%O 2 for 2 hours, 50% xenon for 1 hour. At 4, 8, 24, 48 and 72 hours after reperfusion, hindlimb locomotor function was scored using the Jacobs locomotor scale. At 72 hours after reperfusion, interleukin 6 and interleukin 10 levels in the spinal cord of each group were measured using western blot assays. Iba1 levels were determined using immunohistochemistry and a western blot assay. The number of normal neurons at the injury site was quantified using hematoxylin-eosin staining. At 72 hours after reperfusion, delayed xenon post-conditioning remarkably enhanced hindlimb motor function, increased the number of normal neurons at the injury site, decreased Iba1 levels, and inhibited interleukin-6 and interleukin-10 levels in the spinal cord. Immediate xenon post-conditioning did not noticeably affect the above-mentioned indexes. These findings indicate that delayed xenon post-conditioning after spinal cord injury improves the recovery of neurological function by reducing

  12. Reduced Synaptic Vesicle Recycling during Hypoxia in Cultured Cortical Neurons

    OpenAIRE

    Fedorovich, Sergei; Hofmeijer, Jeannette; van Putten, Michel Johannes Antonius Maria; le Feber, Jakob

    2017-01-01

    Improvement of neuronal recovery in the ischemic penumbra, an area around the core of a brain infarct with some remaining perfusion, has a large potential for the development of therapy against acute ischemic stroke. However, mechanisms that lead to either recovery or secondary damage in the penumbra largely remain unclear. Recent studies in cultured networks of cortical neurons showed that failure of synaptic transmission (referred to as synaptic failure) is a critical factor in the penumbra...

  13. Neurovascular coupling protects neurons against hypoxic injury via inhibition of potassium currents by generation of nitric oxide in direct neuron and endothelium cocultures.

    Science.gov (United States)

    Wu, Kun-Wei; Kou, Zeng-Wei; Mo, Jia-Lin; Deng, Xu-Xu; Sun, Feng-Yan

    2016-10-15

    This study examined the effect of neuron-endothelial coupling on the survival of neurons after ischemia and the possible mechanism underlying that effect. Whole-cell patch-clamp experiments were performed on cortical neurons cultured alone or directly cocultured with brain microvascular endothelial cells (BMEC). Propidium iodide (PI) and NeuN staining were performed to examine neuronal death following oxygen and glucose deprivation (OGD). We found that the neuronal transient outward potassium currents (I A ) decreased in the coculture system, whereas the outward delayed-rectifier potassium currents (I K ) did not. Sodium nitroprusside, a NO donor, enhanced BMEC-induced I A inhibition and nitro-l-arginine methylester, a NOS inhibitor, partially prevented this inhibition. Moreover, the neurons directly cocultured with BMEC showed more resistance to OGD-induced injury compared with the neurons cultured alone, and that neuroprotective effect was abolished by treatment with NS5806, an activator of the I A . These results indicate that vascular endothelial cells assist neurons to prevent hypoxic injury via inhibiting neuronal I A by production of NO in the direct neuron-BMEC coculture system. These results further provide direct evidence of functional coupling between neurons and vascular endothelial cells. This study clearly demonstrates that vascular endothelial cells play beneficial roles in the pathophysiological processes of neurons after hypoxic injury, suggesting that the improvement of neurovascular coupling or functional remodeling may become an important therapeutic target for preventing brain injury. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Spectral components of cytosolic [Ca2+] spiking in neurons

    DEFF Research Database (Denmark)

    Kardos, J; Szilágyi, N; Juhász, G

    1998-01-01

    . Delayed complex responses of large [Ca2+]c spiking observed in cells from a different set of cultures were synthesized by a set of frequencies within the range 0.018-0.117 Hz. Differential frequency patterns are suggested as characteristics of the [Ca2+]c spiking responses of neurons under different...

  15. Edaravone attenuates brain damage in rats after acute CO poisoning through inhibiting apoptosis and oxidative stress.

    Science.gov (United States)

    Li, Qin; Bi, Ming Jun; Bi, Wei Kang; Kang, Hai; Yan, Le Jing; Guo, Yun-Liang

    2016-03-01

    Acute carbon monoxide (CO) poisoning is the most common cause of death from poisoning all over the world and may result in neuropathologic and neurophysiologic changes. Acute brain damage and delayed encephalopathy are the most serious complication, yet their pathogenesis is poorly understood. The present study aimed to evaluate the neuroprotective effects of Edaravone against apoptosis and oxidative stress after acute CO poisoning. The rat model of CO poisoning was established in a hyperbaric oxygen chamber by exposed to CO. Ultrastructure changes were observed by transmission electron microscopy (TEM). TUNEL stain was used to assess apoptosis. Immunohistochemistry and immunofluorescence double stain were used to evaluate the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) protein and their relationship. By dynamically monitored the carboxyhemoglobin (HbCO) level in blood, we successfully established rat model of severe CO poisoning. Ultrastructure changes, including chromatin condensation, cytoplasm dissolution, vacuoles formation, nucleus membrane and cell organelles decomposition, could be observed after CO poisoning. Edaravone could improve the ultrastructure damage. CO poisoning could induce apoptosis. Apoptotic cells were widely distributed in cortex, striatum and hippocampus. Edaravone treatment attenuated neuronal apoptosis as compared with the poisoning group (P Edaravone, the expression of HO-1 and Nrf-2 significantly increased (P Edaravone may inhibit apoptosis, activate the Keapl-Nrf/ARE pathway, and thus improve the ultrastructure damage and neurophysiologic changes following acute CO poisoning. © 2014 Wiley Periodicals, Inc.

  16. Irradiation damage

    Energy Technology Data Exchange (ETDEWEB)

    Howe, L.M

    2000-07-01

    There is considerable interest in irradiation effects in intermetallic compounds from both the applied and fundamental aspects. Initially, this interest was associated mainly with nuclear reactor programs but it now extends to the fields of ion-beam modification of metals, behaviour of amorphous materials, ion-beam processing of electronic materials, and ion-beam simulations of various kinds. The field of irradiation damage in intermetallic compounds is rapidly expanding, and no attempt will be made in this chapter to cover all of the various aspects. Instead, attention will be focused on some specific areas and, hopefully, through these, some insight will be given into the physical processes involved, the present state of our knowledge, and the challenge of obtaining more comprehensive understanding in the future. The specific areas that will be covered are: point defects in intermetallic compounds; irradiation-enhanced ordering and irradiation-induced disordering of ordered alloys; irradiation-induced amorphization.

  17. Irradiation damage

    International Nuclear Information System (INIS)

    Howe, L.M.

    2000-01-01

    There is considerable interest in irradiation effects in intermetallic compounds from both the applied and fundamental aspects. Initially, this interest was associated mainly with nuclear reactor programs but it now extends to the fields of ion-beam modification of metals, behaviour of amorphous materials, ion-beam processing of electronic materials, and ion-beam simulations of various kinds. The field of irradiation damage in intermetallic compounds is rapidly expanding, and no attempt will be made in this chapter to cover all of the various aspects. Instead, attention will be focused on some specific areas and, hopefully, through these, some insight will be given into the physical processes involved, the present state of our knowledge, and the challenge of obtaining more comprehensive understanding in the future. The specific areas that will be covered are: point defects in intermetallic compounds; irradiation-enhanced ordering and irradiation-induced disordering of ordered alloys; irradiation-induced amorphization

  18. Optimal Joint Expected Delay Forwarding in Delay Tolerant Networks

    OpenAIRE

    Jia Xu; Xin Feng; Wen Jun Yang; Ru Chuan Wang; Bing Qing Han

    2013-01-01

    Multicopy forwarding schemes have been employed in delay tolerant network (DTN) to improve the delivery delay and delivery rate. Much effort has been focused on reducing the routing cost while retaining high performance. This paper aims to provide an optimal joint expected delay forwarding (OJEDF) protocol which minimizes the expected delay while satisfying a certain constant on the number of forwardings per message. We propose a comprehensive forwarding metric called joint expected delay (JE...

  19. Kappe neurons, a novel population of olfactory sensory neurons

    OpenAIRE

    Ahuja, Gaurav; Nia, Shahrzad Bozorg; Zapilko, Veronika; Shiriagin, Vladimir; Kowatschew, Daniel; Oka, Yuichiro; Korsching, Sigrun I.

    2014-01-01

    Perception of olfactory stimuli is mediated by distinct populations of olfactory sensory neurons, each with a characteristic set of morphological as well as functional parameters. Beyond two large populations of ciliated and microvillous neurons, a third population, crypt neurons, has been identified in teleost and cartilaginous fishes. We report here a novel, fourth olfactory sensory neuron population in zebrafish, which we named kappe neurons for their characteristic shape. Kappe neurons ar...

  20. [Functional organization and structure of the serotonergic neuronal network of terrestrial snail].

    Science.gov (United States)

    Nikitin, E S; Balaban, P M

    2011-01-01

    The extension of knowledge how the brain works requires permanent improvement of methods of recording of neuronal activity and increase in the number of neurons recorded simultaneously to better understand the collective work of neuronal networks and assemblies. Conventional methods allow simultaneous intracellular recording up to 2-5 neurons and their membrane potentials, currents or monosynaptic connections or observation of spiking of neuronal groups with subsequent discrimination of individual spikes with loss of details of the dynamics of membrane potential. We recorded activity of a compact group of serotonergic neurons (up to 56 simultaneously) in the ganglion of a terrestrial mollusk using the method of optical recording of membrane potential that allowed to record individual action potentials in details with action potential parameters and to reveal morphology of the neurons rcorded. We demonstrated clear clustering in the group in relation with the dynamics of action potentials and phasic or tonic components in the neuronal responses to external electrophysiological and tactile stimuli. Also, we showed that identified neuron Pd2 could induce activation of a significant number of neurons in the group whereas neuron Pd4 did not induce any activation. However, its activation is delayed with regard to activation of the reacting group of neurons. Our data strongly support the concept of possible delegation of the integrative function by the network to a single neuron.

  1. Brainstem neurons survive the identical ischemic stress that kills higher neurons: insight to the persistent vegetative state.

    Directory of Open Access Journals (Sweden)

    C Devin Brisson

    Full Text Available Global ischemia caused by heart attack, pulmonary failure, near-drowning or traumatic brain injury often damages the higher brain but not the brainstem, leading to a 'persistent vegetative state' where the patient is awake but not aware. Approximately 30,000 U.S. patients are held captive in this condition but not a single research study has addressed how the lower brain is preferentially protected in these people. In the higher brain, ischemia elicits a profound anoxic depolarization (AD causing neuronal dysfunction and vasoconstriction within minutes. Might brainstem nuclei generate less damaging AD and so be more resilient? Here we compared resistance to acute injury induced from simulated ischemia by 'higher' hippocampal and striatal neurons versus brainstem neurons in live slices from rat and mouse. Light transmittance (LT imaging in response to 10 minutes of oxygen/glucose deprivation (OGD revealed immediate and acutely damaging AD propagating through gray matter of neocortex, hippocampus, striatum, thalamus and cerebellar cortex. In adjacent brainstem nuclei, OGD-evoked AD caused little tissue injury. Whole-cell patch recordings from hippocampal and striatal neurons under OGD revealed sudden membrane potential loss that did not recover. In contrast brainstem neurons from locus ceruleus and mesencephalic nucleus as well as from sensory and motor nuclei only slowly depolarized and then repolarized post-OGD. Two-photon microscopy confirmed non-recoverable swelling and dendritic beading of hippocampal neurons during OGD, while mesencephalic neurons in midbrain appeared uninjured. All of the above responses were mimicked by bath exposure to 100 µM ouabain which inhibits the Na+/K+ pump or to 1-10 nM palytoxin which converts the pump into an open cationic channel. Therefore during ischemia the Na+/K+ pump of higher neurons fails quickly and extensively compared to naturally resilient hypothalamic and brainstem neurons. The selective survival

  2. Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy

    Directory of Open Access Journals (Sweden)

    Teppei Noda

    2018-02-01

    Full Text Available Primary auditory neurons (PANs play a critical role in hearing by transmitting sound information from the inner ear to the brain. Their progressive degeneration is associated with excessive noise, disease and aging. The loss of PANs leads to permanent hearing impairment since they are incapable of regenerating. Spiral ganglion non-neuronal cells (SGNNCs, comprised mainly of glia, are resident within the modiolus and continue to survive after PAN loss. These attributes make SGNNCs an excellent target for replacing damaged PANs through cellular reprogramming. We used the neurogenic pioneer transcription factor Ascl1 and the auditory neuron differentiation factor NeuroD1 to reprogram SGNNCs into induced neurons (iNs. The overexpression of both Ascl1 and NeuroD1 in vitro generated iNs at high efficiency. Transcriptome analyses revealed that iNs displayed a transcriptome profile resembling that of endogenous PANs, including expression of several key markers of neuronal identity: Tubb3, Map2, Prph, Snap25, and Prox1. Pathway analyses indicated that essential pathways in neuronal growth and maturation were activated in cells upon neuronal induction. Furthermore, iNs extended projections toward cochlear hair cells and cochlear nucleus neurons when cultured with each respective tissue. Taken together, our study demonstrates that PAN-like neurons can be generated from endogenous SGNNCs. This work suggests that gene therapy can be a viable strategy to treat sensorineural hearing loss caused by degeneration of PANs.

  3. Neuronal responses to physiological stress

    DEFF Research Database (Denmark)

    Kagias, Konstantinos; Nehammer, Camilla; Pocock, Roger David John

    2012-01-01

    damage during aging that results in decline and eventual death. Studies have shown that the nervous system plays a pivotal role in responding to stress. Neurons not only receive and process information from the environment but also actively respond to various stresses to promote survival. These responses......Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. It can be divided into three different aspects: environmental stress, intrinsic developmental stress, and aging. Throughout life all living organisms are challenged...... by changes in the environment. Fluctuations in oxygen levels, temperature, and redox state for example, trigger molecular events that enable an organism to adapt, survive, and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner...

  4. NEURON and Python.

    Science.gov (United States)

    Hines, Michael L; Davison, Andrew P; Muller, Eilif

    2009-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications.

  5. Robust Synchronization in an E/I Network with Medium Synaptic Delay and High Level of Heterogeneity

    International Nuclear Information System (INIS)

    Han Fang; Wang Zhi-Jie; Gong Tao; Fan Hong

    2015-01-01

    It is known that both excitatory and inhibitory neuronal networks can achieve robust synchronization only under certain conditions, such as long synaptic delay or low level of heterogeneity. In this work, robust synchronization can be found in an excitatory/inhibitory (E/I) neuronal network with medium synaptic delay and high level of heterogeneity, which often occurs in real neuronal networks. Two effects of post-synaptic potentials (PSP) to network synchronization are presented, and the synaptic contribution of excitatory and inhibitory neurons to robust synchronization in this E/I network is investigated. It is found that both excitatory and inhibitory neurons may contribute to robust synchronization in E/I networks, especially the excitatory PSP has a more positive effect on synchronization in E/I networks than that in excitatory networks. This may explain the strong robustness of synchronization in E/I neuronal networks. (paper)

  6. Assessing delay discounting in mice

    OpenAIRE

    Mitchell, Suzanne H.

    2014-01-01

    Delay discounting (also intertemporal choice or impulsive choice) is the process by which delayed outcomes, such as delayed food delivery, are valued less than the same outcomes delivered immediately or with a shorter delay. This process is of interest because many psychopathologies, including substance dependence, pathological gambling, attention deficit hyperactivity disorder and conduct disorder, are characterized by heightened levels of delay discounting. Some of these disorders are herit...

  7. Spinal cord: motor neuron diseases.

    Science.gov (United States)

    Rezania, Kourosh; Roos, Raymond P

    2013-02-01

    Spinal cord motor neuron diseases affect lower motor neurons in the ventral horn. This article focuses on the most common spinal cord motor neuron disease, amyotrophic lateral sclerosis, which also affects upper motor neurons. Also discussed are other motor neuron diseases that only affect the lower motor neurons. Despite the identification of several genes associated with familial amyotrophic lateral sclerosis, the pathogenesis of this complex disease remains elusive. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Complex Dynamics of Delay-Coupled Neural Networks

    Science.gov (United States)

    Mao, Xiaochen

    2016-09-01

    This paper reveals the complicated dynamics of a delay-coupled system that consists of a pair of sub-networks and multiple bidirectional couplings. Time delays are introduced into the internal connections and network-couplings, respectively. The stability and instability of the coupled network are discussed. The sufficient conditions for the existence of oscillations are given. Case studies of numerical simulations are given to validate the analytical results. Interesting and complicated neuronal activities are observed numerically, such as rest states, periodic oscillations, multiple switches of rest states and oscillations, and the coexistence of different types of oscillations.

  9. Inhibition delay increases neural network capacity through Stirling transform

    Science.gov (United States)

    Nogaret, Alain; King, Alastair

    2018-03-01

    Inhibitory neural networks are found to encode high volumes of information through delayed inhibition. We show that inhibition delay increases storage capacity through a Stirling transform of the minimum capacity which stabilizes locally coherent oscillations. We obtain both the exact and asymptotic formulas for the total number of dynamic attractors. Our results predict a (ln2) -N-fold increase in capacity for an N -neuron network and demonstrate high-density associative memories which host a maximum number of oscillations in analog neural devices.

  10. Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex.

    Science.gov (United States)

    McCarthy, Deirdre M; Bhide, Pradeep G

    2012-01-01

    Cocaine abuse during pregnancy produces harmful effects not only on the mother but also on the unborn child. The neurotransmitters dopamine and serotonin are known as the principal targets of the action of cocaine in the fetal and postnatal brain. However, recent evidence suggests that cocaine can impair cerebral cortical GABA neuron development and function. We sought to analyze the effects of prenatal cocaine exposure on the number and distribution of GABA and projection neurons (inhibitory interneurons and excitatory output neurons, respectively) in the mouse cerebral cortex. We found that the prenatal cocaine exposure decreased GABA neuron numbers and GABA-to-projection neuron ratio in the medial prefrontal cortex of 60-day-old mice. The neighboring prefrontal cortex did not show significant changes in either of these measures. However, there was a significant increase in projection neuron numbers in the prefrontal cortex but not in the medial prefrontal cortex. Thus, the effects of cocaine on GABA and projection neurons appear to be cortical region specific. The population of parvalbumin-immunoreactive GABA neurons was decreased in the medial prefrontal cortex following the prenatal cocaine exposure. The cocaine exposure also delayed the developmental decline in the volume of the medial prefrontal cortex. Thus, prenatal cocaine exposure produced persisting and region-specific effects on cortical cytoarchitecture and impaired the physiological balance between excitatory and inhibitory neurotransmission. These structural changes may underlie the electrophysiological and behavioral effects of prenatal cocaine exposure observed in animal models and human subjects. Copyright © 2012 S. Karger AG, Basel.

  11. Estimating Delays In ASIC's

    Science.gov (United States)

    Burke, Gary; Nesheiwat, Jeffrey; Su, Ling

    1994-01-01

    Verification is important aspect of process of designing application-specific integrated circuit (ASIC). Design must not only be functionally accurate, but must also maintain correct timing. IFA, Intelligent Front Annotation program, assists in verifying timing of ASIC early in design process. This program speeds design-and-verification cycle by estimating delays before layouts completed. Written in C language.

  12. Permissible Delay in Payments

    Directory of Open Access Journals (Sweden)

    Yung-Fu Huang

    2007-01-01

    Full Text Available The main purpose of this paper wants to investigate the optimal retailer's lot-sizing policy with two warehouses under partially permissible delay in payments within the economic order quantity (EOQ framework. In this paper, we want to extend that fully permissible delay in payments to the supplier would offer the retailer partially permissible delay in payments. That is, the retailer must make a partial payment to the supplier when the order is received. Then the retailer must pay off the remaining balance at the end of the permissible delay period. In addition, we want to add the assumption that the retailer's storage space is limited. That is, the retailer will rent the warehouse to store these exceeding items when the order quantity is larger than retailer's storage space. Under these conditions, we model the retailer's inventory system as a cost minimization problem to determine the retailer's optimal cycle time and optimal order quantity. Three theorems are developed to efficiently determine the optimal replenishment policy for the retailer. Finally, numerical examples are given to illustrate these theorems and obtained a lot of managerial insights.

  13. Delayed neutrons in ANSTO

    International Nuclear Information System (INIS)

    Wall, T.

    1988-01-01

    Delayed neutron analysis carried out at the Australian Nuclear Scientific and Technology Organization facilities, provides a fast, high sensitivity, low cost, reliable method, particularly suitable for large batches of samples, and for non destructive analysis of a range of materials. While its main use has been in uranium exploration, other applications include archeological investigations, agriculture, oceanography and biology

  14. Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes

    International Nuclear Information System (INIS)

    Lazar, Shlomi; Egoz, Inbal; Brandeis, Rachel; Chapman, Shira; Bloch-Shilderman, Eugenia; Grauer, Ettie

    2016-01-01

    Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80 μg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48 h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6 h post exposure while TSPO receptor density increased only at 24 h. In all brain regions tested, bax mRNA decreased 1 h post exposure followed by an increase 24 h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous “first response” mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention. - Highlights: • The severity of brain damage post 1LD50 sarin exposure is time dependent. • Sarin induce differential progression of early processes in the rat brain. • Potential treatments should be timed according to early events following exposure. • The biphasic astrocytes activity suggests a delay in anti-inflammatory intervention.

  15. Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes

    Energy Technology Data Exchange (ETDEWEB)

    Lazar, Shlomi; Egoz, Inbal; Brandeis, Rachel; Chapman, Shira; Bloch-Shilderman, Eugenia; Grauer, Ettie, E-mail: ettieg@iibr.gov.il

    2016-11-01

    Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80 μg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48 h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6 h post exposure while TSPO receptor density increased only at 24 h. In all brain regions tested, bax mRNA decreased 1 h post exposure followed by an increase 24 h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous “first response” mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention. - Highlights: • The severity of brain damage post 1LD50 sarin exposure is time dependent. • Sarin induce differential progression of early processes in the rat brain. • Potential treatments should be timed according to early events following exposure. • The biphasic astrocytes activity suggests a delay in anti-inflammatory intervention.

  16. Damaged Skylab

    Science.gov (United States)

    1973-01-01

    The Saturn V vehicle, carrying the unmarned orbital workshop for the Skylab-1 mission, lifted off successfully and all systems performed normally. Sixty-three seconds into the flight, engineers in the operation support and control center saw an unexpected telemetry indication that signalled that damages occurred on one solar array and the micrometeoroid shield during the launch. The micrometeoroid shield, a thin protective cylinder surrounding the workshop protecting it from tiny space particles and the sun's scorching heat, ripped loose from its position around the workshop. This caused the loss of one solar wing and jammed the other. Still unoccupied, the Skylab was stricken with the loss of the heat shield and sunlight beat mercilessly on the lab's sensitive skin. Internal temperatures soared, rendering the station uninhabitable, threatening foods, medicines, films, and experiments. This image, taken during a fly-around inspection by the Skylab-2 crew, shows a crippled Skylab in orbit. The crew found their home in space to be in serious shape; the heat shield gone, one solar wing gone, and the other jammed. The Marshall Space Flight Center (MSFC) developed, tested, rehearsed, and approved three repair options. These options included a parasol sunshade and a twin-pole sunshade to restore the temperature inside the workshop, and a set of metal cutting tools to free the jammed solar panel.

  17. Structural damage

    International Nuclear Information System (INIS)

    Gray, R.E.; Bruhn, R.W.

    1992-01-01

    Virtually all structures show some signs of distress due to deterioration of the building components, to changed loads, or to changed support conditions. Changed support conditions result from ground movements. In mining regions many cases of structural distress are attributed to mining without considering alternative causes. This is particularly true of coal mining since it occurs under extensive areas. Coal mining is estimated to have already undermined more than eight million acres and may eventually undermine 40 million acres in the United States. Other nonmetal and metal underground mines impact much smaller areas. Although it is sometimes difficult, even with careful study, to identify the actual cause of damage, persons responsible for underground coal mining should at least be aware of possible causes of building stress other than mine subsidence. This paper presents information on distress to structures and briefly reviews a number of causes of ground movements other than subsidence: Mass movements, dissolution, erosion, frost action, shrinking and swelling, yield into excavations and compressibility

  18. Neuronal-glial trafficking

    International Nuclear Information System (INIS)

    Bachelard, H.S.

    2001-01-01

    Full text: The name 'glia' originates from the Greek word for glue, because astro glia (or astrocytes) were thought only to provide an anatomical framework for the electrically-excitable neurones. However, awareness that astrocytes perform vital roles in protecting the neurones, which they surround, emerged from evidence that they act as neuroprotective K + -sinks, and that they remove potentially toxic extracellular glutamate from the vicinity of the neurones. The astrocytes convert the glutamate to non-toxic glutamine which is returned to the neurones and used to replenish transmitter glutamate. This 'glutamate-glutamine cycle' (established in the 1960s by Berl and his colleagues) also contributes to protecting the neurones against a build-up of toxic ammonia. Glial cells also supply the neurones with components for free-radical scavenging glutathione. Recent studies have revealed that glial cells play a more positive interactive role in furnishing the neurones with fuels. Studies using radioactive 14 C, 13 C-MRS and 15 N-GCMS have revealed that glia produce alanine, lactate and proline for consumption by neurones, with increased formation of neurotransmitter glutamate. On neuronal activation the release of NH 4 + and glutamate from the neurones stimulates glucose uptake and glycolysis in the glia to produce more alanine, which can be regarded as an 'alanine-glutamate cycle' Use of 14 C-labelled precursors provided early evidence that neurotransmitter GABA may be partly derived from glial glutamine, and this has been confirmed recently in vivo by MRS isotopomer analysis of the GABA and glutamine labelled from 13 C-acetate. Relative rates of intermediary metabolism in glia and neurones can be calculated using a combination of [1- 13 C] glucose and [1,2- 13 C] acetate. When glutamate is released by neurones there is a net neuronal loss of TCA intermediates which have to be replenished. Part of this is derived from carboxylation of pyruvate, (pyruvate carboxylase

  19. Radiation damage prediction system using damage function

    International Nuclear Information System (INIS)

    Tanaka, Yoshihisa; Mori, Seiji

    1979-01-01

    The irradiation damage analysis system using a damage function was investigated. This irradiation damage analysis system consists of the following three processes, the unfolding of a damage function, the calculation of the neutron flux spectrum of the object of damage analysis and the estimation of irradiation effect of the object of damage analysis. The damage function is calculated by applying the SAND-2 code. The ANISN and DOT3, 5 codes are used to calculate neutron flux. The neutron radiation and the allowable time of reactor operation can be estimated based on these calculations of the damage function and neutron flux. The flow diagram of the process of analyzing irradiation damage by a damage function and the flow diagram of SAND-2 code are presented, and the analytical code for estimating damage, which is determined with a damage function and a neutron spectrum, is explained. The application of the irradiation damage analysis system using a damage function was carried out to the core support structure of a fast breeder reactor for the damage estimation and the uncertainty evaluation. The fundamental analytical conditions and the analytical model for this work are presented, then the irradiation data for SUS304, the initial estimated values of a damage function, the error analysis for a damage function and the analytical results are explained concerning the computation of a damage function for 10% total elongation. Concerning the damage estimation of FBR core support structure, the standard and lower limiting values of damage, the permissible neutron flux and the allowable years of reactor operation are presented and were evaluated. (Nakai, Y.)

  20. ALS and other motor neuron diseases.

    Science.gov (United States)

    Tiryaki, Ezgi; Horak, Holli A

    2014-10-01

    This review describes the most common motor neuron disease, ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its pathophysiology, including new genetic underpinnings of the disease. This article also covers other motor neuron diseases, reviews how to distinguish them from ALS, and discusses their pathophysiology. In this article, the spectrum of cognitive involvement in ALS, new concepts about protein synthesis pathology in the etiology of ALS, and new genetic associations will be covered. This concept has changed over the past 3 to 4 years with the discovery of new genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS. The anterior horn cells control all voluntary movement: motor activity, respiratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells. Diseases that damage the anterior horn cells, therefore, have a profound impact. Symptoms of anterior horn cell loss (weakness, falling, choking) lead patients to seek medical attention. Neurologists are the most likely practitioners to recognize and diagnose damage or loss of anterior horn cells. ALS, the prototypical motor neuron disease, demonstrates the impact of this class of disorders. ALS and other motor neuron diseases can represent diagnostic challenges. Neurologists are often called upon to serve as a "medical home" for these patients: coordinating care, arranging for durable medical equipment, and leading discussions about end-of-life care with patients and caregivers. It is important for neurologists to be able to identify motor neuron diseases and to evaluate and treat patients affected by them.

  1. Air pollution and brain damage.

    Science.gov (United States)

    Calderón-Garcidueñas, Lilian; Azzarelli, Biagio; Acuna, Hilda; Garcia, Raquel; Gambling, Todd M; Osnaya, Norma; Monroy, Sylvia; DEL Tizapantzi, Maria Rosario; Carson, Johnny L; Villarreal-Calderon, Anna; Rewcastle, Barry

    2002-01-01

    Exposure to complex mixtures of air pollutants produces inflammation in the upper and lower respiratory tract. Because the nasal cavity is a common portal of entry, respiratory and olfactory epithelia are vulnerable targets for toxicological damage. This study has evaluated, by light and electron microscopy and immunohistochemical expression of nuclear factor-kappa beta (NF-kappaB) and inducible nitric oxide synthase (iNOS), the olfactory and respiratory nasal mucosae, olfactory bulb, and cortical and subcortical structures from 32 healthy mongrel canine residents in Southwest Metropolitan Mexico City (SWMMC), a highly polluted urban region. Findings were compared to those in 8 dogs from Tlaxcala, a less polluted, control city. In SWMMC dogs, expression of nuclear neuronal NF-kappaB and iNOS in cortical endothelial cells occurred at ages 2 and 4 weeks; subsequent damage included alterations of the blood-brain barrier (BBB), degenerating cortical neurons, apoptotic glial white matter cells, deposition of apolipoprotein E (apoE)-positive lipid droplets in smooth muscle cells and pericytes, nonneuritic plaques, and neurofibrillary tangles. Persistent pulmonary inflammation and deteriorating olfactory and respiratory barriers may play a role in the neuropathology observed in the brains of these highly exposed canines. Neurodegenerative disorders such as Alzheimer's may begin early in life with air pollutants playing a crucial role.

  2. Autaptic effects on synchrony of neurons coupled by electrical synapses

    Science.gov (United States)

    Kim, Youngtae

    2017-07-01

    In this paper, we numerically study the effects of a special synapse known as autapse on synchronization of population of Morris-Lecar (ML) neurons coupled by electrical synapses. Several configurations of the ML neuronal populations such as a pair or a ring or a globally coupled network with and without autapses are examined. While most of the papers on the autaptic effects on synchronization have used networks of neurons of same spiking rate, we use the network of neurons of different spiking rates. We find that the optimal autaptic coupling strength and the autaptic time delay enhance synchronization in our neural networks. We use the phase response curve analysis to explain the enhanced synchronization by autapses. Our findings reveal the important relationship between the intraneuronal feedback loop and the interneuronal coupling.

  3. Regenerative memory in time-delayed neuromorphic photonic resonators

    OpenAIRE

    Romeira, B.; Avó, R.; Figueiredo, José M. L.; Barland, S.; Javaloyes, J.

    2016-01-01

    We investigate a photonic regenerative memory based upon a neuromorphic oscillator with a delayed self-feedback (autaptic) connection. We disclose the existence of a unique temporal response characteristic of localized structures enabling an ideal support for bits in an optical buffer memory for storage and reshaping of data information. We link our experimental implementation, based upon a nanoscale nonlinear resonant tunneling diode driving a laser, to the paradigm of neuronal activity, the...

  4. Destabilizing Effects of Impulse in Delayed Bam Neural Networks

    Science.gov (United States)

    Li, Chuandong; Li, Chaojie; Liu, Chao

    This paper further studies the global exponential stability of the equilibrium point of the delayed bidirectional associative memory (DBAM) neural networks with impulse effects. Several results characterizing the aggregated effects of impulse and dynamical property of the impulse-free DBAM on the exponential stability of the considered DBAM have been established. It is shown that the impulsive DBAM will preserve the global exponential stability of the impulse-free DBAM even if the impulses have enlarging effects on the states of neurons.

  5. Single neuron computation

    CERN Document Server

    McKenna, Thomas M; Zornetzer, Steven F

    1992-01-01

    This book contains twenty-two original contributions that provide a comprehensive overview of computational approaches to understanding a single neuron structure. The focus on cellular-level processes is twofold. From a computational neuroscience perspective, a thorough understanding of the information processing performed by single neurons leads to an understanding of circuit- and systems-level activity. From the standpoint of artificial neural networks (ANNs), a single real neuron is as complex an operational unit as an entire ANN, and formalizing the complex computations performed by real n

  6. Mesmerising mirror neurons.

    Science.gov (United States)

    Heyes, Cecilia

    2010-06-01

    Mirror neurons have been hailed as the key to understanding social cognition. I argue that three currents of thought-relating to evolution, atomism and telepathy-have magnified the perceived importance of mirror neurons. When they are understood to be a product of associative learning, rather than an adaptation for social cognition, mirror neurons are no longer mesmerising, but they continue to raise important questions about both the psychology of science and the neural bases of social cognition. Copyright 2010 Elsevier Inc. All rights reserved.

  7. The mirror neuron system.

    Science.gov (United States)

    Cattaneo, Luigi; Rizzolatti, Giacomo

    2009-05-01

    Mirror neurons are a class of neurons, originally discovered in the premotor cortex of monkeys, that discharge both when individuals perform a given motor act and when they observe others perform that same motor act. Ample evidence demonstrates the existence of a cortical network with the properties of mirror neurons (mirror system) in humans. The human mirror system is involved in understanding others' actions and their intentions behind them, and it underlies mechanisms of observational learning. Herein, we will discuss the clinical implications of the mirror system.

  8. White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies.

    Science.gov (United States)

    Venkat, Poornima; Chopp, Michael; Zacharek, Alex; Cui, Chengcheng; Zhang, Li; Li, Qingjiang; Lu, Mei; Zhang, Talan; Liu, Amy; Chen, Jieli

    2017-02-01

    We investigated cognitive function, axonal/white matter (WM) changes and glymphatic function of vascular dementia using a multiple microinfarction (MMI) model in retired breeder (RB) rats. The MMI model induces significant (p rats subjected to MMI exhibit significant axonal/WM damage identified by decreased myelin thickness, oligodendrocyte progenitor cell numbers, axon density, synaptic protein expression in the cortex and striatum, cortical neuronal branching, and dendritic spine density in the cortex and hippocampus compared with age-matched controls. MMI evokes significant dilation of perivascular spaces as well as water channel dysfunction indicated by decreased Aquaporin-4 expression around blood vessels. MMI-induced glymphatic dysfunction with delayed cerebrospinal fluid penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. The MMI model in RB rats decreases Aquaporin-4 and induces glymphatic dysfunction which may play an important role in MMI-induced axonal/WM damage and cognitive deficits. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Topological Acoustic Delay Line

    Science.gov (United States)

    Zhang, Zhiwang; Tian, Ye; Cheng, Ying; Wei, Qi; Liu, Xiaojun; Christensen, Johan

    2018-03-01

    Topological protected wave engineering in artificially structured media is at the frontier of ongoing metamaterials research that is inspired by quantum mechanics. Acoustic analogues of electronic topological insulators have recently led to a wealth of new opportunities in manipulating sound propagation with strikingly unconventional acoustic edge modes immune to backscattering. Earlier fabrications of topological insulators are characterized by an unreconfigurable geometry and a very narrow frequency response, which severely hinders the exploration and design of useful devices. Here we establish topologically protected sound in reconfigurable phononic crystals that can be switched on and off simply by rotating its three-legged "atoms" without altering the lattice structure. In particular, we engineer robust phase delay defects that take advantage of the ultrabroadband reflection-free sound propagation. Such topological delay lines serve as a paradigm in compact acoustic devices, interconnects, and electroacoustic integrated circuits.

  10. Delayed traumatic intracranial hematoma

    International Nuclear Information System (INIS)

    Tomita, Hiroki

    1984-01-01

    CT was performed serially within 24 hours after head injury in 64 patients having Glasgow Coma Scale of 14 or less or cranial fracture shown on roentgenogram. Delayed traumatic extradural hematoma was observed within 7-12 hours after head injury in 6 cases (9.4%). This was prominent in the frontal and occipital regions (67%). Good recovery was seen in 83.3%. Delayed traumatic intracerebral hematoma was observed within 6-24 hours after head injury in 17 cases (26.6%). This higher incidence was related to contre coup injury. Conservative treatment was possible in 14 of the 17 patients (82.4%), showing good recovery in 70%. (Namekawa, K.)

  11. Characterization of neuronal intrinsic properties and synaptic transmission in layer I of anterior cingulate cortex from adult mice

    Directory of Open Access Journals (Sweden)

    Li Xiang-Yao

    2012-07-01

    Full Text Available Abstract The neurons in neocortex layer I (LI provide inhibition to the cortical networks. Despite increasing use of mice for the study of brain functions, few studies were reported about mouse LI neurons. In the present study, we characterized intrinsic properties of LI neurons of the anterior cingulate cortex (ACC, a key cortical area for sensory and cognitive functions, by using whole-cell patch clamp recording approach. Seventy one neurons in LI and 12 pyramidal neurons in LII/III were recorded. Although all of the LI neurons expressed continuous adapting firing characteristics, the unsupervised clustering results revealed five groups in the ACC, including: Spontaneous firing neurons; Delay-sAHP neurons, Delay-fAHP neurons, and two groups of neurons with ADP, named ADP1 and ADP2, respectively. Using pharmacological approaches, we found that LI neurons received both excitatory (mediated by AMPA, kainate and NMDA receptors, and inhibitory inputs (which were mediated by GABAA receptors. Our studies provide the first report characterizing the electrophysiological properties of neurons in LI of the ACC from adult mice.

  12. Time-Delay Interferometry

    Directory of Open Access Journals (Sweden)

    Massimo Tinto

    2014-08-01

    Full Text Available Equal-arm detectors of gravitational radiation allow phase measurements many orders of magnitude below the intrinsic phase stability of the laser injecting light into their arms. This is because the noise in the laser light is common to both arms, experiencing exactly the same delay, and thus cancels when it is differenced at the photo detector. In this situation, much lower level secondary noises then set the overall performance. If, however, the two arms have different lengths (as will necessarily be the case with space-borne interferometers, the laser noise experiences different delays in the two arms and will hence not directly cancel at the detector. In order to solve this problem, a technique involving heterodyne interferometry with unequal arm lengths and independent phase-difference readouts has been proposed. It relies on properly time-shifting and linearly combining independent Doppler measurements, and for this reason it has been called time-delay interferometry (TDI. This article provides an overview of the theory, mathematical foundations, and experimental aspects associated with the implementation of TDI. Although emphasis on the application of TDI to the Laser Interferometer Space Antenna (LISA mission appears throughout this article, TDI can be incorporated into the design of any future space-based mission aiming to search for gravitational waves via interferometric measurements. We have purposely left out all theoretical aspects that data analysts will need to account for when analyzing the TDI data combinations.

  13. Effect of normabaric hyperoxia treatment on neuronal damage ...

    Indian Academy of Sciences (India)

    2013-01-10

    Jan 10, 2013 ... imperative to identify a treatment to address the devastating post-TBI consequences. Therefore, the .... with 5 min tap water (to allow the stain to develop), dip. 8 times (rapidly) in .... grey/white maters (Graham et al. 2000).

  14. Effect of normabaric hyperoxia treatment on neuronal damage ...

    Indian Academy of Sciences (India)

    Traumatic brain injury (TBI) causes significant mortality in most developing countries worldwide. At present, it is imperative to identify a treatment to address the devastating post-TBI consequences. Therefore, the present study has been performed to assess the specific effect of immediate exposure to normabaric hyperoxia ...

  15. Ketogenic Diet Provides Neuroprotective Effects against Ischemic Stroke Neuronal Damages

    Directory of Open Access Journals (Sweden)

    Sheida Shaafi

    2014-12-01

    Full Text Available Ischemic stroke is a leading cause of death and disability in the world. Many mechanisms contribute in cell death in ischemic stroke. Ketogenic diet which has been successfully used in the drug-resistant epilepsy has been shown to be effective in many other neurologic disorders. The mechanisms underlying of its effects are not well studied, but it seems that its neuroprotective ability is mediated at least through alleviation of excitotoxicity, oxidative stress and apoptosis events. On the basis of these mechanisms, it is postulated that ketogenic diet could provide benefits to treatment of cerebral ischemic injuries.

  16. Kramers-Moyal expansion for stochastic differential equations with single and multiple delays: Applications to financial physics and neurophysics

    International Nuclear Information System (INIS)

    Frank, T.D.

    2007-01-01

    We present a generalized Kramers-Moyal expansion for stochastic differential equations with single and multiple delays. In particular, we show that the delay Fokker-Planck equation derived earlier in the literature is a special case of the proposed Kramers-Moyal expansion. Applications for bond pricing and a self-inhibitory neuron model are discussed

  17. Neuromorphic Silicon Neuron Circuits

    Science.gov (United States)

    Indiveri, Giacomo; Linares-Barranco, Bernabé; Hamilton, Tara Julia; van Schaik, André; Etienne-Cummings, Ralph; Delbruck, Tobi; Liu, Shih-Chii; Dudek, Piotr; Häfliger, Philipp; Renaud, Sylvie; Schemmel, Johannes; Cauwenberghs, Gert; Arthur, John; Hynna, Kai; Folowosele, Fopefolu; Saighi, Sylvain; Serrano-Gotarredona, Teresa; Wijekoon, Jayawan; Wang, Yingxue; Boahen, Kwabena

    2011-01-01

    Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain–machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance-based Hodgkin–Huxley models to bi-dimensional generalized adaptive integrate and fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips. PMID:21747754

  18. Neuromorphic silicon neuron circuits

    Directory of Open Access Journals (Sweden)

    Giacomo eIndiveri

    2011-05-01

    Full Text Available Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain-machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance based Hodgkin-Huxley models to bi-dimensional generalized adaptive Integrate and Fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips.

  19. N-Methyl-d-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection.

    Science.gov (United States)

    Costa, Vivian V; Del Sarto, Juliana L; Rocha, Rebeca F; Silva, Flavia R; Doria, Juliana G; Olmo, Isabella G; Marques, Rafael E; Queiroz-Junior, Celso M; Foureaux, Giselle; Araújo, Julia Maria S; Cramer, Allysson; Real, Ana Luíza C V; Ribeiro, Lucas S; Sardi, Silvia I; Ferreira, Anderson J; Machado, Fabiana S; de Oliveira, Antônio C; Teixeira, Antônio L; Nakaya, Helder I; Souza, Danielle G; Ribeiro, Fabiola M; Teixeira, Mauro M

    2017-04-25

    Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N -methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration. IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment. Copyright © 2017 Costa et al.

  20. Distinct subsets of nucleus basalis neurons exhibit similar sensitivity to excitotoxicity

    NARCIS (Netherlands)

    Harkany, Tibor; Varga, Csaba; Grosche, Jens; Mulder, Jan; Luiten, Paul G.M.; Hortobágyi, Tibor; Penke, Botond; Härtig, Wolfgang

    2002-01-01

    Excitotoxic lesions in the magnocellular nucleus basalis (MBN) lead to a significant damage of cholinergic neurons concomitant with increased amyloid precursor protein (APP) expression in the cerebral cortex. However, the sensitivity of non-cholinergic neurons to excitotoxicity, and changes of APP

  1. Kv2 Channel Regulation of Action Potential Repolarization and Firing Patterns in Superior Cervical Ganglion Neurons and Hippocampal CA1 Pyramidal Neurons

    Science.gov (United States)

    Liu, Pin W.

    2014-01-01

    Kv2 family “delayed-rectifier” potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60–80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from −70 mV, but not −80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at −70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation. PMID:24695716

  2. Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

    Science.gov (United States)

    Tepper, James M; Wilson, Charles J; Koós, Tibor

    2008-08-01

    There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of

  3. Repair and fixation of potentially lethal damage (PLD) as demonstrated by delayed plating or incubation with araA in contact inhibited refed plateau-phase C3H mouse embryo 10T1/2 cells grown in the presence of BrdUrd

    International Nuclear Information System (INIS)

    Iliakis, G.; Wright, E.; Ngo, F.Q.H.

    1987-01-01

    CH3 mouse 10 T 1/2 cells showing strong inhibition of growth at confluency were grown under daily refeeding in the presence of BrdUrd (from 0 to 1 μM) and exposed to γ-rays either while exponentially growing or in the plateau phase. An increase in radiosensitivity was observed in both growth conditions mainly reflected by a reduction in Dq. Greater radiosensitization was observed in exponentially growing than in plateau-phase cells, and 3-4 times higher BrdUrd concentrations were required in plateau-phase cells for similar potentiation in killing. This effect could not be entirely attributed to a reduction in BrdUrd incorporation since measurements with 3 H-BrdUrd showed reductions in incorporation between only 17-47% in plateau-phase cells. The rate of repair of potentially lethal damage (PLD) as demonstrated by delayed plating was not affected by the incorporation of BrdUrd, but the amount of repair (measured as the relative increase in cell survival) was higher for BrdUrd containing cells. Post-irradiation treatment of cells in the plateau-phase (no BrdUrd) with 9-β-D-arabinofuranosyladenine (araA) caused fixation of radiation-induced PLD. AraA treatment of cells grown in the presence of various amounts of BrdUrd also caused fixation of PLD, but resulted in survival levels similar to those observed with cells growing in BrdUrd-free medium. This result indicates that BrdUrd mediated radiosensitization cannot be observed when cells are prevented from repairing PLD by postirradiation incubation with araA. Based on these findings we propose that the mechanism of radiosensitization by BrdUrd incorporation might be, by increasing probability of fixation, mediated by the postirrdiation progression of cells through the cycle, of a sector of PLD also sensitive to post-irradiation treatment with araA. For this sector of PLD the term α-PLD has been proposed. (orig.)

  4. ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation.

    Science.gov (United States)

    Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C; Chen, Adam; Tamrazian, Eric; Babaniyi, Olusegun; Selig, Martin; Hynynen, Meri; Woolf, Clifford J; Brown, Robert H

    2014-01-28

    ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.

  5. Effect of Phase Response Curve Skew on Synchronization with and without Conduction Delays

    Directory of Open Access Journals (Sweden)

    Carmen eCanavier

    2013-12-01

    Full Text Available A central problem in cortical processing including sensory binding and attentional gating is how neurons can synchronize their responses with zero or near-zero time lag. For a spontaneously firing neuron, an input from another neuron can delay or advance the next spike by different amounts depending upon the timing of the input relative to the previous spike. This information constitutes the phase response curve (PRC. We present a simple graphical method for determining the effect of PRC shape on synchronization tendencies and illustrate it using type 1 PRCs, which consist entirely of advances (delays in response to excitation (inhibition. We obtained the following generic solutions for type 1 PRCs, which include the pulse coupled leaky integrate and fire model. For pairs with mutual excitation, exact synchrony can be stable for strong coupling because of the stabilizing effect of the causal limit region of the PRC in which an input triggers a spike immediately upon arrival. However, synchrony is unstable for short delays, because delayed inputs arrive during a refractory period and cannot trigger an immediate spike. Right skew destabilizes antiphase and enables modes with time lags that grow as the conduction delay is increased. Therefore, right skew favors near-synchrony at short conduction delays and a gradual transition between synchrony and antiphase for pairs coupled by mutual excitation. For pairs with mutual inhibition, zero time lag synchrony is stable for conduction delays ranging from zero to a substantial fraction of the period for pairs. However, for right skew there is a preferred antiphase mode at short delays. In contrast to mutual excitation, left skew destabilizes antiphase for mutual inhibition so that synchrony dominates at short delays as well. These pairwise synchronization tendencies constrain the synchronization properties of neurons embedded in larger networks.

  6. Role of neuronal and inducible nitric oxide synthases in the guinea pig ileum myenteric plexus during in vitro ischemia and reperfusion.

    Science.gov (United States)

    Giaroni, C; Marchet, S; Carpanese, E; Prandoni, V; Oldrini, R; Bartolini, B; Moro, E; Vigetti, D; Crema, F; Lecchini, S; Frigo, G

    2013-02-01

    Intestinal ischemia and reperfusion (I/R) injury leads to abnormalities in motility, namely delay of transit, caused by damage to myenteric neurons. Alterations of the nitrergic transmission may occur in these conditions. This study investigated whether an in vitro I/R injury may affect nitric oxide (NO) production from the myenteric plexus of the guinea pig ileum and which NO synthase (NOS) isoform is involved. The distribution of the neuronal (n) and inducible (i) NOS was determined by immunohistochemistry during 60 min of glucose/oxygen deprivation (in vitro ischemia) followed by 60 min of reperfusion. The protein and mRNA levels of nNOS and iNOS were investigated by Western-immunoblotting and real time RT-PCR, respectively. NO levels were quantified as nitrite/nitrate. After in vitro I/R the proportion of nNOS-expressing neurons and protein levels remained unchanged. nNOS mRNA levels increased 60 min after inducing ischemia and in the following 5 min of reperfusion. iNOS-immunoreactive neurons, protein and mRNA levels were up-regulated during the whole I/R period. A significant increase of nitrite/nitrate levels was observed in the first 5 min after inducing I/R and was significantly reduced by N(ω) -propyl-l-arginine and 1400 W, selective inhibitors of nNOS and iNOS, respectively. Our data demonstrate that both iNOS and nNOS represent sources for NO overproduction in ileal myenteric plexus during I/R, although iNOS undergoes more consistent changes suggesting a more relevant role for this isoform in the alterations occurring in myenteric neurons following I/R. © 2012 Blackwell Publishing Ltd.

  7. Auditory stimuli elicit hippocampal neuronal responses during sleep

    Directory of Open Access Journals (Sweden)

    Ekaterina eVinnik

    2012-06-01

    Full Text Available To investigate how hippocampal neurons code behaviorally salient stimuli, we recorded from neurons in the CA1 region of hippocampus in rats while they learned to associate the presence of sound with water reward. Rats learned to alternate between two reward ports at which, in 50 percent of the trials, sound stimuli were presented followed by water reward after a 3-second delay. Sound at the water port predicted subsequent reward delivery in 100 percent of the trials and the absence of sound predicted reward omission. During this task, 40% of recorded neurons fired differently according to which of the 2 reward ports the rat was visiting. A smaller fraction of neurons demonstrated onset response to sound/nosepoke (19% and reward delivery (24%. When the sounds were played during passive wakefulness, 8% of neurons responded with short latency onset responses; 25% of neurons responded to sounds when they were played during sleep. Based on the current findings and the results of previous experiments we propose the existence of two types of hippocampal neuronal responses to sounds: sound-onset responses with very short latency and longer-lasting sound-specific responses that are likely to be present when the animal is actively engaged in the task. During sleep the short-latency responses in hippocampus are intermingled with sustained activity which in the current experiment was detected for 1-2 seconds.

  8. NeuronBank: a tool for cataloging neuronal circuitry

    Directory of Open Access Journals (Sweden)

    Paul S Katz

    2010-04-01

    Full Text Available The basic unit of any nervous system is the neuron. Therefore, understanding the operation of nervous systems ultimately requires an inventory of their constituent neurons and synaptic connectivity, which form neural circuits. The presence of uniquely identifiable neurons or classes of neurons in many invertebrates has facilitated the construction of cellular-level connectivity diagrams that can be generalized across individuals within a species. Homologous neurons can also be recognized across species. Here we describe NeuronBank.org, a web-based tool that we are developing for cataloging, searching, and analyzing neuronal circuitry within and across species. Information from a single species is represented in an individual branch of NeuronBank. Users can search within a branch or perform queries across branches to look for similarities in neuronal circuits across species. The branches allow for an extensible ontology so that additional characteristics can be added as knowledge grows. Each entry in NeuronBank generates a unique accession ID, allowing it to be easily cited. There is also an automatic link to a Wiki page allowing an encyclopedic explanation of the entry. All of the 44 previously published neurons plus one previously unpublished neuron from the mollusc, Tritonia diomedea, have been entered into a branch of NeuronBank as have 4 previously published neurons from the mollusc, Melibe leonina. The ability to organize information about neuronal circuits will make this information more accessible, ultimately aiding research on these important models.

  9. Mechanisms of motor recovery after subtotal spinal cord injury: insights from the study of mice carrying a mutation (WldS) that delays cellular responses to injury.

    Science.gov (United States)

    Zhang, Z; Guth, L; Steward, O

    1998-01-01

    Partial lesions of the mammalian spinal cord result in an immediate motor impairment that recovers gradually over time; however, the cellular mechanisms responsible for the transient nature of this paralysis have not been defined. A unique opportunity to identify those injury-induced cellular responses that mediate the recovery of function has arisen from the discovery of a unique mutant strain of mice in which the onset of Wallerian degeneration is dramatically delayed. In this strain of mice (designated WldS for Wallerian degeneration, slow), many of the cellular responses to spinal cord injury are also delayed. We have used this experimental animal model to evaluate possible causal relationships between these delayed cellular responses and the onset of functional recovery. For this purpose, we have compared the time course of locomotor recovery in C57BL/6 (control) mice and in WldS (mutant) mice by hemisecting the spinal cord at T8 and evaluating locomotor function at daily postoperative intervals. The time course of locomotor recovery (as determined by the Tarlov open-field walking procedure) was substantially delayed in mice carrying the WldS mutation: C57BL/6 control mice began to stand and walk within 6 days (mean Tarlov score of 4), whereas mutant mice did not exhibit comparable locomotor function until 16 days postoperatively. (a) The rapid return of locomotor function in the C57BL/6 mice suggests that the recovery resulted from processes of functional plasticity rather than from regeneration or collateral sprouting of nerve fibers. (b) The marked delay in the return of locomotor function in WldS mice indicates that the processes of neuroplasticity are induced by degenerative changes in the damaged neurons. (c) These strains of mice can be effectively used in future studies to elucidate the specific biochemical and physiological alterations responsible for inducing functional plasticity and restoring locomotor function after spinal cord injury.

  10. Modular networks with delayed coupling: Synchronization and frequency control

    Science.gov (United States)

    Maslennikov, Oleg V.; Nekorkin, Vladimir I.

    2014-07-01

    We study the collective dynamics of modular networks consisting of map-based neurons which generate irregular spike sequences. Three types of intramodule topology are considered: a random Erdös-Rényi network, a small-world Watts-Strogatz network, and a scale-free Barabási-Albert network. The interaction between the neurons of different modules is organized by relatively sparse connections with time delay. For all the types of the network topology considered, we found that with increasing delay two regimes of module synchronization alternate with each other: inphase and antiphase. At the same time, the average rate of collective oscillations decreases within each of the time-delay intervals corresponding to a particular synchronization regime. A dual role of the time delay is thus established: controlling a synchronization mode and degree and controlling an average network frequency. Furthermore, we investigate the influence on the modular synchronization by other parameters: the strength of intermodule coupling and the individual firing rate.

  11. Delayed child-bearing.

    Science.gov (United States)

    Johnson, Jo-Ann; Tough, Suzanne

    2012-01-01

    To provide an overview of delayed child-bearing and to describe the implications for women and health care providers. Delayed child-bearing, which has increased greatly in recent decades, is associated with an increased risk of infertility, pregnancy complications, and adverse pregnancy outcome. This guideline provides information that will optimize the counselling and care of Canadian women with respect to their reproductive choices. Maternal age is the most important determinant of fertility, and obstetric and perinatal risks increase with maternal age. Many women are unaware of the success rates or limitations of assisted reproductive technology and of the increased medical risks of delayed child-bearing, including multiple births, preterm delivery, stillbirth, and Caesarean section. This guideline provides a framework to address these issues. Studies published between 2000 and August 2010 were retrieved through searches of PubMed and the Cochrane Library using appropriate key words (delayed child-bearing, deferred pregnancy, maternal age, assisted reproductive technology, infertility, and multiple births) and MeSH terms (maternal age, reproductive behaviour, fertility). The Internet was also searched using similar key words, and national and international medical specialty societies were searched for clinical practice guidelines and position statements. Data were extracted based on the aims, sample, authors, year, and results. The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS 1. Women who delay child-bearing are at increased risk of infertility. Prospective parents, especially women, should know that their fecundity and fertility begin to decline significantly after 32 years of age. Prospective parents should know that assisted reproductive technologies cannot guarantee a live birth or completely

  12. Neuronal avalanches and learning

    Energy Technology Data Exchange (ETDEWEB)

    Arcangelis, Lucilla de, E-mail: dearcangelis@na.infn.it [Department of Information Engineering and CNISM, Second University of Naples, 81031 Aversa (Italy)

    2011-05-01

    Networks of living neurons represent one of the most fascinating systems of biology. If the physical and chemical mechanisms at the basis of the functioning of a single neuron are quite well understood, the collective behaviour of a system of many neurons is an extremely intriguing subject. Crucial ingredient of this complex behaviour is the plasticity property of the network, namely the capacity to adapt and evolve depending on the level of activity. This plastic ability is believed, nowadays, to be at the basis of learning and memory in real brains. Spontaneous neuronal activity has recently shown features in common to other complex systems. Experimental data have, in fact, shown that electrical information propagates in a cortex slice via an avalanche mode. These avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems and successful models have been developed to describe their behaviour. In this contribution we discuss a statistical mechanical model for the complex activity in a neuronal network. The model implements the main physiological properties of living neurons and is able to reproduce recent experimental results. Then, we discuss the learning abilities of this neuronal network. Learning occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. The system is able to learn all the tested rules, in particular the exclusive OR (XOR) and a random rule with three inputs. The learning dynamics exhibits universal features as function of the strength of plastic adaptation. Any rule could be learned provided that the plastic adaptation is sufficiently slow.

  13. Neuronal avalanches and learning

    International Nuclear Information System (INIS)

    Arcangelis, Lucilla de

    2011-01-01

    Networks of living neurons represent one of the most fascinating systems of biology. If the physical and chemical mechanisms at the basis of the functioning of a single neuron are quite well understood, the collective behaviour of a system of many neurons is an extremely intriguing subject. Crucial ingredient of this complex behaviour is the plasticity property of the network, namely the capacity to adapt and evolve depending on the level of activity. This plastic ability is believed, nowadays, to be at the basis of learning and memory in real brains. Spontaneous neuronal activity has recently shown features in common to other complex systems. Experimental data have, in fact, shown that electrical information propagates in a cortex slice via an avalanche mode. These avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems and successful models have been developed to describe their behaviour. In this contribution we discuss a statistical mechanical model for the complex activity in a neuronal network. The model implements the main physiological properties of living neurons and is able to reproduce recent experimental results. Then, we discuss the learning abilities of this neuronal network. Learning occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. The system is able to learn all the tested rules, in particular the exclusive OR (XOR) and a random rule with three inputs. The learning dynamics exhibits universal features as function of the strength of plastic adaptation. Any rule could be learned provided that the plastic adaptation is sufficiently slow.

  14. Delaying information search

    Directory of Open Access Journals (Sweden)

    Yaniv Shani

    2012-11-01

    Full Text Available In three studies, we examined factors that may temporarily attenuate information search. People are generally curious and dislike uncertainty, which typically encourages them to look for relevant information. Despite these strong forces that promote information search, people sometimes deliberately delay obtaining valuable information. We find they may do so when they are concerned that the information might interfere with future pleasurable activities. Interestingly, the decision to search or to postpone searching for information is influenced not only by the value and importance of the information itself but also by well-being maintenance goals related to possible detrimental effects that negative knowledge may have on unrelated future plans.

  15. Multiple synchronization transitions in scale-free neuronal networks with electrical and chemical hybrid synapses

    International Nuclear Information System (INIS)

    Liu, Chen; Wang, Jiang; Wang, Lin; Yu, Haitao; Deng, Bin; Wei, Xile; Tsang, Kaiming; Chan, Wailok

    2014-01-01

    Highlights: • Synchronization transitions in hybrid scale-free neuronal networks are investigated. • Multiple synchronization transitions can be induced by the time delay. • Effect of synchronization transitions depends on the ratio of the electrical and chemical synapses. • Coupling strength and the density of inter-neuronal links can enhance the synchronization. -- Abstract: The impacts of information transmission delay on the synchronization transitions in scale-free neuronal networks with electrical and chemical hybrid synapses are investigated. Numerical results show that multiple appearances of synchronization regions transitions can be induced by different information transmission delays. With the time delay increasing, the synchronization of neuronal activities can be enhanced or destroyed, irrespective of the probability of chemical synapses in the whole hybrid neuronal network. In particular, for larger probability of electrical synapses, the regions of synchronous activities appear broader with stronger synchronization ability of electrical synapses compared with chemical ones. Moreover, it can be found that increasing the coupling strength can promote synchronization monotonously, playing the similar role of the increasing the probability of the electrical synapses. Interestingly, the structures and parameters of the scale-free neuronal networks, especially the structural evolvement plays a more subtle role in the synchronization transitions. In the network formation process, it is found that every new vertex is attached to the more old vertices already present in the network, the more synchronous activities will be emerge

  16. Vehicle barrier with access delay

    Science.gov (United States)

    Swahlan, David J; Wilke, Jason

    2013-09-03

    An access delay vehicle barrier for stopping unauthorized entry into secure areas by a vehicle ramming attack includes access delay features for preventing and/or delaying an adversary from defeating or compromising the barrier. A horizontally deployed barrier member can include an exterior steel casing, an interior steel reinforcing member and access delay members disposed within the casing and between the casing and the interior reinforcing member. Access delay members can include wooden structural lumber, concrete and/or polymeric members that in combination with the exterior casing and interior reinforcing member act cooperatively to impair an adversarial attach by thermal, mechanical and/or explosive tools.

  17. Distinct neuronal interactions in anterior inferotemporal areas of macaque monkeys during retrieval of object association memory.

    Science.gov (United States)

    Hirabayashi, Toshiyuki; Tamura, Keita; Takeuchi, Daigo; Takeda, Masaki; Koyano, Kenji W; Miyashita, Yasushi

    2014-07-09

    In macaque monkeys, the anterior inferotemporal cortex, a region crucial for object memory processing, is composed of two adjacent, hierarchically distinct areas, TE and 36, for which different functional roles and neuronal responses in object memory tasks have been characterized. However, it remains unknown how the neuronal interactions differ between these areas during memory retrieval. Here, we conducted simultaneous recordings from multiple single-units in each of these areas while monkeys performed an object association memory task and examined the inter-area differences in neuronal interactions during the delay period. Although memory neurons showing sustained activity for the presented cue stimulus, cue-holding (CH) neurons, interacted with each other in both areas, only those neurons in area 36 interacted with another type of memory neurons coding for the to-be-recalled paired associate (pair-recall neurons) during memory retrieval. Furthermore, pairs of CH neurons in area TE showed functional coupling in response to each individual object during memory retention, whereas the same class of neuron pairs in area 36 exhibited a comparable strength of coupling in response to both associated objects. These results suggest predominant neuronal interactions in area 36 during the mnemonic processing, which may underlie the pivotal role of this brain area in both storage and retrieval of object association memory. Copyright © 2014 the authors 0270-6474/14/349377-12$15.00/0.

  18. Endogenous fields enhanced stochastic resonance in a randomly coupled neuronal network

    International Nuclear Information System (INIS)

    Deng, Bin; Wang, Lin; Wang, Jiang; Wei, Xi-le; Yu, Hai-tao

    2014-01-01

    Highlights: • We study effects of endogenous fields on stochastic resonance in a neural network. • Stochastic resonance can be notably enhanced by endogenous field feedback. • Endogenous field feedback delay plays a vital role in stochastic resonance. • The parameters of low-passed filter play a subtle role in SR. - Abstract: Endogenous field, evoked by structured neuronal network activity in vivo, is correlated with many vital neuronal processes. In this paper, the effects of endogenous fields on stochastic resonance (SR) in a randomly connected neuronal network are investigated. The network consists of excitatory and inhibitory neurons and the axonal conduction delays between neurons are also considered. Numerical results elucidate that endogenous field feedback results in more rhythmic macroscope activation of the network for proper time delay and feedback coefficient. The response of the network to the weak periodic stimulation can be notably enhanced by endogenous field feedback. Moreover, the endogenous field feedback delay plays a vital role in SR. We reveal that appropriately tuned delays of the feedback can either induce the enhancement of SR, appearing at every integer multiple of the weak input signal’s oscillation period, or the depression of SR, appearing at every integer multiple of half the weak input signal’s oscillation period for the same feedback coefficient. Interestingly, the parameters of low-passed filter which is used in obtaining the endogenous field feedback signal play a subtle role in SR

  19. Synchronous bursts on scale-free neuronal networks with attractive and repulsive coupling.

    Directory of Open Access Journals (Sweden)

    Qingyun Wang

    Full Text Available This paper investigates the dependence of synchronization transitions of bursting oscillations on the information transmission delay over scale-free neuronal networks with attractive and repulsive coupling. It is shown that for both types of coupling, the delay always plays a subtle role in either promoting or impairing synchronization. In particular, depending on the inherent oscillation period of individual neurons, regions of irregular and regular propagating excitatory fronts appear intermittently as the delay increases. These delay-induced synchronization transitions are manifested as well-expressed minima in the measure for spatiotemporal synchrony. For attractive coupling, the minima appear at every integer multiple of the average oscillation period, while for the repulsive coupling, they appear at every odd multiple of the half of the average oscillation period. The obtained results are robust to the variations of the dynamics of individual neurons, the system size, and the neuronal firing type. Hence, they can be used to characterize attractively or repulsively coupled scale-free neuronal networks with delays.

  20. Regulation of Neuronal Protein Trafficking and Translocation by SUMOylation

    Directory of Open Access Journals (Sweden)

    Jeremy M. Henley

    2012-05-01

    Full Text Available Post-translational modifications of proteins are essential for cell function. Covalent modification by SUMO (small ubiquitin-like modifier plays a role in multiple cell processes, including transcriptional regulation, DNA damage repair, protein localization and trafficking. Factors affecting protein localization and trafficking are particularly crucial in neurons because of their polarization, morphological complexity and functional specialization. SUMOylation has emerged as a major mediator of intranuclear and nucleo-cytoplasmic translocations of proteins involved in critical pathways such as circadian rhythm, apoptosis and protein degradation. In addition, SUMO-regulated re-localization of extranuclear proteins is required to sustain neuronal excitability and synaptic transmission. Thus, SUMOylation is a key arbiter of neuronal viability and function. Here, we provide an overview of recent advances in our understanding of regulation of neuronal protein localization and translocation by SUMO and highlight exciting areas of ongoing research.

  1. Simple and effective graphene laser processing for neuron patterning application

    Science.gov (United States)

    Lorenzoni, Matteo; Brandi, Fernando; Dante, Silvia; Giugni, Andrea; Torre, Bruno

    2013-06-01

    A straightforward fabrication technique to obtain patterned substrates promoting ordered neuron growth is presented. Chemical vapor deposition (CVD) single layer graphene (SLG) was machined by means of single pulse UV laser ablation technique at the lowest effective laser fluence in order to minimize laser damage effects. Patterned substrates were then coated with poly-D-lysine by means of a simple immersion in solution. Primary embryonic hippocampal neurons were cultured on our substrate, demonstrating an ordered interconnected neuron pattern mimicking the pattern design. Surprisingly, the functionalization is more effective on the SLG, resulting in notably higher alignment for neuron adhesion and growth. Therefore the proposed technique should be considered a valuable candidate to realize a new generation of highly specialized biosensors.

  2. Delayed rule following.

    Science.gov (United States)

    Schmitt, D R

    2001-01-01

    Although the elements of a fully stated rule (discriminative stimulus [S(D)], some behavior, and a consequence) can occur nearly contemporaneously with the statement of the rule, there is often a delay between the rule statement and the S(D). The effects of this delay on rule following have not been studied in behavior analysis, but they have been investigated in rule-like settings in the areas of prospective memory (remembering to do something in the future) and goal pursuit. Discriminative events for some behavior can be event based (a specific setting stimulus) or time based. The latter are more demanding with respect to intention following and show age-related deficits. Studies suggest that the specificity with which the components of a rule (termed intention) are stated has a substantial effect on intention following, with more detailed specifications increasing following. Reminders of an intention, too, are most effective when they refer specifically to both the behavior and its occasion. Covert review and written notes are two effective strategies for remembering everyday intentions, but people who use notes appear not to be able to switch quickly to covert review. By focusing on aspects of the setting and rule structure, research on prospective memory and goal pursuit expands the agenda for a more complete explanation of rule effects.

  3. Pseudotumoral delayed cerebral radionecrosis

    International Nuclear Information System (INIS)

    Ciaudo-Lacroix, C.; Lapresle, J.

    1985-01-01

    A 60 year-old woman with a scalp epithelioma underwent radiotherapy, the dose being 57 Gray. A first epileptic seizure occurred twenty months later. Neurological examination revealed signs of left hemisphere involvement. γEG, angiography, CT scans, demonstrated a pseudotumoral avascular process. On account of the localisation, the patient being right-handed, no surgical procedure was performed. In spite of corticotherapy and anticonvulsive treatment, seizures recurred and neurological signs slowly progressed. The patient died, 22 months after the first seizure, of an associated disseminated carcinoma with cachexia. Neuropathological examination showed a massive lesion presenting all the features of delayed radionecrosis in the left hemisphere: situated mainly in the white matter; numerous vascular abnormalities; wide-spread demyelination; disappearance of oligoglial cells. The Authors recall the clinical and anatomical aspects of this condition for which the only successful treatment is surgical removal when location and size of the lesion permit. Finally, the mechanisms which have been proposed to explain this delayed cerebral radionecrosis are discussed [fr

  4. Pseudotumoral delayed cerebral radionecrosis

    Energy Technology Data Exchange (ETDEWEB)

    Ciaudo-Lacroix, C; Lapresle, J [Centre Hospitalier de Bicetre, 94 - Le Kremlin-Bicetre (France)

    1985-01-01

    A 60 year-old woman with a scalp epithelioma underwent radiotherapy, the dose being 57 Gray. A first epileptic seizure occurred twenty months later. Neurological examination revealed signs of left hemisphere involvement. ..gamma..EG, angiography, CT scans, demonstrated a pseudotumoral avascular process. On account of the localisation, the patient being right-handed, no surgical procedure was performed. In spite of corticotherapy and anticonvulsive treatment, seizures recurred and neurological signs slowly progressed. The patient died, 22 months after the first seizure, of an associated disseminated carcinoma with cachexia. Neuropathological examination showed a massive lesion presenting all the features of delayed radionecrosis in the left hemisphere: situated mainly in the white matter; numerous vascular abnormalities; wide-spread demyelination; disappearance of oligoglial cells. The Authors recall the clinical and anatomical aspects of this condition for which the only successful treatment is surgical removal when location and size of the lesion permit. Finally, the mechanisms which have been proposed to explain this delayed cerebral radionecrosis are discussed.

  5. Type a niemann-pick disease. Description of three cases with delayed myelination.

    Science.gov (United States)

    D'Amico, A; Sibilio, M; Caranci, F; Bartiromo, F; Taurisano, R; Balivo, F; Melis, D; Parenti, G; Cirillo, S; Elefante, R; Brunetti, A

    2008-06-03

    We describe three patients with type A Niemann-Pick disease (NPD-A). NPD-A is an autosomal recess