Expression Profiling of Genes Involved in the Development and Function of Skeletal Muscles in Ts1Cje Mouse Model of Down Syndrome

@#Introduction: Down syndrome (DS) is caused by trisomy of human chromosome 21 (HSA21). Motor dysfunction due to hypotonia has limited labour productivity and have significant effects on socio-economic status in DS individuals. Ts1Cje, a mouse model of DS that exhibits muscle weakness was employed, to investigate the expression profile of selected trisomic and disomic genes involved in skeletal muscle structure and function. Methods: Quadriceps and triceps were harvested from the Ts1Cje (C57BL/6) postnatal day 60-70 mice and corresponding wild-type littermates. Total RNA extracted from these tissues was subjected for quantitative expression profiling of three trisomic genes (Itsn1, Synj1 and Rcan1) involved in neurotransmission and six disomic genes (Lamc1, Leprel1, Myl6b, Msn, Pgm5 and Tmod1) essential for maintenance of muscle structure and function. Real-time quantitative PCR method was used for the profiling. Results: Differential gene expression in DS is reflected by 1.5-fold or more increase in the level of expression as predicted by the gene dosage imbalance hypothesis. The analysis showed no significant changes in the expression level of trisomic genes (Itsn1, Synj1 and Rcan1). On contrary, disomic genes, Leprel1 and Pgm5, were upregulated for more than 1.5-fold in DS quadriceps whereas Lamc1, Myl6b and Pgm5 were upregulated for more than 1.5 fold in DS triceps as compared to the wild-type group. Conclusions: Our findings suggest that the dysregulation of Lamc1, Leprel1, Myl6b and Pgm5 genes is associated to muscle weakness seen in Ts1Cje and may play a role in molecular pathogenesis of muscle weakness in DS.

Study of Changes in Sympathetic and Parasympathetic Autonomic Functions in Patients of Depression in Rural Western Maharashtra

Introduction The deficiency of monoaminergic neurotransmission is important key pathology of depression. With these changes in excitatory neurotransmission in brain it can be hypothesised that this alteration may result into changes in various sympathetic and parasympathetic parameters like Blood pressure, Heart rate and expiratory and inspiratory ratio. Methodology It is a Case Control Observational Study done in collaboration with department of Psychaitry and all patients of depression satisfying the inclusion and exclusion criteria were studied for the changes in Blood pressure using handgrip test and Orthostatic Hypotensive Test while changes resting heart rate was recorded. Result and Conclusion There was increase in heart rate found in depression whereas blood pressure diastolic and systolic were found to be lower than a normal individual.

The potential role of myostatin and neurotransmission genes in elite sport performances.

Elite athletes are those who represent their sport at such major competition as the Olympic Games or World contests. The most outstanding athletes appear to emerge as a result of endogenous biologic characteristics interacting with exogenous influences of the environment, often described as a ‘Nature and Nurture’ struggle. In this work, we assessed the contribution given by 4 genes involved in muscles development (MSTN) and behavioural insights (5HTT, DAT and MAOA) to athletic performances. As for neurotransmission, 5HTT, DAT and MAOA genes have been considered as directly involved in the management of aggressiveness and anxiety. Genotypes and allelic frequencies of 5HTTLPR, MAOA-u VNTR, DAT VNTR and MSTN K153R were determined in 50 elite athletes and compared with 100 control athletes. In this work we found a significant correlation between the dopamine transporter genotype 9/9 and allele 9 and elite sport performances. On the contrary, no association was found between muscle development regulation or serotonin pathway and elite performances. Our data, for the first time, suggest a strong role of dopamine neurotransmitter in determining sport success, highlighting the role of emotional control and psycological management to reach high-level performances.

Effects of FXR gene deletion on neurobehaviors and neurotransmission systems in female mice / 中国药理学通报

Aim To investigate how Farnesoid X re-ceptor (FXR),a nuclear hormone receptor,acts on neurological behaviors such as emotion,social behav-ior,memory and so on.Methods FXR’s function in central nervous system was evaluated by conducting a battery of behavioral tests including elevated plus maze test (EPMT),forced-swimming test (FST),social in-teraction test (SIT ), and passive avoidance test (PAT),and the contents of neurotransmitters were de-termined by the LC-MS /MS method in FXR knockout (KO)female mice and their wild-type controls.Re-sults FXR KO mice showed significantly increased immobility time in FST (P <0.01 ),and it showed in-creased tendency to enter the open arms in EMPT (P<0.01 ).The number of probing the open arms by FXR KO mice was more than that of the controls.Mo-reover,in SIT,FXR KO mice had remarkably in-creased sniffing interactions with the stranger mouse in the same cage (P <0.01 ).But in PAT,the latency for FXR KO mice to enter the dark chamber on the test day and the number of FXR KO mice to enter the dark chamber didn’t differ from those wild-type mice.In hippocampus,the contents of GABA,Glu,and NE were decreased prominently in FXR KO mice (P <0.05,P <0.05 and P <0.01 ,respectively)as well as the ratio of GABA to Glu (P <0.05).But in pre-frontal cortex,none of the neurotransmitters examined showed any difference between FXR KO mice and their controls.Conclusion FXR may be involved in main-tenance of the homeostasis of neural transmission in the central nervous system,thereby influences the emotion-al and social behavior in animals.

Peripheral Biomarker Candidates of Posttraumatic Stress Disorder

There is high variability in the manifestation of physical and mental health problems following exposure to trauma and disaster. Although most people may show a range of acute symptoms in the aftermath of traumatic events, chronic and persistent mental disorders may not be developed in all individuals who were exposed to traumatic events. The most common long-term pathological consequence after trauma exposure is posttraumatic stress disorder (PTSD). However, comorbid conditions including depression, anxiety disorder, substance use-related problems, and a variety of other symptoms may frequently be observed in individuals with trauma exposure. Post-traumatic syndrome (PTS) is defined collectively as vast psychosocial problems that could be experienced in response to traumatic events. It is important to predict who will continue to suffer from physical and mental health problems and who will recover following trauma exposure. However, given the heterogeneity and variability in symptom manifestations, it is difficult to find identify biomarkers which predict the development of PTSD. In this review, we will summarize the results of recent studies with regard to putative biomarkers of PTSD and suggest future research directions for biomarker discovery for PTSD.

Novedad y modulación de la memoria: Mecanismos neurobiológicos implicados / Novelty and modulation of memory: Neurobiological mechanisms involved

La exposición a estímulos novedosos es un protocolo simple de emplear que involucra múltiples sistemas y procesos de memoria tales como codificación, consolidación y recuperación de la información. Esto hace plausible de emplearlo como un tratamiento útil para estudiar los mecanismos comportamentales, fisiológicos y moleculares implicados en esta función cognitiva. Se presentan estudios en modelos animales que dan cuenta de cómo la exploración de un ambiente novedoso puede ser útil para mejorar o deteriorar la memoria, en diferentes períodos ontogenéticos. Además, se presentan investigaciones que demuestran la participación de los diversos sistemas de neurotransmisión en este fenómeno así como los mecanismos moleculares implicados en este tipo de tratamiento. De este modo este tipo de tratamiento, no invasivo y sencillo de aplicar, adquiere relevancia para la ciencia aplicada como una posible alternativa para el desarrollo de estrategias de intervención en la temática.

Exposure to novel stimuli is a simple procedure to use that involved several systems and memory processes, such as acquisition, consolidation and recall of the information. Which make it a possible treatment to study the behavioral, physiological and molecular mechanism involved in this cognitive function. Novelty detection plays an important role in adaptation to the environmental changes and in the avoidance of possible dangerous. A novel stimulus elicits a response that will produce habituation when it becomes familiar. When animals are first exposed to a novel environment they explore it actively and in parallel they compare it to previous experiences, stored in its memory to evaluate the degree of novelty. On one side, it includes the response to novelty, activation, and stress-related factors and on the other hand, a response that decreases as the environment becomes familiar, which requires different processes related to learning, recall and recognition. Also, multiple studies showed that animals prefer to explore novel objects, compared with those with whom they had previous experience. Moreover, it has been shown that the ability to respond to novel stimuli is related to self-administration of various drugs, the discovery of spontaneous tumors, and even life expectancy since it was found that neophobic animals die younger than their counterpart's neophilic. In this work we presented studies that indicated how the exploration of a novel environment could be a useful tool to enhanced or deteriorated memory in different ontogenetic stages. The modulation of memory depends on the different characteristic of the treatment presentation. It was reported that the novelty presented prior to an acquisition of some training task can generate an improvement in memory performance. Although, it was founded that the novelty exploration produce an amnesic effect if it was presented after learning, showing the opposite effect. This have been shown in different paradigms such us consummatory successive negative contrast (cSNC) paradigm and inhibition avoidance, in different phases of the training. It was also important to note that this phenomenon involves different time window parameters, for example it is required that the novelty were presented at least one hour before the learning. Furthermore we mentioned data that shows that exposure to novelty during infancy induces a lasting effect of improved cognition and long-term memory that persists even in adulthood. The study of the effect of novelty in the postnatal period and its subsequent influence on other periods opens the possibility of the creative developing of strategies to improve learning and memory processes throughout the subject's life. Besides, we presented research that exhibited the implication of several neurotransmitter systems in this phenomenon and the molecular mechanisms involved in this treatment. Practically all the principal neurotransmitter systems, such as cholinergic, glutamatergic, adrenergic, among others, are involved. A lot of studies indicate that cholinergic neurotransmission plays a critical role in the processes of attention, learning and memory. The same functions correspond to the adrenergic system. The gabaergic system is also involved in the perception of novel stimuli. Glutamate receptors play an important role in the memory processes mainly. In addition, a vast number of studies also reported that the molecular brain activation is very extensive in all the process of explore a novel environment, realizing the complexity of this mechanism. Thus, this type of treatment, non-invasive and easy to apply, becomes relevant for applied science as a possible alternative for the development of many intervention strategies in the topic. Also the study of this phenomenon in post -natal period, allows thinking about possible strategies applicable in the development of this cognitive function.

Kv7 channels in modulation of central monoaminergic neurotransmission / 中国药理学通报

The KCNQ gene family encodes five Kv7 channel sub-units(Kv7. 1-5) and four of these (Kv7. 2-5) channels are ex-pressed in the central nervous system ( CNS ) . Neuronal Kv7 channels participate in both pre-and post-synaptic modulation of neurotransmissions. Activation of neuronal Kv7 channels inhibits neuronal excitability and limits the release of monoaminergic neu-rotransmitter. Kv7 channel openers provide novel therapeutic op-tions in the treatment of disease states characterized by overactiv-ity of monoaminergic neurons ( e. g. schizophrenia, anxiety and drug abuse) . This review summarizes the studies on expression and functional role of Kv7 channels in monoaminergic neurotrans-mission in the CNS and the potential therapeutic effect of Kv7 channel openers on the disease characterized by overactivity of monoaminergic neurons.

Activation of group II metabotropic glutamate receptors blocks zinc release from hippocampal mossy fibers

BACKGROUND: The hippocampal CA3 area contains large amounts of vesicular zinc in the mossy fiber terminals which is released during synaptic activity, depending on presynaptic calcium. Another characteristic of these synapses is the presynaptic localization of high concentrations of group II metabotropic glutamate receptors, specifically activated by DCG-IV. Previous work has shown that DCG-IV affects only mossy fiber-evoked responses but not the signals from associational-commissural afferents, blocking mossy fiber synaptic transmission. Since zinc is released from mossy fibers even for single stimuli and it is generally assumed to be co-released with glutamate, the aim of the work was to investigate the effect of DCG-IV on mossy fiber zinc signals. RESULTS: Studies were performed using the membrane-permeant fluorescent zinc probe TSQ, and indicate that DCG-IV almost completely abolishes mossy fiber zinc changes as it does with synaptic transmission. CONCLUSIONS: Zinc signaling is regulated by the activation of type II metabotropic receptors, as it has been previously shown for glutamate, further supporting the corelease of glutamate and zinc from mossy fibers.

Effects of long-term fluoxetine treatment on adrenergic plasticity in rat vas deferens

Chronic antidepressant administration increases neurotrophin levels in the central and peripheral nervous system, leading to an increase of neuronal sprouting, reestablishment of neural networks and neurotransmitter levels. Injured peripheral nerves regenerate at very slow rates. However, the recovery of the hypogastric nerve in rodents after injury is significantly improved with neurotrophin administration. Accordingly, our goal was to determine whether treatment with the antidepressant fluoxetine affects catecholamine levels and neuronal function, after surgical denervation of the rat vas deferens. Noradrenaline levels in the denervated vas deferens were higher in fluoxetine-treated animals than in the vehicle-treated group, as measured by high performance liquid chromatography. In functional studies of smooth muscle contraction, the responses induced by phenylephrine or ATP, as well as pre-synaptic α2-adrenoceptor reactivity, were not modified by chronic treatment with the antidepressant. However, the contraction mediated by neuronal release of noradrenaline induced by tyramine was increased on days 7 and 21 after denervation in rats treated with fluoxetine. These data indicate that fluoxetine can improve functional recovery after rat vas deferens denervation.

A administração crônica de antidepressivos aumenta os níveis de neurotrofinas no sistema nervoso central, levando a um aumento da arborização neuronal, restabelecendo a rede neural e os níveis de neurotransmissores. Lesões do sistema nervoso periférico mostram uma regeneração muito lenta. Entretanto, a recuperação após a lesão do nervo hipogástrico em roedores é significativamente melhorada após a administração de neurotrofinas. Nesse sentido, nosso objetivo foi verificar se o tratamento com o antidepressivo, fluoxetina, interfere nos níveis de catecolaminas e na função neuronal, após a desnervação cirúrgica do ducto deferente de rato. Nos vasos deferentes desnervados, os níveis de catecolaminas nos grupos tratados com fluoxetina foram maiores que no grupo veículo, quantificados em cromatografia líquida de alta eficiência (CLAE). Nos estudos funcionais, a contração da musculatura lisa induzida pela fenilefrina ou pelo ATP, assim como a reatividade pré-sináptica α2-adrenérgica, não foram modificadas com o tratamento crônico de fluoxetina. Contudo, nas contrações mediadas pela liberação neuronal de norepinefrina induzida por tiramina, observou-se aumento da contração nos dias 7 e 21 após a desnevação em ratos tratados com fluoxetina. Esses dados indicam que a fluoxetina pode melhorar a recuperação funcional do vaso deferente de rato após a desnervação.

Alpha-Synuclein Function and Dysfunction on Cellular Membranes

Alpha-synuclein is a small neuronal protein that is closely associated with the etiology of Parkinson's disease. Mutations in and alterations in expression levels of alpha-synuclein cause autosomal dominant early onset heredity forms of Parkinson's disease, and sporadic Parkinson's disease is defined in part by the presence of Lewy bodies and Lewy neurites that are composed primarily of alpha-synuclein deposited in an aggregated amyloid fibril state. The normal function of alpha-synuclein is poorly understood, and the precise mechanisms by which it leads to toxicity and cell death are also unclear. Although alpha-synuclein is a highly soluble, cytoplasmic protein, it binds to a variety of cellular membranes of different properties and compositions. These interactions are considered critical for at least some normal functions of alpha-synuclein, and may well play critical roles in both the aggregation of the protein and its mechanisms of toxicity. Here we review the known features of alpha-synuclein membrane interactions in the context of both the putative functions of the protein and of its pathological roles in disease.

Responses to Enteric Motor Neurons in the Gastric Fundus of Mice With Reduced Intramuscular Interstitial Cells of Cajal

BACKGROUND/AIMS: Interstitial cells of Cajal (ICC) play important functions in motor activity of the gastrointestinal tract. The role of ICC as pacemakers is well established, however their participation in neurotransmission is controversial. Studies using mutant animals that lack ICC have yielded variable conclusions on their importance in enteric motor responses. The purpose of this study was to: (1) clarify the role of intramuscular ICC (ICC-IM) in gastric motor-neurotransmission and (2) evaluate remodeling of enteric motor responses in W/W(V) mice. METHODS: Kit immunohistochemistry and post-junctional contractile responses were performed on fundus muscles from wild-type and W/W(V) mice and quantitative polymerase chain reaction (qPCR) was used to evaluate differences in muscarinic and neurokinin receptor expression. RESULTS: Although ICC-IM were greatly reduced in comparison with wild-type mice, we found that ICC-IM persisted in the fundus of many W/W(V) animals. ICC-IM were not observed in W/W(V) group 1 (46%) but were observed in W/W(V) group 2 (40%). Evoked neural responses consisted of excitatory and inhibitory components. The inhibitory component (nitrergic) was absent in W/W(V) group 1 and reduced in W/W(V) group 2. Enhanced excitatory responses (cholinergic) were observed in both W/W(V) groups and qPCR revealed that muscarinic-M3 receptor expression was significantly augmented in the W/W(V) fundus compared to wild-type controls. CONCLUSIONS: This study demonstrates that ICC-IM mediate nitrergic inhibitory neurotransmission in the fundus and provides evidence of plasticity changes in neuronal responses that may explain discrepancies in previous functional studies which utilized mutant animals to examine the role of ICC-IM in gastric enteric motor responses.

Altitude May Contribute to Regional Variation in Methamphetamine Use in the United States: A Population Database Study

OBJECTIVE: Methamphetamine (MA) use rates in the United States (US) have consistently demonstrated geographical variation and have been higher in the West and Midwest. This uneven pattern of use could be explained by regional differences in MA manufacturing and distribution, but may also result from differences in altitude. The hypobaric hypoxia found at high altitude alters neurotransmitter synthesis in the brain, which may contribute to MA use. The present study investigated the relationship between mean altitude and MA use rate in the 48 contiguous US states and the District of Columbia. METHODS: State-level estimates of past year MA use were extracted from the National Survey on Drug Use and Health report. The mean altitude of each state was calculated using the Shuttle Radar Topography Mission altitude data set. RESULTS: There was a significant positive correlation between mean state altitude and MA use rate (r=0.66, p<0.0001). Multivariate linear regression analysis showed that altitude remained a significant predictor for MA use rate (beta=0.36, p=0.02), after adjusting for age, ethnicity, education, socioeconomic level, employment, MA laboratory incidents, subpopulations, and other substance use. CONCLUSION: Altitude appears to a possible contributing factor for regional variation of MA use in the US. Further studies will be required to determine biological changes in neurotransmission resulting from chronic mild hypoxia at high altitude in MA users.

The Amygdala's Neurochemical Ratios after 12 Weeks Administration of 20 mg Long-acting Methylphenidate in Children with Attention Deficit and Hyperactivity Disorder: A Pilot Study Using 1H Magnetic Resonance Spectroscopy

OBJECTIVE: Recent pediatric studies have suggested a correlation between decreased amygdala volume and attention deficit and hyperactivity disorder (ADHD) symptoms, including the emotional dysregulation. To investigate the hypothesis that medication treatment of ADHD specifically improves amygdala function, we used 1H magnetic resonance spectroscopy (MRS) to study the effect of 12 weeks of treatment with daily 20 mg long-acting methylphenidate on the Glu/Cr, NAA/Cr, Cho/Cr, and mI/Cr ratios in the amygdala of medication-naive children with ADHD. METHODS: This was a prospective study, using a pre- and post-test design, on a single group of 21 children (average age 8.52 years, 17 males and 4 females) diagnosed with ADHD. Low Time Echo MRS scans sampled voxels of interest (1.5x1.5x2.0) from both the right and left amygdala. RESULTS: There was significant clinical improvement after 12 weeks of treatment with 20 mg long-acting methylphenidate. On 1H MRS, there were no statistical significant differences of NAA/Cr ratio, Cho/Cr ratio, mI/Cr ratio before and after 12 weeks administration of 20 mg long-acting methylphenidate both in the right and left amygdala. In addition, Glu/Cr ratio decreased 14.1% in the right amygdala (p=0.029) and 11.4% in the left amygdala (p=0.008). Standardized mean effect sizes ranged from 0.14-0.32. CONCLUSION: The findings are consistent with the possibility that hyperglutamatergic processes in the amygdale are related to the hyperactive-impulsive symptoms of ADHD.

Anticonvulsant and Depressant Activity of Methanol Leaf Extract of Croton zambesicus.

Aims: To study anticonvulsant and central nervous system depressant activity of methanol leaf extract of Croton zambesicus (MECZ) in Swiss albino mice and investigate the role of serotonin in these activities. Methodology: Anticonvulsant activity of graded doses (200, 300 and 400 mg/kg p.o) of MECZ was assessed through seizures induced by picrotoxin and pentylenetetrazole (PTZ). Effects of the extract on pentobarbitone-induced sleep and amphetamine-induced stereotype behavior were also evaluated. Possible involvement of serotonergic pathways was studied using cyproheptadine (4mg/kg i.p), a non-selective serotonin antagonist (5-HT1/5HT2). Results: In both picrotoxin and PTZ-induced seizures, the extract significantly delayed onset of seizure (p<0.05) in a dose-dependent manner and provided significant protection against death. There was a dose-dependent increase of pentobarbitone sleeping time and a significant reduction (p<0.05) in the sleep latency. The extract also produced a significant reduction in amphetamine-induced stereotype behavior. Pretreatment with cyproheptadine abolished the anticonvulsant effect of the extract. The inhibitory effect of the extract on amphetamine-induced hyperactivity and its potentiation of pentobarbitone-induced sleep were also reversed by cyproheptadine. Conclusion: The results of this study showed that methanol extract of Croton zambesicus leaf possesses anticonvulsant activity and other CNS depressant activities and these activities are possibly mediated through interaction between serotonergic and GABAergic transmissions.

Synaptic vesicle pool size, release probability and synaptic depression are sensitive to Ca2+ buffering capacity in the developing rat calyx of Held

The calyx of Held, a specialized synaptic terminal in the medial nucleus of the trapezoid body, undergoes a series of changes during postnatal development that prepares this synapse for reliable high frequency firing. These changes reduce short-term synaptic depression during tetanic stimulation and thereby prevent action potential failures during a stimulus train. We measured presynaptic membrane capacitance changes in calyces from young postnatal day 5-7 (p5-7) or older (p10-12) rat pups to examine the effect of calcium buffer capacity on vesicle pool size and the efficiency of exocytosis. Vesicle pool size was sensitive to the choice and concentration of exogenous Ca2+ buffer, and this sensitivity was much stronger in younger animals. Pool size and exocytosis efficiency in p5-7 calyces were depressed by 0.2 mM EGTA to a greater extent than with 0.05 mM BAPTA, even though BAPTA is a 100-fold faster Ca2+ buffer. However, this was not the case for p10-12 calyces. With 5 mM EGTA, exocytosis efficiency was reduced to a much larger extent in young calyces compared to older calyces. Depression of exocytosis using pairs of 10-ms depolarizations was reduced by 0.2 mM EGTA compared to 0.05 mM BAPTA to a similar extent in both age groups. These results indicate a developmentally regulated heterogeneity in the sensitivity of different vesicle pools to Ca2+ buffer capacity. We propose that, during development, a population of vesicles that are tightly coupled to Ca2+ channels expands at the expense of vesicles more distant from Ca2+ channels.

N100 Amplitude Slopes in Major Depressive Disorder, Bipolar Disorder, Schizophrenia and Normal Controls

OBJECTIVES: N100 amplitude slope(the intensity dependence of the cortical auditory evoked potentials) is widely considered as an indirect indicator of central serotonergic neurotransmission. However, there are only a few studies about N100 amplitude slopes of major psychiatric disorders. In this study, we examined N100 amplitude slope differences among major depressive disorder(MDD), bipolar disorder(BD), schizophrenia (SCZ) and normal controls(NC). METHODS: We measured the N100 amplitude slopes of 35 patients with MDD, 33 patients with BD, 27 patients with SCZ and 35 NC subjects. Amplitude differences from N1 to P2 at the five different sound intensities(55, 65, 75, 85 and 95dB) were examined at Cz electrode. The N100 amplitude slope was calculated as the linear regression of five N1/P2 peak-to-peak amplitudes across stimulus intensities. RESULTS: BD patients showed significantly reduced N100 amplitude slope compared with NC(0.54+/-0.70 vs. 0.96+/-0.72, p=0.035). N100 amplitude slope of SCZ patients was significantly reduced compared with NC(0.50 +/-0.47 vs. 0.96+/-0.72, p=0.027). N100 amplitude slope of BD patients was significantly lower than that of MDD patients(0.54+/-0.70 vs. 0.94+/-0.60, p=0.046). SCZ patients also showed significant reduction of N100 amplitude slope compared with MDD patients(0.50+/-0.47 vs. 0.94+/-0.60, p=0.036). There was no significant difference of N100 amplitude slope between MDD patients and NC(0.94+/-0.60 vs. 0.96+/-0.72, p=1.000). CONCLUSION: Interestingly, the N100 amplitude slopes of BD and SCZ were reduced compared to NC and MDD patients. Our results suggest the predictive use of N100 amplitude slope in making differential diagnoses of major psychiatric disorders. Clinical implications of N100 amplitude slope in major psychiatric disorders were discussed.

The glycine receptor / 한양의대학술지

The glycine receptor (GlyR), a member of the pentameric ligand gated ion channel family, is best known for mediating inhibitory neurotransmission in motor and sensory circuits of the spinal cord, and is also present in the brain stem, cerebellum and retina When glycine binds to its site on the external receptor surface, the pore opens allowing Cl- to passively diffuse across the membrane. Because molecules that increase GlyR current may have clinical potentials as muscle relaxant and peripheral analgesic drug, it is important to understand and study the physiology and molecular pharmacology of the GlyR. We review the pharmacology and physiologic properties, structures, function and heritable disorders of glycinergic neurotransmission.

Mecanismos celulares y moleculares de la neurotoxicidad por plomo

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Abstract: Lead, a heavy metal, has been used by humans for many technological aims, a fact that has determined its actual widespread distribution. Although various actions have been taken to diminish the use and distribution of lead in the environment, it remains a significant health problem. The evolution of technological processes applied in the industry has followed economic interest. Its only in recent times that criteria related to health and ecology have been considered while designing new industries. Particularly susceptible groups are children and workers involved in mining, metallurgy, paint manufacturing and battery recycling. The communities living in areas where those industries are settled have also a higher lead exposure risk. Its high biological toxicity has determined lead to become one of the most significant environmental contaminants with pathogenic potential for humans. The toxic mechanism of lead is essentially due to its capability to substitute other polyvalent cations (particularly divalent cations such as calcium and zinc) into the molecular machinery of living organisms. Thanks to its ionic structure, lead establishes very favorable interactions, usually with higher affinity, with chemical groups that normally coordinate divalent cations in proteins. The coordination of cations in proteins is usually achieved by negatively charged acidic residues. These residues establish ionic interactions with the positively charged ion, resulting in a change in the structure and electric charge of the protein. These interactions determine that lead may affect different biologically significant processes, including metal transporting proteins, ionic channels, cell adhesion molecules, diverse enzymes which have metallic cofactors, signaling molecules such as calmodulin and protein kinase C and DNA binding proteins, among other molecular targets. Lead interactions with the coordinating amino acid residues in proteins may induce an abnormal conformational configuration of proteins, as compared to the conformational structure acquired when interacting with commonly active cations, thus significantly altering its functional properties in the very complex molecular machinery. Among the biologically active sites usually occupied by lead, those related to calcium seem to have the most significant pathological importance for lead toxicity due to their widespread distribution and highly significant functional relevance for the normal cell function. Two of the principal calcium binding motifs in proteins, the EF-hand motif and the C2 motif, have an intrinsic high affinity for lead. In the case of EF-hand motifs, calmodulin is one of the most remarkable targets for lead due its importance in regulating cellular processes, being activated by lead at lower concentrations than required for calcium and displaying an abnormal activity. The C2 motif is expressed mainly in calcium dependent membrane associated proteins such as protein kinase C (PKC) or synaptotagmin. The principal characteristic in these motifs is an electrical change in the protein after the calcium binding, allowing its interaction with biological membranes. In synaptotagmin, according with the electrical characteristics of lead, the interaction of the complex lead-synaptotagmin with biological membranes is similar to the interaction calcium-synaptotagmin with membranes, which is eminently electrical. Hence, the conformation of this complex is probably different to the conformation with calcium, fact evidenced by the failure of lead-synaptotagmin to interact with other proteins of the exocitic machinery. In relation to lead neurotoxicity, membrane ionic channels seem to be among the most relevant molecular targets of lead. In particular, calcium and potassium channel function may be significantly impaired by lead, affecting the activation of calcium activated potassium channels, the inactivation process of calcium channels, and the ionic conductance of calcium channels. As occurs with other heavy metals, lead is capable of blocking the calcium channel, probably at the selectivity filter. The high affinity lead binding to the acidic residues of the filter provokes a slow flux of the metal trough the channel pore, blocking the calcium conductance. The regulation of ionic channels will be significantly altered also. Calmodulin is a common calcium sensing protein for many ionic channels and its alteration by lead could affect the channel operation. Abnormal functioning of regulatory and signaling proteins such as calmodulin, protein kinase C and synaptotagmins, which normally require calcium for its activity, may also display an abnormal functioning, thus determining a widespread metabolic influence of lead poisoning. Lead distributes evenly into the cell thus reaching intracellular organelles, including the endoplasmic reticulum, mitochondria and the cell nucleus. This results in significant alterations of intracellular calcium metabolism and regulation due in part to the malfunctioning of calcium channels and ionic pumps in plasma membrane, endoplasmic reticulum and mitochondria. Inadequate energy generation due to mitochondrial damage and malfunctioning in cation dependent enzymes, alterations in protein folding due to the direct binding of lead to calcium activated reticular chaperones, or indirectly, altering the intrareticular calcium levels, and the disruption of the structure of DNA binding motifs such as zinc fingers, among others, promotes alterations in gene expression and DNA reparation. Lead poisoning is one of the most important chronic environmental illnesses affecting children in modern life. Developing central nervous system is particularly susceptible to lead toxicity. At critical times in development, lead may have a disorganizing influence with long-lasting effects which may continue into teenage and beyond. Mechanisms originating this disorganizing influence in the central nervous system are a consequence of the interaction of lead with various targets as previously described; alterations of cell molecular machinery, at the systems level induce excitotoxic phenomena, interferes with neurotransmission at neurotransmitter synthesis, release and receptor activation levels, alters intracellular signaling and produce cell membrane peroxidative damage. Compared to adult lead poisoning, pediatric lead is most common and its effects may occur at reduced blood levels with subclinical symptoms; thus a high index of suspicion is necessary for physicians when dealing with pediatric patients. Long-term effects of lead may produce cognitive and motor impairment, with behavioral alterations. The particular vulnerability of the immature nervous system to the lead poisoning is probably due to the fact that in this stage of development the establishment of appropriate neural networks is highly dependent on the synaptic activity, which in turn could be altered by lead. Lead poisoning has been considered as a potential co-factor in complex neuropsychological alterations such as schizophrenia. In this sense it is worth to note the possibility that the physical and psychic symptoms of Vincent Van Gogh may have been due to chronic lead poisoning. The following are among the clinical symptoms described by Van Gogh in his autographed letters: initial debilitation, stomatitis with loss of teeth, recurring abdominal pains, anemia (with a "plumbic" skin tone), neuropathy of the radial and saturnine encephalopathy, including epileptic crises, progressive character changes and periods of delirium, all of which meet present criteria for diagnosis of Organic Mental Disorder due to cerebral lesion or somatic illness, and Organic Character Disorder (DSM-IV-R). Apha-thujone, found in absinthe and in many popular herbal medicines, may also have contributed to Van Gogh symptoms since he was a well-known absynthe drinker. Many countries, including Mexico, have implemented politics aimed to eliminate lead from the majority of their industrial processes. This has been carried out with considerable effort, and in some cases, with open confrontations between the scientific community and industrial sector. Although there have been actually significant advances to eliminate lead from many products (gasoline, painting manufacturing, etc.), lead is not degradable, thence once it is released in the environment it remains there for long periods of time. This implies that we should have to deal with lead poisoning in the years to come and to be aware of this diagnostic possibility in any suspicious case. This review is centered in the description of the molecular mechanisms of lead toxicity and its repercussion in the cellular excitability and central nervous system function.

Clinical Application of I-123 MIBG Cardiac Imaging / 대한핵의학회잡지

Cardiac neurotransmission imaging allows in vivo assessment of presynaptic reuptake, neurotransmitter storage and postsynaptic receptors. Among the various neurotransmitter, I-123 MIBG is most available and relatively well- established. Metaiodobenzylguanidine (MIBG) is an analogue of the false neurotransmitter guanethidine. It is taken up to adrenergic neurons by uptake-1 mechanism as same as norepinephrine. As tagged with I-123, it can be used to image sympathetic function in various organs including heart with planar or SPECT techniques. I-123 MIBG imaging has a unique advantage to evaluate myocardial neuronal activity in which the heart has no significant structural abnormality or even no functional derangement measured with other conventional examination. In patients with cardiomyopathy and heart failure, this imaging has most sensitive technique to predict prognosis and treatment response of betablocker or ACE inhibitor. In diabetic patients, it allow very early detection of autonomic neuropathy. In patients with dangerous arrhythmia such as ventricular tachycardia or fibrillation, MIBG imaging may be only an abnormal result among various exams. In patients with ischemic heart disease, sympathetic derangement may be used as the method of risk stratification. In heart transplanted patients, sympathetic reinnervation is well evaluated. Adriamycin-induced cardiotoxicity is detected earlier than ventricular dysfunction with sympathetic dysfunction. Neurodegenerative disorder such as Parkinson's disease or dementia with Lewy bodies has also cardiac sympathetic dysfunction. Noninvasive assessment of cardiac sympathetic nerve activity with I-123 MIBG imaging may be improve understanding of the pathophysiology of cardiac disease and make a contribution to predict survival and therapy efficacy.

Inhibitory Effect of Purinergic Antagonists to the Electrically Stimulated Contraction of Canine Detrusor Muscle / 대한비뇨기과학회지

Cholinergic neurotransmission plays a major role in the postganglionic nerve evoked contractile response of the urinary bladder, but there is atropine-resistant contraction that is not completely blocked by atropine and may be related with nonadrenergic-noncholinergic (NANC) neurotransmission. Among the NANC neurotransmission, adenosine triphosphate(ATP) is an important transmitter in purinergic neurotransmission which is known to many vertebrates including human beings. The aim of this study is to determine the role and existence of purinergic neurotransmission in the canine detrusor muscle. In vitro contractile responses to electrical stimulation after pretreatment with atropine were measured in the presence of purinergic antagonist such as theophylline, b, r-methylene ATP and verapamil. Field stimulation( frequency 0.5-40 Hz; pulse width l ms; 10V square wave) produced a contraction that was abolished by tetrodotoxin( 0.1uM) and reduced by 42.5% after atropine ( 10uM) pretreatment. The contractile response was reduced by 44.1%, 30.3% and 60.1 % after the treatment of theophylline( 1uM, 10uM and 100uM) in the presence of atropine, 11.1%, 22.7% and 30.3% after the treatment of b, r-methylene ATP ( 5uM, 50uM and 500uM) and 17.6%, 39.4% and 60.1 % after the treatment of verapamil( 0.1u M, 1uM and 10uM) at 20 Hz frequency. These reduced contractile responses were statistically significant (p <0.05), especially in higher concentration, and relatively frequency-dependent and verapamil decreased the contractile response most significantly. These data demonstrate that purinergic neurotransmission is related to the contraction of canine detrusor muscle. On the other hand contractile responses were persisted after pretreatment of higher dose antagonist, which suggests that another mechanism such as peptidergic mechanism be related to the contraction of canine detrusor muscle.