Ergic System Research Articles

Emerging strategies in the management of essential tremor.

Currently available therapies for essential tremor (ET) provide sufficient control only for less than a half of patients and many unmet needs exist. This is in part due to the empiric nature of existing treatment options and persisting uncertainties about the pathogenesis of ET. The emerging concept of ET as a possible neurodegenerative disorder, better understanding of associated biochemical changes, including alterations in the γ-aminobutyric acid (GABA)-ergic system and gap junctions, and the identification of the role of the leucine-rich repeat and immunoglobulin-like domain-containing 1 (LINGO-1) gene in ET pathogenesis suggest new avenues for more targeted therapies. Here we review the most promising new approaches to treating ET, including allosteric modulation of GABA receptors and modifications of the LINGO-1 pathway. Medically refractory tremor can be successfully treated by high-frequency deep brain stimulation (DBS) of the ventral intermediate nucleus, but surgical therapies are also fraught with limitations due to adverse effects of stimulation and the loss of therapeutic response. The selection of additional thalamic and extrathalamic targets for electrode placements and the development of a closed-loop DBS system enabling automatic adjustment of stimulation parameters in response to changes in electrophysiologic brain activity are also reviewed. Tremor cancellation methods using exoskeleton and external hand-held devices are also briefly discussed.

Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABAA-ergic Systems.

It has been known that RA, one of major constituents of Perilla frutescens which has been used as a traditional folk remedy for sedation in oriental countries, shows the anxiolytic-like and sedative effects. This study was performed to know whether RA may enhance pentobarbital-induced sleep through γ-aminobutyric acid (GABA)A-ergic systems in rodents. RA (0.5, 1.0 and 2.0 mg/kg, p.o.) reduced the locomotor activity in mice. RA decreased sleep latency and increased the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleeping mice. RA also increased sleeping time and number of falling sleep mice after treatment with sub-hypnotic pentobarbital (28 mg/kg, i.p.). In electroencephalogram (EEG) recording, RA (2.0 mg/kg) not only decreased the counts of sleep/wake cycles and REM sleep, but also increased the total and NREM sleep in rats. The power density of NREM sleep showed the increase in δ-waves and the decrease in α-waves. On the other hand, RA (0.1, 1.0 and 10 μg/ml) increased intracellular Cl− influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase (GAD65/67) and GABAA receptors subunits except β1 subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through GABAA-ergic transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia.

Sedative and hypnotic effects of supercritical carbon dioxide fluid extraction from Schisandra chinensis in mice

Schisandra chinensis is a traditional Chinese medicine that has been used for treating insomnia and neurasthenia for centuries. Lignans, which are considered to be the bioactive components, are apt to be extracted by supercritical carbon dioxide. This study was conducted to investigate the sedative and hypnotic activities of the supercritical carbon dioxide fluid extraction of S. chinensis (SFES) in mice and the possible mechanisms. SFES exhibited an obvious sedative effect on shortening the locomotor activity in mice in a dose-dependent (10–200 mg/kg) manner. SFES (50 mg/kg, 100 mg/kg, and 200 mg/kg, intragstrically) showed a strong hypnotic effect in synergy with pentobarbital in mouse sleep, and reversal of insomnia induced by caffeine, p-chlorophenylalanine and flumazenil by decreasing sleep latency, sleep recovery, and increasing sleeping time. In addition, it produced a synergistic effect with 5-hydroxytryptophan (2.5 mg/kg, intraperitoneally). The behavioral pharmacological results suggest that SFES has significant sedative and hypnotic activities, and the mechanisms might be relevant to the serotonergic and γ-aminobutyric acid (GABA)ergic system.

Indicators nitroxide ergic system at mycoplasma pneumonia in combination with herpes infection in children with immunotherapy

Indicators nitroxide ergic system at mycoplasma pneumonia in combination with herpes infection in children with immunotherapy

Indicators nitroxide ergic system at mycoplasma pneumonia in combination with herpes infection in children with immunotherapy

Indicators nitroxide ergic system at mycoplasma pneumonia in combination with herpes infection in children with immunotherapy

Nerolidol exhibits antinociceptive and anti-inflammatory activity: involvement of the GABAergic system and proinflammatory cytokines.

Nerolidol, an acyclic sesquiterpene found as a major constituent of several essential oils, has several pharmacological activities, but its action in pain processes has never been studied. The purpose of our research was to evaluate the antinociceptive and anti-inflammatory activities of nerolidol, as well as possible mechanisms of action, in experimental mouse models of pain. Antinociceptive activity was evaluated using the acetic acid-induced writhing test, the formalin test, and the hot-plate test. The nerolidol-treated group showed lesser acetic acid-induced abdominal contractions than the control group in all of the three doses tested (200, 300, and 400 mg/kg, p.o.). The formalin test doses of 300 and 400 mg/kg p.o. inhibited licking time, in both the first phase and the second phase. In the hot-plate test, nerolidol did not alter latency at any of the observed time points. Motor coordination, evaluated through the rotarod test, was not hindered in animals treated with nerolidol. Regarding the mechanism of action, the antinociceptive activity of nerolidol is related to the GABAergic system, and not to the opioidergic or ATP-sensitive K(+) channels. Treatment with nerolidol reduced carrageenan-induced paw edema. In the model of carrageenan-induced peritonitis, nerolidol decreased the influx of polymorphonuclear cells and also reduced levels of tumor necrosis factor (TNF-α) in peritoneal lavage. Nerolidol reduced production of interleukin 1 beta (IL-1β) in LPS-stimulated, peritoneal macrophages. Thus, these results showed that nerolidol has antinociceptive activity with possible involvement of the GABAergic system, and anti-inflammatory activity, attributed to the suppression of TNF-α and IL-1β proinflammatory cytokines.

BMSCs transplantation improves cognitive impairment via up-regulation of hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion

Bone marrow mesenchymal stem cells (BMSCs) transplantation can ameliorate cognitive impairment in chronic ischemic brain injury, but the underlying mechanism is poorly understood. It is considered that the hippocampus holds the capabilities of memory consolidation and spatial navigation, and the gamma amino butyric acid (GABA)ergic system plays an important role in the control of learning and memory processes. Herein, we investigated whether transplantation of BMSCs could improve cognitive impairment via regulating the hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion. Animals treated with permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO) (a rat model of chronic cerebral hypoperfusion) received intravenous injections of BMSCs or saline as experimental group and control group I, the sham-operated rats received intravenous injections of BMSCs or saline as the sham group and control group II. Four weeks later, the Morris Water Maze was employed to evaluate the cognitive changes of each group, immunohistochemistry and western blotting was used to investigate the GABAergic system expression including GABA, glutamic acid decarboxylase 67 (GAD67) or GABAB receptor 1 (GABABR1) in the hippocampus. Our results showed that the 2VO model presented decreased capacities of learning and memory and down-regulated the expression of GABA, GAD67 or GABABR1 in the hippocampal CA1 subfield in comparison to the sham group (P<0.05), while administration of BMSCs (experimental group) manifested increased performances of learning sessions and probe tasks, as well as up-regulated expression of GABA, GAD67 or GABABR1 compared with the control group I (P<0.05). Collectively, these findings suggest that transplantation of BMSCs is capable of improving cognitive impairment via up-regulating the hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion. Hence, BMSCs transplantation could serve as an important tool for cell therapy in chronic cerebral hypoperfusion disorders.

Identification of candidate genes for familial early-onset essential tremor.

Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts l-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G>A (p.(Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C>T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved amino-acid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone.

γ-Aminobutyric acid (GABA) administration improves action selection processes: a randomised controlled trial.

In order to accomplish a task goal, real-life environments require us to develop different action control strategies in order to rapidly react to fast-moving visual and auditory stimuli. When engaging in complex scenarios, it is essential to prioritise and cascade different actions. Recent studies have pointed to an important role of the gamma-aminobutyric acid (GABA)-ergic system in the neuromodulation of action cascading. In this study we assessed the specific causal role of the GABA-ergic system in modulating the efficiency of action cascading by administering 800 mg of synthetic GABA or 800 mg oral of microcrystalline cellulose (placebo). In a double-blind, randomised, between-group design, 30 healthy adults performed a stop-change paradigm. Results showed that the administration of GABA, compared to placebo, increased action selection when an interruption (stop) and a change towards an alternative response were required simultaneously, and when such a change had to occur after the completion of the stop process. These findings, involving the systemic administration of synthetic GABA, provide the first evidence for a possible causal role of the GABA-ergic system in modulating performance in action cascading.

Environmental Enrichment Reduces Anxiety by Differentially Activating Serotonergic and Neuropeptide Y (NPY)-Ergic System in Indian Field Mouse (Mus booduga): An Animal Model of Post-Traumatic Stress Disorder.

Exposure to a predator elicits an innate fear response and mimics several behavioral disorders related to post-traumatic stress disorder (PTSD). The protective role of an enriched condition (EC) against psychogenic stressors in various animal models has been well documented. However, this condition has not been tested in field mice in the context of PTSD. In this study, we show that field mice (Mus booduga) housed under EC exhibit predominantly proactive and less reactive behavior compared with mice housed under standard conditions (SC) during exposure to their natural predator (field rat Rattus rattus). Furthermore, we observed that EC mice displayed less anxiety-like behavior in an elevated plus maze (EPM) and light/dark-box after exposure to the predator (7 hrs/7 days). In EC mice, predator exposure elevated the level of serotonin (5-Hydroxytrypamine, [5-HT]) in the amygdala as part of the coping response. Subsequently, the serotonin transporter (SERT) and 5-HT1A receptor were up-regulated significantly, but the same did not occur in the 5-HT2C receptor, which is associated with the activation of calmodulin-dependent protein kinase-II (CaMKII) and a transcription factor cAMP response element binding protein (CREB). Our results show that predator exposure induced the activation of CaMKII/CREB, which is accompanied with increased levels of histone acetylation (H3, H4) and decreased histone deacetylases (HDAC1, 2). Subsequently, in the amygdala, the transcription of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY) and its Y1 receptor were up-regulated, whereas the Y2 receptor was down-regulated. Therefore, EC facilitated a coping response against a fear associated cue in a PTSD animal model and reduced anxiety by differentially activating serotonergic and NPY-ergic systems.

The role of the GABA system in amphetamine-type stimulant use disorders.

Abuse of amphetamine-type stimulants (ATS) has become a global public health problem. ATS causes severe neurotoxicity, which could lead to addiction and could induce psychotic disorders or cognitive dysfunctions. However, until now, there has been a lack of effective medicines for treating ATS-related problems. Findings from recent studies indicate that in addition to the traditional dopamine-ergic system, the GABA (gamma-aminobutyric acid)-ergic system plays an important role in ATS abuse. However, the exact mechanisms of the GABA-ergic system in amphetamine-type stimulant use disorders are not fully understood. This review discusses the role of the GABA-ergic system in ATS use disorders, including ATS induced psychotic disorders and cognitive dysfunctions. We conclude that the GABA-ergic system are importantly involved in the development of ATS use disorders through multiple pathways, and that therapies or medicines that target specific members of the GABA-ergic system may be novel effective interventions for the treatment of ATS use disorders.

Increased anxiety-like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS mouse model.

Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease primarily characterized by motor neuron death, causes damages beyond motor-related areas. In particular, cognitive impairments and hippocampal damage have been reported in ALS patients. We investigated spatial navigation learning and hippocampal interneurons in a mutant SOD1(G93A) mouse (mSOD1) model of ALS. Behavioral tests were performed by using presymptomatic mSOD1 mice. General motor activity was comparable to that of wild-type mice in the open-field test, in which, however mSOD1 exhibited increased anxiety-like behavior. In the Barnes maze test, mSOD1 mice displayed a delay in learning, outperformed wild-type mice during the first probe trial, and exhibited impaired long-term memory. Stereological counts of parvalbumin-positive interneurons, which are crucial for hippocampal physiology and known to be altered in other central nervous system regions of mSOD1 mice, were also performed. At postnatal day (P) 56, the population of parvalbumin-positive interneurons in mSOD1 mice was already reduced in CA1 and in CA3, and at P90 the reduction extended to the dentate gyrus. Loss of parvalbumin-positive hippocampal interneurons occurred mostly during the presymptomatic stage. Western blot analysis showed that hippocampal parvalbumin expression levels were already reduced in mSOD1 mice at P56. The hippocampal alterations in mSOD1 mice could at least partly account for the increased anxiety-like behavior and deficits in spatial navigation learning. Our study provides evidence for cognitive alterations and damage to the γ-aminobutyric acid (GABA)ergic system in the hippocampus of murine ALS, thereby revealing selective deficits antecedent to the onset of motor symptoms.

In utero exposure to valproic acid changes sleep in juvenile rats: a model for sleep disturbances in autism.

To determine whether sleep disturbances are found in the valproic acid model of autism spectrum disorders (ASD). Comparative study for sleep behavior, sleep architecture, electroencephalogram (EEG) spectral analysis, and glutamic acid decarboxylase (GAD) 65/67 protein expression in juvenile rats exposed to valproic acid (VPA), sodium salt, or saline in utero. N/A. Juvenile (postnatal day 32) male and female Sprague-Dawley rats. In utero exposure to either saline or 400 mg/kg VPA administered intraperitoneally to the dams on gestational day 12.5. On postnatal days 22-24, all rats were implanted with transmitters to record EEG and electromyogram (EMG) activity. During the light phase, when nocturnal animals are typically quiescent, the VPA-exposed animals spent significantly more time in wake (∼35 min) and significantly less time in non-rapid eye movement (NREM) sleep (∼26 min) compared to the saline controls. Furthermore, spectral analysis of the EEG revelled that VPA-exposed animals exhibited increased high-frequency activity during wake and rapid eye movement (REM) sleep and reduced theta power across all vigilance states. Interestingly, the gamma-aminobutyric acid (GABA)-ergic system, which modulates the induction and maintenance of sleep states, was also disrupted, with reduced levels of both GAD 65 and GAD67 in the cortical tissue of VPA-exposed animals compared to saline controls. To date, the current animal models of ASD have been underutilized in the investigation of associated sleep disturbances. The VPA animal model recapitulates aspects of sleep disruptions reported clinically, providing a tool to investigate cellular and molecular dysregulation contributing to sleep disruptions in ASD.

Pachymic Acid Enhances Pentobarbital-Induced Sleeping Behaviors via GABAA-ergic Systems in Mice.

This study was investigated to know whether pachymic acid (PA), one of the predominant triterpenoids in Poria cocos (Hoelen) has the sedative-hypnotic effects, and underlying mechanisms are mediated via γ-aminobutyric acid (GABA)-ergic systems. Oral administration of PA markedly suppressed locomotion activity in mice. This compound also prolonged sleeping time, and reduced sleep latency showing synergic effects with muscimol (0.2 mg/kg) in shortening sleep onset and enhancing sleep time induced by pentobarbital, both at the hypnotic (40 mg/kg) and sub-hypnotic (28 mg/kg) doses. Additionally, PA elevated intracellular chloride levels in hypothalamic primary cultured neuronal cells of rats. Moreover, Western blotting quantitative results showed that PA increased the amount of protein level expression of GAD65/67 over a broader range of doses. PA increased α- and β-subunits protein levels, but decreased γ-subunit protein levels in GABAA receptors. The present experiment provides evidence for the hypnotic effects as PA enhanced pentobarbital-induced sleeping behaviors via GABAA-ergic mechanisms in rodents. Taken together, it is proposed that PA may be useful for the treatment of sleep disturbed subjects with insomnia.

Novel dose-dependent alterations in excitatory GABA during embryonic development associated with lead (Pb) neurotoxicity

Lead (Pb) is a heavy metal that is toxic to numerous physiological processes. Its use in industrial applications is widespread and results in an increased risk of human environmental exposure. The central nervous system (CNS) is most sensitive to Pb exposure during early development due to rapid cell proliferation and migration, axonal growth, and synaptogenesis. One of the key components of CNS development is the Gamma-aminobutyric acid (GABA)-ergic system. GABA is the primary inhibitory neurotransmitter in the adult brain. However, during development GABA acts as an excitatory neurotrophic factor which contributes to these cellular processes. Multiple studies report effects of Pb on GABA in the mature brain; however, little is known regarding the adverse effects of Pb exposure on the GABAergic system during embryonic development. To characterize the effects of Pb on the GABAergic system during development, zebrafish embryos were exposed to 10, 50, or 100ppb Pb or a control treatment. Tissue up-take, gross morphological alterations, gene expression, and neurotransmitter levels were analyzed. Analysis revealed that alterations in gene expression throughout the GABAergic system and GABA levels were dose and developmental time point specific. These data provide a framework for further analysis of the effects of Pb on the GABAergic system during the excitatory phase and as GABA transitions to an inhibitory neurotransmitter during development.

Feeling safe in the plane: neural mechanisms underlying superior action control in airplane pilot trainees--a combined EEG/MRS study.

In day-to-day life, we need to apply strategies to cascade different actions for efficient unfolding of behavior. While deficits in action cascading are examined extensively, almost nothing is known about the neuronal mechanisms mediating superior performance above the normal level. To examine this question, we investigate action control in airplane pilot trainees. We use a stop-change paradigm that is able to estimate the efficiency of action cascading on the basis of mathematical constraints. Behavioral and EEG data is analyzed along these constraints and integrated with neurochemical data obtained using Magnetic Resonance Spectroscopy (MRS) from the striatal gamma-aminobutyric acid (GABA) -ergic system. We show that high performance in action cascading, as exemplified in airplane pilot trainees, can be driven by intensified attentional processes, circumventing response selection processes. The results indicate that the efficiency of action cascading and hence the speed of responding as well as attentional gating functions are modulated by striatal GABA and Glutamate + Glutamine concentrations. In superior performance in action cascading similar increases in the concentrations of GABA and Glutamate + Glutamine lead to stronger neurophysiological and behavioral effects as compared to subjects with normal performance in action cascading.

Psycho-emotional state of rats under thyroid dysfunction.

Spontaneous behavioral activity of white rats and concentration of glutamate, glycine and gamma-aminobutyric acid in the neocortex in experimental hyper- and hypothyroidism was investigated. It was found that an excess of thyroid hormones was accompanied by emotional and anxiolytic effects in terms of reducing duration of grooming by 37% and increasing number of transitions and the time spent in the illuminated cross-shaped maze arms (26 % and 35%). Such behavior changes occurred against a background of increasing concentrations of GABA by 52 % (p&lt;0,05) in the cortex of animals with experimental hyperthyroidism. Perhaps, the psycho-emotional state of the organism is modulated by thyroid hormones through the GABA - ergic system of neocortex.

Gastrodiae Rhizoma Ethanol Extract Enhances Pentobarbital‐Induced Sleeping Behaviors and Rapid Eye Movement Sleep via the Activation of GABAA‐ergic Transmission in Rodents

This research was designed to identify whether Gastrodiae Rhizoma ethanol extract (GREE) enhances pentobarbital-induced sleep via γ-aminobutyric acid- (GABA-) ergic systems and modulated sleep architectures in animals. GREE (25, 50, and 100 mg/kg, p.o.) inhibited locomotor activity in mice, in a dose-dependent manner. GREE not only prolonged total sleep time, but also reduced sleep latency time in pentobarbital (42 mg/kg)-treated mice. Subhypnotic pentobarbital (28 mg/kg, i.p.) also increased the number of total sleeping animals in concomitant administration of GREE. GREE (100 mg/kg) alone reduced the count of sleep-wake cycles in electroencephalogram. Furthermore, GREE increased total sleep time and rapid eye movement (REM) sleep. From the in vitro experiments, GREE increased intracellular chloride level in primary cultured cerebellar granule cells. Protein expressions of glutamine acid decarboxylase (GAD) and GABAA receptors subtypes by western blot were increased. Therefore, our study suggested that GREE enhances pentobarbital-induced sleeping behaviors and increased REM via the activation of GABAA-ergic transmission in rodents.

Pharmacotherapeutic options for treatment of insomnia

Insomnia is a functionally debilitating condition characterized by repeated difficulty with sleep initiation, maintenance, or quality of sleep despite adequate opportunity. If left untreated, it can lead to increased risk of depression, poor memory, reduced concentration, poor work performance, and poor general health. Although gamma-aminobutyric acid (GABA) ergic system remains the primary target for current insomnia treatments, still over-the-counter (OTC) drugs with a different mechanism of action are in use for insomnia. OTC drugs target only one of the parallel arousing systems and may improve mild insomnia for a short period. They are not likely to improve symptoms over long-term and thus are not the ideal agents. Studies evaluating the efficacy and outcomes of sedative hypnotic drugs beyond 1 year are limited. Currently, there are no Food and Drug Administration approved pharmacotherapies for insomnia in the pediatric population. Increased understanding of complex neuronal networks involved in sleep and wake has led to the development of new drugs for insomnia that target a diverse range of receptors. Potential agents under investigations are targeting mechanisms and pathways including histamine (H 1 ) receptor, melatonin, and orexin receptors. This review describes the pharmacotherapy of insomnia and the drugs under development for the treatment of insomnia.

Protective effect of leaf extract of Pandanus odoratissimus Linn on experimental model of epilepsy

Objective: Study the anticonvulsant activity of ethanol extract Pandanus odoratissimus Linn in Swiss albino mice. Research Design and Methods: P. odoratissimus Linn (Pandanaceae) was evaluated for anticonvulsant activity in rodents. Animal models used include maximal electroshock test (MES); picrotoxin induced convulsions (PIC) and strychnine induced convulsion - (SIC). Results: Increase in latency to seizures as well as a reduction in duration and frequency of seizures indicated anticonvulsant activity. The selected extract was more effective in all models used except the SIC. P. odoratissimus ethanol extract (100 and 200 mg/kg body weight) significantly (P < 0.05-0.01) shortened the duration of convulsions in MES and PIC-induced seizures. Delay in the onset of convulsions in the two tests was significant (P < 0.01). Reduction in the frequency of seizures was also significant (P < 0.05, 0.01) in both tests. P. odoratissimus further delayed the onset of seizures in PIC induced seizures model while producing (66.7% and 83.33%) protection against death in mice. Diazepam (5 mg/kg) and marketed drug sample of P. odoratissimus (0.5 mg/kg) were used as reference anticonvulsant drugs for various models. Diazepam blocked the effect of the extract in the PIC and SIC tests significantly suggesting that P. odoratissimus may be acting by enhancing the effects of the gamma amino butyric acid ergic system. Conclusions: The ethanol extracts of P. odoratissimus Linn possess anticonvulsant activity since it delays the duration and the latency of seizures produced by MES and PIC.