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At the time when the number of children with autism spectrum disorders (ASD) is increasing, the number of studies that investigate the clinical features of the disease, pathogenesis, etiological factors and methods of treatment is increasing too. There is no single answer to the questions of etiology and pathogenesis of this disorder for today. In this article, we present modern literature data regarding the problem of neurotransmitter metabolism in children with ASD. Also, the data obtained during the determination of gamma-aminobutyric acid (GABA) concentration in the blood plasma of children with cognitive epileptiform disintegration (n = 45) and children with ASD without epileptic seizures (n = 15) are given. According to the results of the study, there was a decrease in the average concentration of GABA in children with cognitive epileptiform disintegration as compared to the control group (n = 12). There were no significant differences in the mean concentration of GABA between the group of children with ASD without epileptic seizures and the control group (p < 0.001). Our results and a review of literature data allow us to state the necessity of using drugs that regulate the metabolism of neurotransmitters, especially GABA, in the treatment of children with ASD.

Bio-neuronal led psychiatric abnormalities transpired by the loss of neuronal structure and function (neurodegeneration), pro-inflammatory cytokines, microglial dysfunction, altered neurotransmission, toxicants, serotonin deficiency, kynurenine pathway, and excessively produced neurotoxic substances. These uncontrolled happenings in the etiology of psychiatric disorders initiate further changes in neurotransmitter metabolism, pathologic microglial, cell activation, and impaired neuroplasticity. Inflammatory cytokines, the outcome of dysfunctional mitochondria, dysregulation of the immune system, and under stress functions of the brain are leading biochemical factors for depression and anxiety. Nanoscale drug delivery platforms, inexpensive diagnostics using nanomaterials, nano-scale imaging technologies, and ligand-conjugated nanocrystals used for elucidating the molecular mechanisms and foremost cellular communications liable for such disorders are highly capable features to study for efficient diagnosis and therapy of the mental illness. These theranostic tools made up of multifunctional nanomaterials have the potential for effective and accurate diagnosis, imaging of psychiatric disorders, and are at the forefront of leading technologies in nanotheranostics openings field as they can collectively and efficiently target the stimulated territories of the cerebellum (cells and tissues) through molecular-scale interactions with higher bioavailability, and bio-accessibility. Specifically, the nanoplatforms based neurological changes are playing a significant role in the diagnosis of psychiatric disorders and portraying the routes of functional restoration of mental disorders by newer imaging tools at nano-level in all directions. Because of these nanotherapeutic platforms, the molecules of nanomedicine can penetrate the Blood-Brain Barrier with an increased half-life of drug molecules. The discoveries in nanotheranostics and nanotherapeutics inbuilt unique multi-functionalities are providing the best multiplicities of novel nanotherapeutic potentialities with no toxicity concerns at the level of nano range.

Introduction. Despite the apparent connection of the existing neurological disorders and changes in the psycho-emotional sphere with sleep disorders in patients with chronic mercury intoxication (CRI), these relationships remain the least studied in the clinic neurointoxications. The study aimed to establish a connection between neurophysiological, biochemical, and psychopathological indicators in patients with occupational chronic mercury intoxication and insomnia. Materials and methods. Thirty-six patients took part in the examination in the remote period of CRI. The average age of patients in this group was 50.7±1.05 years, with an average work experience of 14.7±1.05. The authors carried out a psychological examination to determine the levels of depression, anxiety, asthenic state, computed electroencephalography (EEG), cognitive evoked potentials (CEP), polysomnography, the level of neurotransmitters. Results. The study showed that asthenization, when exposed to mercury, occurs due to a decrease in the limbic-hypothalamo-reticular complex activity (the presence of equivalent dipole sources of pathological activity in the area of diencephalic formations (thalamus, hypothalamus) in 56.2±5.6% of cases. The study showed a decrease in activity cerebral cortex, confirmed by weakening the coherent connections of the α-range in the occipital, central and frontal leads according to the data of coherent EEG analysis and changes on the part of the CEP. There was a direct correlation between the level of total sleep time and the serotonin level (rs=0.45), an inverse relationship between the level of depression and histamine level (rs=-0.56). Conclusion. The studies carried out to make it possible to establish the mechanisms of insomnia disorders in chronic mercury intoxication, which cause a weakening of the tone of the cerebral cortex and changes in neurotransmitter metabolism, as well as disorders of the reticular system with limbic structures. The study showed a close direct relationship between neurophysiological, psychological, and biochemical parameters in implementing insomnia in patients with chronic mercury intoxication.

Цель исследования - сравнительный анализ содержания про- и противовоспалительных цитокинов и аутоантител к нейромедиаторам дофамину, норадреналину, серотонину, глутамату и ГАМК в сыворотке крови пациенток с алкогольной зависимостью и депрессией разной степени тяжести. Методика. Клиническое обследование и создание банка биологического материала выполнены на базе отделений аффективных расстройств и аддиктивных состояний и лаборатории клинической психонейроиммунологии и нейробиологии НИИ психического здоровья Томского НИМЦ РАН. Исследована сыворотка крови 52 женщин в возрасте 40-55 лет: 17 условно здоровых лиц, и 35 пациенток с аффективными и аддиктивными расстройствами. В соответствии с МКБ-10 у 6 пациенток диагностирован синдром зависимости от алкоголя (F10.2). У 29 пациенток диагностирована депрессия разной степени тяжести. В подгруппу легкой депрессии (сумма баллов по шкале Гамильтона HDRS до 16 баллов включительно) вошли 13 пациенток: 5 с депрессивным эпизодом легкой степени F32.0 и 8 с дистимией F34.1. В подгруппу умеренной депрессии (сумма баллов по шкале Гамильтона выше 16 баллов) вошли 16 пациенток: 7 с депрессивным эпизодом средней степени F32.1 и 9 с рекуррентной депрессией F33.1. Антитела к нейромедиаторам дофамину, норадреналину, серотонину, глутамату и ГАМК в сыворотке крови определяли методом твердофазного иммуноферментного анализа на полистироловых планшетах, активированных соответствующими тест-антигенами. Интерлейкины в сыворотке крови определяли методом иммуноферментного анализа с использованием тест-систем производства ООО Цитокин (Санкт-Петербург). Определяли баланс провоспалительных цитокинов - интерлейкинов (ИЛ 1β, ИЛ 6) и противовоспалительных - ИЛ 10. Результаты. Уровень аутоантител к нейромедиаторам связан с тяжестью депрессии. При легкой депрессии отличия от контрольного уровня незначительны. При умеренной депрессии повышен уровень антител к серотонину, глутамату и ГАМК. Спектр антител при алкоголизме сходен с таковым при умеренной депрессии. Можно предполагать, что данные паттерны отражают коморбидное течение депрессии и аддикции. Соотношение содержания провоспалительного (ИЛ 6) и противовоспалительного (ИЛ 10) цитокинов в сыворотке крови при алкоголизме незначительно отличалось от контрольного уровня, в то время как при отягощении депрессии это соотношение существенно повышалось и у 20% обследованных в явной форме указывало на преобладание воспаления над компенсаторными процессами. Заключение. Феномен нейровоспаления не является достаточным для понимания нейроиммунных механизмов коморбидной патологии. Иммунорегуляция нейромедиаторного обмена является новым источником информации о нейроиммунном дисбалансе при сочетанных расстройствах. Aim. Comparative analysis of concentrations of pro- and anti-inflammatory cytokines and autoantibodies to the neurotransmitters dopamine, norepinephrine, 5-hydroxytryptamine, glutamate, and GABA in the blood serum of female patients with alcohol dependence and depression of different severity. Methods. Clinical examination and creation of a bank of biological material were performed at the Departments of Affective Disorders and Addictive Conditions and the Laboratory of Clinical Psychoneuroimmunology and Neurobiology of the Mental Health Institute, Tomsk Scientific Research Center of the Russian Academy of Sciences. Blood serum of 52 women aged 40-55 years was studied, including 17 conditionally healthy individuals, and 35 patients with affective and addictive disorders. In accordance with ICD-10, 6 patients were diagnosed with alcohol dependence syndrome (F10.2), and 29 patients were diagnosed with depression of different severity. The subgroup of mild depression with a Hamilton Depression Rating Scale (HDRS) score 16 included 16 patients (7 with a moderate depressive episode F32.1 and 9 with recurrent depression F33.1). Serum antibodies to the neurotransmitters dopamine (DA), norepinephrine (NA), 5-hydroxytryptamine (5-HT), glutamate (GLU), and GABA were determined by enzyme-linked immunosorbent assay (ELISA) on polystyrene plates activated with the respective test antigens. Serum interleukins (IL) were measured using ELISA test systems. The balance of pro-inflammatory (IL 1β and IL 6) and anti-inflammatory (IL 10) cytokines was determined. Statistical analysis was performed with the φ Fisher criteria, and data were graphically presented as mean values. Results. Concentrations of autoantibodies to neurotransmitters were related with the severity of depression. In mild depression, differences from the control values were negligible. In moderate depression, levels of antibodies to 5-hydroxytryptamine, glutamate, and GABA were increased. In alcohol dependence, the array of antibodies was similar to that in moderate depression. These patterns apparently reflect the comorbid course of depression and addiction. The ratio of pro-inflammatory (IL 6) to anti-inflammatory (IL 10) cytokine serum concentrations in alcohol dependence was slightly different from the control ratio. At the same time in more severe depression, this ratio significantly increased and clearly indicated prevalence of inflammation over compensatory processes in 20% of the patients. Conclusion. The phenomenon of neuroinflammation is not sufficient to understand neuroimmune mechanisms of the comorbid pathology. Immunoregulation of neurotransmitter metabolism is a new source of information about neuroimmune imbalance in combined disorders.

PICALM and CLU genes have been linked to alterations in brain biochemical processes that may have an impact on Alzheimer’s disease (AD) development and neurophysiological dynamics. The aim of this study is to analyze the relationship between the electroencephalographic (EEG) activity and the PICALM and CLU alleles described as conferring risk or protective effects on AD patients and healthy controls. For this purpose, EEG activity was acquired from: 18 AD patients and 12 controls carrying risk alleles of both PICALM and CLU genes, and 35 AD patients and 12 controls carrying both protective alleles. Relative power (RP) in the conventional EEG frequency bands (delta, theta, alpha, beta, and gamma) was computed to quantify the brain activity at source level. In addition, spatial entropy (SE) was calculated in each band to characterize the regional distribution of the RP values throughout the brain. Statistically significant differences in global RP and SE at beta band (p-values < 0.05, Mann–Whitney U-test) were found between genotypes in the AD group. Furthermore, RP showed statistically significant differences in 58 cortical regions out of the 68 analyzed in AD. No statistically significant differences were found in the control group at any frequency band. Our results suggest that PICALM and CLU AD-inducing genotypes are involved in physiological processes related to disruption in beta power, which may be associated with physiological disturbances such as alterations in beta-amyloid and neurotransmitter metabolism.

Objective The aim: A correction of cholinergic insufficiency for the treatment of cognitive impairment in chronic brain ischemia. Patients and methods Materials and methods: In the period 2014 - 2017, 88 people aged 40 to 68 years were comprehensively examined in dynamics. Patients were divided into three groups, statistically comparable to the main disease - CCI 2 degrees, gender and age. In addition to the protocol, patients with discirculatory encephalopathy of all the investigated groups received a complex of drugs aimed at correcting neurotransmitter metabolism. Results Results: The statistically significant manifestations of the recovery of cognitive function (according to the MMSE scale) after the application of the developed complex therapy were associated mainly with a decrease in impulsivity due to an increase in the level of attention. The statistically significant manifestations of a decrease in the level of anxietydepressive disorders (according to the DASS-21 scale) after the application of the developed complex therapy were associated mainly with a decrease in anxiety due to the restoration of neurohumoral balance. Conclusion Conclusions: The inclusion in the treatment protocol for CCI complex of drugs aimed at eliminating cholinergic deficiency, acetylcholinesterase inhibitors in combination with choline precursors, leads to the correction of cognitive impairment in chronic brain ischemia.

Background Patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) frequently show depressive symptoms clinically and increasing evidence indicates a correlation between CP/CPPS and depression. However, the underlying mechanisms of CP/CPPS-related depression remain poorly understood. Here, we sought to determine the role of hippocampal microglial activation and neurobiological changes in a mouse model of experimental autoimmune prostatitis (EAP)-induced depression and the treatment efficacy of Chinese herb extract baicalein. Methods EAP was induced through intradermal injection of prostate antigen and adjuvant twice. Then, mice were assessed for affective behaviors in the open field test, elevated plus maze, forced swim test, and tail suspension test. The morphology and function of microglia and astrocytes were detected by immunofluorescence, Western blotting, and transmission electron microscopy. Proinflammatory mediators along with serotonin transporter (SLC6A4/SERT) and indoleamine 2,3-dioxygenase (IDO) were quantified with reverse transcription-polymerase chain reaction (RT‑PCR), and serum serotonin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Proton magnetic resonance spectroscopy (1H-MRS) was performed to measure hippocampal glutamate levels. In addition, baicalein was used in a subset of EAP mice to test its anti-depressant action. Results EAP was successfully established and induced depressive- and anxiety-like behavior in mice. Increasing levels of co-expressed ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) and ultrastructural observations suggested microglial activation and reactive astrocytosis in the hippocampus. These activated microglia resulted in increased expressions of multiple proinflammatory cytokines. Simultaneously, EAP mice showed higher gene expressions of SLC6A4 and IDO and lower concentrations of serotonin. 1H-MRS indicated a decrease in the glutamate + glutamine (Glx)/total creatine (tCr) ratio in EAP mice. Furthermore, baicalein treatment alleviated the depressive-like behavior and neuroinflammation by suppressing the nuclear factor-kappa B (NF-κB) pathway. Conclusion Our data indicate that EAP-induced depressive-like behavior is linked to microglia activation and subsequent neurotransmitter metabolism. Moreover, baicalein attenuates behavioral changes by inhibiting neuroinflammation via downregulation of the NF-κB pathway.

Background: Post-stroke depression (PSD) is a frequent and serious complication of stroke. However, the underlying molecular basis of PSD remains largely unknown, and no empirical laboratory tests were available to diagnose this disorder. Materials and methods: A proton nuclear magnetic resonance (1H NMR)-based metabonomic approach was employed to profile plasma samples from 32 PSD, 35 stroke patients and 35 healthy comparison subjects (the training set) in order to identify metabolite biomarkers for PSD. Then, 10 PSD, 11 stroke patients and 11 healthy comparison subjects (test set) were used to validate the diagnostic performance of these biomarkers. Results: The multivariate statistical analysis demonstrated that PSD group was significantly distinguishable from non-PSD groups (non-depression stroke patients and healthy comparison group). Five plasma metabolites (phenylalanine, tyrosine, 1-methylhistidine, 3-methylhistidine and LDL CH3-(CH2)n-) were identified responsible for distinguishing PSD from non-PSD subjects. These metabolites were mainly involved in neurotransmitter metabolism and oxidative stress. The biomarker panel composing of these metabolites was capable of distinguishing test samples with a sensitivity of 100.0% and a specificity of 95.5%. Conclusion: Our findings suggest that plasma disturbances of neurotransmitter levels and oxidative stress were implicated in the onset of PSD; these disturbed metabolites biomarkers facilitate to the development of diagnostic tool for PSD.

Iron is essential for the functioning of all cells and organs, most critically for the developing brain in the fundamental neuronal processes of myelination, energy and neurotransmitter metabolism. Iron deficiency, especially in the first 1000 days of life, can result in long-lasting, irreversible deficits in cognition, motor function and behaviour. Pregnant women, infants and young children are most vulnerable to iron deficiency, due to their high requirements to support growth and development, coupled with a frequently inadequate dietary supply. An unrecognised problem is that even if iron intake is adequate, common pregnancy-related and lifestyle factors can affect maternal–fetal iron supply in utero, resulting in an increased risk of deficiency for the mother and her fetus. Although preterm birth, gestational diabetes mellitus and intrauterine growth restriction are known risk factors, more recent evidence suggests that maternal obesity and delivery by caesarean section further increase the risk of iron deficiency in the newborn infant, which can persist into early childhood. Despite the considerable threat that early-life iron deficiency poses to long-term neurological development, life chances and a country's overall social and economic progress, strategies to tackle the issue are non-existent, too limited or totally inappropriate. Prevention strategies, focused on improving the health and nutritional status of women of reproductive age are required. Delayed cord clamping should be considered a priority. Better screening strategies to enable the early detection of iron deficiency during pregnancy and early-life should be prioritised, with intervention strategies to protect maternal health and the developing brain.

Accumulating evidence has shown that inflammation, the gut microbiota and neurotransmitters are closely associated with the pathophysiology of depression. However, the links between the gut microbiota and neurotransmitter metabolism remain poorly understood. The present study aimed to investigate the neuroinflammatory reactions in chronic restraint stress (CRS)-induced depression and to delineate the potential links between the gut microbiota and neurotransmitter metabolism. C57BL/6 mice were subjected to chronic restraint stress for 5 weeks, followed by behavioural tests (the sucrose preference test, forced swim test, open field test and elevated plus maze) and analysis. The results showed that CRS significantly increased IL-1β, IL-2, IL-6 and TNFα levels and decreased BDNF expression, accompanied by the activation of IκBα-p-NF-κB signalling in the mouse hippocampus. In addition, the neurotransmitter metabolomics results showed that CRS resulted in decreased levels of plasma 5-HT, DA, and NE and their corresponding metabolites, and gut microbiota fecal metabolites with the 16S rRNA gene sequencing indicated that CRS caused marked microbiota dysbiosis in mice, with a significant increase in Helicobacter, Lactobacillus, and Oscillibacter and a decrease in Parabacteroides, Ruminococcus, and Prevotella. Notably, CRS-induced depressive behaviours and the disturbance of neurotransmitter metabolism and microbiota dysbiosis can be substantially restored by dexamethasone (DXMS) administration. Furthermore, a Pearson heatmap focusing on correlations between the microbiota, behaviours and neurotransmitters showed that Helicobacter, Lactobacillus, and Oscillibacter were positively correlated with depressive behaviours but were negatively correlated with neurotransmitter metabolism, and Parabacteroides and Ruminococcus were negatively correlated with depressive behaviours but were positively correlated with neurotransmitter metabolism. Taken together, the results suggest that inflammation is involved in microbiota dysbiosis and the disturbance of neurotransmitter metabolism in CRS-induced depressive changes, and the delineation of the potential links between the microbiota and neurotransmitter metabolism will provide novel strategies for depression treatment.

Polymorphisms of neurotransmitter metabolism genes were studied in patients with prostate cancer (PC) characterized by either reduced or extended serum prostate-specific antigen doubling time (PSADT) corresponding to unfavorable and favorable disease prognosis respectively. The 'unfavorable prognosis' group (40 cases) was defined by PSADT ≤ 2 months, whereas patients in the 'favorable prognosis' group (67 cases) had PSADT ≥ 30 months. The following gene polymorphisms known to be associated with neuropsychiatric disorders were investigated: a) the STin2 VNTR in the serotonin transporter SLC6A4 gene; b) the 30-bp VNTR in the monoamine oxidase A MAOA gene; c) the Val158Met polymorphism in the catechol-ortho-methyltransferase COMT gene; d) the promoter region C-521T polymorphism and the 48 VNTR in the third exon of the dopamine receptor DRD4 gene. The STin2 12R/10R variant of the SLC6A4 gene (OR = 2.278; 95% CI = 0.953-5.444) and the -521T/T homozygosity of the DRD4 gene (OR = 1.579; 95% CI = 0.663-3.761) tended to be overrepresented in PC patients with unfavorable disease prognosis. These gene variants are regarded as protective against schizophrenia, and the observed trend may be directly related to a reduced PC risk described for schizophrenia patients. These results warrant further investigation of the potential role of neurotransmitter metabolism gene polymorphisms in PC pathogenesis.

Inborn errors of neurotransmitter metabolism are ultrarare disorders affecting neurotransmitter biosynthesis, breakdown or transport or their essential cofactors. Neurotransmitter dysfunctions could also result from the impairment of neuronal receptors, intracellular signaling, vesicle release or other synaptic abnormalities. Epilepsy is the main clinical hallmark in some of these diseases (e.g. disorders of GABA metabolism, glycine encephalopathy) while it is infrequent in others (e.g. all the disorders of monoamine metabolism in exception for dihydropteridine reductase deficiency). This review analyzes the epileptogenic mechanisms, the epilepsy phenotypes and the principle for the clinical management of epilepsy in primary and secondary inherited disorders of neurotransmitter metabolism (disorders of GABA, serine and glycine metabolism, disorders of neurotransmitter receptors and secondary neurotransmitter diseases).

Recent studies have shown that long-term alcohol intake from food can lead to numerous mental disorders in humans, and the social and health effects of excessive intake of alcohol currently represent serious problems for governments and families worldwide. However, to date, it has not been determined how alcohol affects the hypothalamic–pituitary–adrenal (HPA) axis. The zebrafish offers a good model for studying the toxicology of food-grade ethanol. In the present study, using zebrafish larvae exposed to 1% ethanol, we performed zebrafish behavioral analysis. Samples were collected for enzyme-linked immunosorbent assay (ELISA) and quantitative real time-polymerase chain reaction (qRT-PCR) experiments, and statistical analysis was performed. We found that ethanol decreased the locomotor activity of zebrafish larvae, which showed a more intense reaction to external stimuli. Ethanol also increased the level of HPA axis hormones in zebrafish larvae, influenced the level of neurotransmitters, and altered the expression of key genes in neurotransmitter metabolism. Ethanol exposure affects zebrafish behavior, increases the level of HPA axis hormones in zebrafish larvae, affects the level of neurotransmitters, and affects the expression of key genes in dopamine and serotonin metabolism. These findings may help to elucidate the effects of ethanol on HPA axis activity.

Recent studies have revealed significant roles of neurotransmitters and gut microbiota along the gut-brain axis in Parkinson's disease (PD); however, the potential mechanisms remain poorly understood. In the current study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced characteristic PD neurobehavior changes accompanied by increased α-synuclein, apoptotic protein Bim, and cleaved caspase-3 and decreased expression of tyrosine hydroxylase (TH). Meanwhile, the tryptophan (Trp) and tyrosine (Tyr) neurotransmitter metabolites involving kynurenine (KYN), serotonin (5-HT), and dopamine (DA) pathways were significantly changed in serum. Furthermore, the step-limited enzymes, which are responsible for the key metabolic pathways of these neurotransmitters, were obviously dysregulated. The 16S rRNA gene sequence results indicated that the abundance and diversity of the microbiota were obviously decreased in MPTP-treated mice, the presence of Ruminococcus, Parabacteroides and Parasutterella genera were obviously increased, while Coriobacteriaceae, Flavonifractor, Lachnospiraceae, Lactobacillaceae, and Rikenellaceae abundance was markedly decreased. The connectivity between the gut microbiota and neurotransmitter metabolism revealed that the gut microbiota dysbiosis was associated with disturbance of the DA, KYN, and 5-HT metabolic pathways. Therefore, our results provide evidence that gut-microbiota-brain axis disturbance may play an important role in PD development and targeting this axis might provide a promising therapeutic strategy for PD.

The effect of a multicomponent nutraceutical on cerebral ischemia/reperfusion injury in male Wistar rats was investigated. Animals were administered with the nutraceutical, Trevo™, for 7 days before 30 min of bilateral common carotid artery occlusion-induced cerebral ischemia and 24 hr of reperfusion. Behavioral assessment, biochemical estimations in the brain cortex, striatum, and hippocampus, and hippocampal histopathological evaluation were carried out after treatments. Results showed that ischemia/reperfusion-induced motor and cognitive deficits were abated in rats pretreated with Trevo™. Additionally, prophylaxis with Trevo™ blunted ischemia/reperfusion-induced redox stress, proinflammatory events, disturbances in neurotransmitter metabolism, mitochondrial dysfunction, and histoarchitectural aberrations in the discreet brain regions. In summary, supplementation with Trevo™ provided neuroprotection to rats against transient cerebral ischemia/reperfusion injury and could be explored as a promising approach in stroke prevention. PRACTICAL APPLICATIONS: There is a worldwide increase in the incidence of cerebral ischemia or stroke. Although an advanced health care system and effective control of risk factors have led to the declining incidence in developed nations, a definitive cure for stroke remains elusive and the situation is growing worse in developing nations. The results of the present study revealed that supplementation with Trevo™ ameliorated neurobehavioral, neurochemical, and histopathological consequences of brain ischemia/reperfusion injury and could, therefore, be beneficial in stroke prevention and management.

Acute and chronic mental stress are both linked to somatic and psychiatric morbidity, however, the neurobiological pathways of these associations are still not fully elucidated. Mental stress is known to be immunomodulatory, which is one of the basic concepts of psychoneuroimmunology. In the present study, neurotransmitter precursor amino acid levels and derived biogenic amines were analyzed prior to and at 0, 30 and 60 min following an acute mental stress test (with/without chronic mental stress) in 53 healthy subjects. Psychometric measurements of mental stress, depression and anxiety were collected. Kynurenine/tryptophan was influenced by the factor acute mental stress (KYN/TRP increase), no influence of the factor chronic mental stress or any interaction was found. Phenylalanine/tyrosine was influenced by the factor acute mental stress (PHE/TYR increase) as well as by chronic mental stress (PHE/TYR decrease). Interactions were not significant. KYN/TRP correlated with state anxiety values, while PHE/TYR correlated negatively with chronic stress parameters. Kynurenic acid was significantly reduced in the acute and quinolinic acid in the chronic mental stress condition. In conclusion, neurotransmitter precursor amino acid levels and derived biogenic amines are influenced by acute and chronic mental stress. Mechanisms beyond direct immunological responses may be relevant for the modulation of neurotransmitter metabolism such as effects on enzyme function through cofactor availability or stress hormones.

Chronic intranasal administration of antibodies to glutamate to aging C57Bl/6 mice improved passive avoidance conditioning, had no effect on horizontal and vertical locomotor activity, but slowed locomotion in the open-field test. Administration of antibodies to glutamate increased the content of dopamine and its metabolites in mouse hippocampus, but had no effect on the metabolism of neurotransmitter amino acids. In the frontal cortex, antibodies to glutamate did not affect neurotransmitter metabolism, but increased the level of both excitatory and inhibitory amino acids without changing their ratio.

As an important environmental pollutant, the heavy metal cadmium has a significant negative impact on the stability of the ecological environment and on organismal health. Previous studies have shown that cadmium chloride can damage the nervous, skeletal, endocrine, and reproductive systems, but to our knowledge, the effects of cadmium on the behavior, neurotransmitter levels, and neuronal development in the offspring of exposed animals have not been reported. In the present study, sexually-mature zebrafish were exposed to cadmium chloride at different concentrations for 60 days, and in this background, behavior, neurotransmitters level, neuro-development and neurotransmitter metabolism was investigated in the F1 offspring. The results showed that exposure of the parental zebrafish to cadmium chloride resulted swimming speed and distance of F1 offspring significantly reduced; the levels of neurotransmitters, such as dopamine, serotonin, and acetylcholine is disrupted. neuro-development and neurotransmitter metabolism related genes expression pattern was altered, which cause zebrafish F1 offspring developmental neurotoxicity. These findings provide further insights into the harm posed by cadmium chloride to the aquatic ecosystems.

BACKGROUND: This study explored the association between pulmonary function (PF) and older adults’ language performance accuracy. Study rationale was anchored in aging research reporting PF as a reliable risk factor affecting cognition among the elderly. METHODS: 180 adult English native speakers aged 55 to 84 years participated in the study. PF was measured through forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio (FFR). Language performance was assessed with an action naming test and an object naming test, and two tests of sentence comprehension, one manipulating syntactic complexity and the other, semantic negation. Greater PF was predicted to be positively associated with all tasks. RESULTS: Unadjusted models revealed FVC and FEV1 effects on language performance among older adults. Participants with higher FVC showed better naming on both tasks and those with higher FEV1 had better object naming only. In covariate-adjusted models, only a positive FVC-object naming association remained. CONCLUSION: Findings were discussed in terms of brain oxygenation mechanisms, whereby good PF may implicate efficient oxygenation, supporting neurotransmitter metabolism that protects against neural effects of cerebrovascular risk. Effects on object naming were linked to putative differential oxygenation demands across language tasks.

Alzheimer's disease (AD) has been associated with the disturbance of brain glucose metabolism. The present study investigates brain glucose metabolism using 13C NMR metabolomics in combination with intravenous [1-13C]-glucose infusion in APP/PS1 transgenic mouse model of amyloid pathology at 10 months of age. We found that brain glucose was significantly accumulated in APP/PS1 mice relative to wild-type (WT) mice. Reductions in 13C fluxes into the specific carbon sites of tricarboxylic acid (TCA) intermediate (succinate) as well as neurotransmitters (glutamate, glutamine, γ-aminobutyric acid and aspartate) from [1-13C]-glucose were also detected in the brain of APP/PS1 mice. In addition, our results reveal that the 13C-enrichments of the C3 of alanine were significantly lower and the C3 of lactate have a tendency to be lower in the brain of APP/PS1 mice than WT mice. Taken together, the development of amyloid pathology could cause a reduction in glucose utilization and further result in decreases in energy and neurotransmitter metabolism as well as the lactate-alanine shuttle in the brain.

We investigated age-related changes in in vivo and in vitro functions and gene expression of the bladder of male and female mice. Mature and aged (12 and 27–30 month old) C57BL/6 mice of both sexes were used. Frequency volume, conscious free-moving cystometry and detrusor contractile and relaxant properties in in vitro organ bath were evaluated. mRNA expression level of muscarinic, purinergic, and β-adrenergic receptors and gene expression changes by cDNA microarray analysis of the bladder were determined. Cystometry demonstrated storage and voiding dysfunctions with ageing in both sexes. Detrusor strips from aged mice showed weaker contractile responses particularly in the cholinergic component and weaker relaxant responses to isoproterenol. These age-related impairments were generally severer in males. mRNA expression of bladder tissue was decreased for M3 muscarinic receptors in aged males and β2-adrenoceptors in aged females. cDNA microarray analysis results, albeit substantial sex difference, indicated “cell-to-cell signaling and interaction” as the most common feature of age-related gene expression. In summary, aged mice demonstrated voiding and storage dysfunctions resembling to detrusor hyperactivity with impaired contractility (DHIC), which were more pronounced in males. Genomic changes associated with aging may contribute to the age-related bladder functional deterioration in mice.

Background: Disruption of electrolyte, redox and neurochemical homeostasis alongside cellular energy crisis is a hallmark of cerebral ischaemia and reperfusion injury. Purpose: This study investigated the effect of kolaviron (KV) on cortical and striatal cation imbalance, oxidative stress and neurochemical disturbances as well as neurobehavioural deficits in animals subjected to bilateral common carotid artery occlusion (BCCAO)-induced ischaemia/reperfusion injury. Methods: KV was administered at a dose of 100 or 200 mg/kg to male Wistar rats 1 h before a 30 min BCCAO/4 h reperfusion (I/R). This was followed by neurobehavioral assessment and biochemical evaluations of cation levels, oxidative stress indicators, lactate dehydrogenase activity and acetylcholinesterase (AChE) activity in the brain of animals. Conclusion: KV significantly restored altered cortical and striatal Ca2+, Na+, K+ and Mg2+ levels, ameliorated redox imbalance, lactic acidosis and modified AChE activity caused by I/R injury. The favourable neurobehavioural effects of KV correlated with biochemical outcomes. The pharmacological potential of KV in the treatment and management of ischemic stroke and allied pathological conditions via multiple targets (neurotransmitter metabolism, bioenergetic failure and ionic homeostasis) is highlighted by the study.

Background Iron deficiency anemia (IDA) causes detrimental effects on physical growth which is attributed to poor appetite, altered endocrinologic profile and neurotransmitter metabolism. Objective To investigate the iron status of preschool children with IDA and its association with the degree of growth retardation at presentation, and to detect the effect of iron supplementation on growth velocity (GV) over a period of one year. Materials and methods A case-control study conducted in Diabetes Endocrine Metabolism Pediatric Unit in collaboration with the Pediatric Hematology clinic at Children’s Hospital, Cairo University included baseline and follow up anthropometric and hematological parameters of 40 IDA patients with mean age 2 ± 0.8 years compared to 40 healthy clinically non-anemic, age and sex-matched controls with mean age 2.7 ± 1.1 years. A daily total dose of 6 mg/kg/day of ferrous sulfate in 2–3 divided doses were given between meals to patients with IDA. Results At presentation, patients with IDA had low hemoglobin, hematocrits, serum iron, serum ferritin, height standard deviation score (SDS), weight SDS, and body mass index (BMI) SDS which improved significantly after treatment. The GV of IDA patients correlated significantly with serum ferritin concentration and also their BMI SDS correlated significantly with the serum ferritin concentration. Conclusion IDA during the first 6 years of life, when growth is fast, adversely affects both linear growth and weight gain which is reversible with iron therapy, thus adequate iron status is crucial for normal growth (height, weight and GV). The findings of the present study supported the beneficial effects of oral iron supplementation on physical growth parameters of IDA preschool children.

To examine whether edible peptide intake affects neurotransmitter metabolism in the brain, we evaluated the effect of peptides derived from soy proteins or fish collagen on free amino acids and monoamines in the mouse brain. Ingestion of soy peptides led to markedly higher levels of tyrosine, a catecholamine precursor, in the serum, and cerebral cortex compared to those following ingestion of vehicle alone or collagen peptides. Soy peptide ingestion also effectively increased 3-methoxy-4-hydroxyphenylethyleneglycol and normetanephrine, the principal metabolites of noradrenaline, in the cerebral cortex, hippocampus, and brainstem, whereas collagen peptides did not exert such effects. Further, soy peptide ingestion led to a significant increase in noradrenaline itself in the brainstem, where noradrenergic neurons are present. Noradrenergic turnover was also markedly stimulated in these regions after soy peptide ingestion. These in vivo observations suggest that soy peptide ingestion can maintain and promote the synthesis and metabolism of noradrenaline in the brain.

Perinatal exposure to bisphenol A (BPA) contributes to neurological disorders in offspring, but the underlying mechanisms are still poorly understood. The abnormal release of neuroactive metabolites in the tryptophan (TRP) and dopamine (DA) pathways is considered to be closely associated with some disorders. Thus, in this study, TRP and DA pathways in adult female mouse offspring were investigated when the pregnant mice were given either vehicle or BPA (2, 10, or 100 μg/kg/d) from day 6 of gestation until weaning. Then, the serum and brain samples of offspring were collected at 3, 6 and 9 months, and 12 neuroactive metabolites in the TRP and DA pathways were detected. The results showed that, in the TRP pathway, TRP levels decreased, whereas kynurenine (KYN) levels and TRP turnover increased in the brain. In the serum, TRP, KYN and 5-hydroxytryptamine (5-HT) levels decreased significantly. For the DA pathway, DA and DA metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA), reduced significantly in the brain and serum. DA turnover decreased dramatically in the brain but enhanced in the serum. The disturbance of these two metabolic pathways might be one of the potential mechanisms of BPA-induced neuropsychiatric disorders.

Introduction: Non-suicidal self-injury (NSSI) is a rapidly increasing mental health problem that requires more clinical attention. In this study, we aimed to explore the biobehavioral markers of NSSI in participants with mood disorders. Methods: A total of 45 participants with mood disorders (bipolar I, II, and major depressive disorder) were included in the study. Behavioral impulsivity was measured using the immediate memory task (IMT)/delayed memory task (DMT) and the go-no-go (GNG) tests. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1 β), and interleukin 6 (IL-6) and resting-state quantitative electroencephalography (qEEG) were measured. Results: The NSSI group had shorter GNG reaction time (GNG-RT) and higher TNF-α levels compared to the non-NSSI group. TNF-α was positively correlated with frontal theta power. In addition, GNG-RT showed a significant positive association with frontal alpha activity. Conclusion: NSSI in mood disorders was associated with increased behavioral impulsivity and greater inflammation. Increased pro-inflammatory cytokines were associated with frontal theta power. Increased inflammation might change major neurotransmitter metabolism, which eventually affects frontal function and decreases response inhibition. Further studies to explore their causal relationship are warranted.

Background There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. Methods and findings We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. Conclusions In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD., Uma Mahajan and coworkers study metabolic perturbations in specific brain regions in Alzheimer disease., Author summary Why was this study done? A growing body of evidence suggests that Alzheimer disease (AD) may be associated with dysregulation of multiple metabolic pathways, and identifying novel molecular targets underlying AD pathogenesis is essential for developing effective AD treatments. Past studies have shown that abnormalities in choline-related biochemical pathways may be associated with AD pathogenesis, specifically the transmethylation, polyamine synthesis/catabolism and related pathways. Our study tested the hypothesis that dysregulation of choline-related biochemical pathways in the brain is associated with AD pathogenesis; we examined metabolites within biochemical reactions linked to transmethylation and polyamine synthesis/catabolism. What did the researchers do and find? We performed quantitative and targeted metabolomics on brain tissue samples (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) and transcriptomics from Gene Expression Omnibus data (entorhinal cortex [AD: n = 25; CN: n = 52] and hippocampus [AD: n = 29; CN: n = 56]) to identify aberrations across 6 biochemical reactions linked to the transmethylation and polyamine pathways: methionine cycle, transsulfuration and glutathione synthesis, polyamine synthesis and catabolism, urea cycle, glutamate-aspartate metabolism, and neurotransmitter metabolism. We found significant metabolite alterations associated with AD mainly in the inferior temporal gyrus (ITG) across all pathways tested, as well as associations between metabolite concentrations and severity of AD pathology. Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. What do these findings mean? Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to severity of AD pathology and the expression of clinical symptoms. This study adds to a comprehensive understanding of the metabolic basis of AD pathogenesis and provides insights into novel targets for disease-modifying therapies. The cross-sectional nature of the study limits our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression.

Inherited neurotransmitter disorders are primary defects of neurotransmitter metabolism and transport or of their cofactor metabolism. They include defects of catecholamine, serotonin, biopterin, glycine, pyridoxine, and gamma amino butyric acid metabolism. The diagnosis is suspected by cerebrospinal fluid amino acid and neurotransmitter analysis in inherited neurotransmitter disorders. Lumbar punctures are widely used among patients with neurological signs and symptoms such as seizures, developmental delay, central hypotonia, and movement disorders including chorea, choreoathetosis, dystonia, dyskinesia, and ataxia. As some of the inherited neurotransmitter disorders are treatable, CSF neurotransmitter measurements would be necessary to diagnose these disorders for the initiation of the disease-specific treatment.

BACKGROUND: Cholinesterase inhibitors represent three of the four treatments for Alzheimer's disease (AD), and target the pathological reduction of acetylcholine levels. Here we aimed to study the role of other neurotransmitter pathways in AD pathology.OBJECTIVE: This study aimed to determine associations between AD pathology at both symptomatic and asymptomatic stages of disease progression, and the metabolism of a range of non-cholinergic neurotransmitters.METHODS: Tissue samples were obtained from three groups, controls, AD, and 'asymptomatic AD' (ASYMAD), i.e., cognitively normal individuals that had significant AD neuropathology. Three brain areas were studied, the middle frontal gyrus (MFG), the inferior temporal gyrus (ITG), and the cerebellum.RESULTS: 12 of 15 metabolites involved in neurotransmitter metabolism were shown to be associated with AD pathology. Decreases in dopamine were most pronounced in the MFG with lower levels seen in the ASYMAD group compared to control (FC = 0.78, p = 2.9×10-2). In the ITG significant changes were seen in GABAergic and serotonin metabolism between control and AD patients; however, these changes were not seen between control and ASYMAD individuals.CONCLUSION: These results indicate that dopamine could be depleted in brains with AD pathology but intact cognition, while an imbalance of several neurotransmitters is evident in the brains of AD patients.

We studied the effects of the addition of large neutral amino acids, such as tyrosine (Tyr) and tryptophan (Trp), in mice DBA/2J and tetrahybrid mice DBCB receiving a high-fat, high-carbohydrate diet (HFCD) for 65 days. The locomotor activity, anxiety, muscle tone, mass of internal organs, liver morphology, adipokines, cytokines, and biochemical indices of animals were assessed. The Tyr supplementation potentiated increased anxiety in EPM and contributed to a muscle tone increase, a decrease in the AST/ALT ratio, and an increase in protein anabolism in both mice strains. Tyr contributed to a decrease in liver fatty degeneration and ALT reduction only in DBCB that were sensitive to the development of obesity. The addition of Trp caused an increase in muscle tone and potentiated an increase in anxiety with age in animals of both genotypes. Trp had toxic effects on the livers of mice, which was manifested in increased fatty degeneration in DBCB, edema, and the appearance of micronuclei in DBA/2J. The main identified effects of Tyr on mice are considered in the light of its modulating effect on the dopamine neurotransmitter metabolism, while for the Trp supplement, effects were presumably associated with the synthesis of its toxic metabolites by representatives of the intestinal microflora.

Chronic inflammation, which changes the neurotransmitter metabolism and kindles neuroendocrine system dysfunction in the central nervous system, might cause fibromyalgia (FM) formation. In FM patients without traditional FM risk factors, such as hypertension, hyperlipidemia, diabetes, sleep disorder, depression, and anxiety, the chronic inflammatory process is a possible risk factor for FM. Thus, we investigated whether chronic osteomyelitis (COM), a disease characterized by chronic inflammation, increases FM risk. Including data for 1 million enrollees, the Longitudinal Health Insurance Database was used, and 1,244 COM patients without FM history and 4,976 randomly selected sex- and age-matched control subjects without COM or FM history were extracted. The development of FM over a 13-year follow-up period from 1999 to 2011 was evaluated, and FM risk was estimated using the Cox proportional regression model. The aforementioned FM risk factors were more common in COM patients, who had a significantly greater FM risk than did the control subjects. Compared with those who had no associated risk factors, patients with COM had a greater FM risk than did the control subjects (adjusted hazard ratio [aHR] = 1.32, 95% confidence interval [CI], .99–1.75). Younger people had an even greater risk (age younger than 35 years: aHR = 1.58, 95% CI, 1.03–2.44; age 60 years or older: aHR = 1.03, 95% CI, .78–1.36). To our knowledge, this is the first study to link COM to an enhanced risk of FM development. The results imply that COM is a predictor of FM, suggesting that close follow-up for patients with COM is required to prevent FM, especially in younger populations. Perspective COM is associated with the augmented risk of developing FM, and rigorous treatments for COM patients might decrease the future risk of FM formation, especially in those with relatively younger ages.

The analysis demonstrates the role of the EEG mapping in evaluation of neurotoxicity in two children aged 9 and 13 with non-Hodgkin’s lymphoma (NHL) who underwent treatment by m-BFM-90 scheme. The evaluation of brain bioelectrical activity was performed prior treatment, after induction, protocol-M, and after chemotherapy course. The healthy children were allocated to the control group. We detected that EEG in the children with NHL before the beginning of the treatment differed from the EEG in the healthy children of the same age. Patients showed alpha and beta activity deficiency and an increase in values of the spectral density of the theta frequency band in fronto-central parts of the cortex. This fact indicates a certain dysfunction of diencephalic brain stem structures, probably, due to metabolic disorders of neurotransmitter metabolism in connection with the pathological process. During chemotherapy, the normalization of the functional state of the brain was registered in the adolescent aged 13, while clinical, biochemical, and neurophysiological parameters in the nine-year child revealed neurotoxicity. Comparison of EEG mapping data of the patient with symptoms of neurotoxicity during therapy with those before the treatment showed an increase in the spectral density values in the theta- and beta-2 bands and a decrease in the alpha-2 band (p

Item does not contain fulltext Previous studies have suggested that alterations in excitatory/inhibitory neurotransmitters might play a crucial role in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopy (1H-MRS) can provide valuable information about abnormal brain metabolism and neurotransmitter concentrations. However, few 1H-MRS studies have been published on the imbalance of the two most abundant neurotransmitters in ASD: glutamate (Glu) and gamma-aminobutyric acid (GABA). Moreover, to our knowledge none of these published studies is performed with a study population consisting purely of high-functioning autism (HFA) adolescents. Selecting only individuals with HFA eliminates factors possibly related to intellectual impairment instead of ASD. This study aims to assess Glu and GABA neurotransmitter concentrations in HFA. Occipital concentrations of Glu and GABA plus macromolecules (GABA+) were obtained using 1H-MRS relative to creatine (Cr) in adolescents with HFA (n=15 and n=13 respectively) and a healthy control group (n=17). Multiple linear regression revealed significantly higher Glu/Cr and lower GABA+/Glu concentrations in the HFA group compared to the controls. These results imply that imbalanced neurotransmitter levels of excitation and inhibition are associated with HFA in adolescents. 6 p.

Gases that are not metabolized by the organism are thus chemically inactive under normal conditions. Such gases include the "noble gases" of the Periodic Table as well as hydrogen and nitrogen. At increasing pressure, nitrogen induces narcosis at 4 absolute atmospheres (ATAs) and more in humans and at 11 ATA and more in rats. Electrophysiological and neuropharmacological studies suggest that the striatum is a target of nitrogen narcosis. Glutamate and dopamine release from the striatum in rats are decreased by exposure to nitrogen at a pressure of 31 ATA (75% of the anesthetic threshold). Striatal dopamine levels decrease during exposure to compressed argon, an inert gas more narcotic than nitrogen, or to nitrous oxide, an anesthetic gas. Inversely, striatal dopamine levels increase during exposure to compressed helium, an inert gas with a very low narcotic potency. Exposure to nitrogen at high pressure does not change N-methyl-d-aspartate (NMDA) glutamate receptor activities in Substantia Nigra compacta and striatum but enhances gama amino butyric acidA (GABAA) receptor activities in Substantia Nigra compacta. The decrease in striatal dopamine levels in response to hyperbaric nitrogen exposure is suppressed by recurrent exposure to nitrogen narcosis, and dopamine levels increase after four or five exposures. This change, the lack of improvement of motor disturbances, the desensitization of GABAA receptors on dopamine cells during recurrent exposures and the long-lasting decrease of glutamate coupled with the higher sensitivity of NMDA receptors, suggest a nitrogen toxicity induced by repetitive exposures to narcosis. These differential changes in different neurotransmitter receptors would support the binding protein theory. © 2016 American Physiological Society. Compr Physiol 6:1579-1590, 2016.

Background Major depressive disorder (MDD) is a serious debilitating psychiatric disorder. However, the molecular mechanisms of MDD remain largely unknown, and no objective laboratory-based tests are available to diagnose this disorder. Methods A gas chromatography-mass spectrometry (GC-MS) based metabolomic approach was used to compare peripheral blood mononuclear cells (PBMC) metabolic profiling of 50 first onset drug-naive MDD subjects and 50 healthy controls (training samples), to identify potential metabolite biomarkers for MDD. An independent sample cohort including 58 MDD patients, 40 schizophrenia (SCZ) patients and 56 healthy controls (test samples) was used to validate diagnostic generalizability and specificity of identified biomarkers. Results 17 PBMC metabolites responsible for discriminating MDD group from healthy control group were identified. These metabolites were mainly involved in disturbances of energy and neurotransmitter metabolism. This PBMC metabolite signature could effectively discriminate MDD subjects from the healthy controls with an AUC of 0.926 in training samples and 0.870 in test samples. Moreover, this metabolite signature enabled distinguishing MDD subjects from schizophrenia subjects with an AUC of 0.899. Limitations This study was limited by potential confounding effects of different drug treatments in some MDD and schizophrenia subjects, and lack of animal studies to further validate the identified metabolite pathways in MDD. Conclusion These findings suggest that early disturbances of PBMC energy and neurotransmitter metabolism may be associated with the onset of MDD. This PBMC metabolite signature may facilitate development of a laboratory-based diagnostic test for MDD.

Type 1 diabetes (T1D) has been reported to cause cognitive decline, but brain metabolic changes during this process are still far from being fully understood. Here, we found that streptozotocin (STZ)-induced T1D mice exhibited impaired learning and memory at 11 weeks after STZ treatment but not at 3 weeks. Therefore, we studied metabolic alterations in six different brain regions of T1D mice with and without cognitive decline, and attempted to identify key metabolic pathways related to diabetic cognitive dysfunction. The results demonstrate that lactate had already increased in all brain regions of T1D mice prior to cognitive decline, but a decreased TCA cycle was only observed in hippocampus, cortex and striatum of T1D mice with cognitive impairment. Reduced N-acetylaspartate and choline were found in all brain regions of T1D mice, irrespective of cognitive decline. In addition, disrupted neurotransmitter metabolism was noted to occur in T1D mice before cognitive deficit. Of note, we found that the level of uridine was significantly reduced in cerebellum, cortex, hypothalamus and midbrain of T1D mice when cognitive decline was presented. Therefore, brain region-specific metabolic alterations may comprise possible biomarkers for the early-diagnosis and monitoring of diabetic cognitive decline. Moreover, down-regulated TCA cycle and pyrimidine metabolism could be closely related to T1D-associated cognitive impairment.

The menopausal syndrome is associated with a combination of neuropsychic, autonomic, vascular, and metabolic disorders. Sex steroids regulate neurotransmitter metabolism, activate neuronal plasticity, improve cerebral blood flow, maintain a stable mood, and have an antidepressant effect. In Russia, only 1% of women use menopausal hormone therapy (MHT). The reason for the low adherence to MHT is avoidance of using hormones because of the possible risks of cancer.To evaluate the effect of subnarcotic doses of xenon on the menopausal syndrome signs in patients during the menopausal transition.A comparative study including 32 randomly selected female patients with menopausal syndrome during the menopausal transition was conducted. Group 1 (the study treatment group) included 16 patients who refused to use MHT. They received a course of xenon therapy, consisting of 5 procedures every other day. Group 2 (control group) included 16 patients receiving MHT. Menopausal symptoms were assessed using the Greene Menopausal Scale. Psychoemotional status was determined using the Spielberger-Hanin neuropsychological test. Estradiol and progesterone concentrations were measured in a morning saliva sample to determine the steroid profile. The parameters were assessed and compared at baseline and 1 month after the start of therapy.In assessing the severity of the menopausal syndrome in women in both groups, the significantly decreased mean final Green's scale score was observed: from 17.12±3.28 to 6.12±4.34 points in group 1 and from 16.01±4.12 to 4.02±3.12 points in group 2. Also a significant decrease in state and trait anxiety compared with baseline data was demonstrated. In the study treatment group, the trait anxiety score decreased from 53.1 [35.1; 66.0] to 27.2 [25.3; 30.0] points, and in the control group, from 55.6 [38.2; 70.4] to 22.0 [20.2; 25.0] points. Similar change was shown for the state anxiety score in the study groups. A decrease from 40.1 [35.3; 45.0] to 21.0 [23.2; 27.3] points in group 1 and from 46.1 [45.2; 52.0] to 20.1 [16.3; 23.0] points in group 2 was observed. At one month, the significant increase of estradiol (from 1.1 [0.5; 2.1] to 12.2 [10.3; 14.4] pg/mL) and progesterone (from 14.0 [4.4; 20.1] to 100.2 [60.6; 130.0] pg/mL) was observed in the MHT group of patients. No significant changes in hormone levels were recorded in the xenon therapy group.The xenon inhalations in subnarcotic doses are an effective method to control the vasomotor and psychoemotional signs and symptoms of the menopausal syndrome in patients who refuse to use MHT or have contraindications to this type of therapy.Климактерический синдром сопровождается комплексом нервно-психических, вегетососудистых и обменных нарушений. Половые стероиды регулируют обмен нейротрансмиттеров, активируют нейрональную пластичность, улучшают церебральное кровообращение, поддерживают стабильное настроение, обладают антидепрессивным эффектом. В России только 1% женщин используют менопаузальную гормональную терапию (МГТ). Причиной низкой приверженности МГТ является опасение использования гормонов в связи с возможными рисками возникновения онкологических заболеваний.Оценить влияние субнаркотических доз ксенона на проявления климактерического синдрома у пациенток в периоде менопаузального перехода.Проведено сравнительное исследование с участием 32 случайно выбранных пациенток с климактерическим синдромом в периоде менопаузального перехода. В 1-ю (основную) группу вошли 16 пациенток, отказавшихся использовать МГТ. Им проведен курс ксенонотерапии, состоящий из 5 процедур через день. Во 2-ю (контрольную) группу включены 16 пациенток, принимающих МГТ. Оценку менопаузальных симптомов проводили с использованием климактерической шкалы Грина. Определение состояния психоэмоционального статуса выполняли с применением нейропсихологического теста Спилбергера—Ханина. Для анализа стероидного профиля определяли концентрацию эстрадиола и прогестерона в утренней пробе слюны. Оценку и сравнение показателей проводили исходно и через 1 мес после начала терапии.При оценке степени тяжести климактерического синдрома у женщин в обеих группах средний итоговый балл по шкале Грина статистически значимо уменьшился: с 17,12±3,28 до 6,12±4,34 балла в 1-й группе и с 16,01±4,12 до 4,02±3,12 балла во 2-й группе. Также отмечено значимое снижение показателей ситуативной и личностной тревожности по сравнению с исходными данными. В основной группе показатель личностной тревожности снизился с 53,1 [35,1; 66,0] до 27,2 [25,3; 30,0] балла, в контрольной — с 55,6 [38,2; 70,4] до 22,0 [20,2; 25,0] балла. Аналогичная динамика выявлена для показателей ситуативной тревожности в группах исследования. Наблюдали снижение показателя с 40,1 [35,3; 45,0] до 21,0 [23,2; 27,3] балла в 1-й группе и с 46,1 [45,2; 52,0] до 20,1 [16,3; 23,0] балла во 2-й группе. Через месяц в группе пациенток, применявших МГТ, существенно повысился уровень эстрадиола (с 1,1 [0,5; 2,1] до 12,2 [10,3; 14,4] пг/мл) и прогестерона (с 14,0 [4,4; 20,1] до 100,2 [60,6; 130,0] пг/мл). Значимых изменений концентрации гормонов в группе ксенонотерапии не зафиксировано.Применение ингаляции ксенона в субнаркотических дозировках позволяет эффективно купировать вазомоторные и психоэмоциональные проявления климактерического синдрома у пациенток, не желающих применять МГТ или имеющих противопоказания к этому виду терапии.

Huntington's disease (HD) is a hereditary and fatal disease causing profound neurodegeneration. Deficits in cerebral energy and neurotransmitter metabolism have been suggested to play a central role in the neuronal dysfunction and death associated with HD. The branched-chain amino acids (BCAAs), leucine, isoleucine and valine, are important for cerebral nitrogen homeostasis, neurotransmitter recycling and can be utilized as energy substrates in the tricarboxylic acid (TCA) cycle. Reduced levels of BCAAs in HD have been validated by several reports. However, it is still unknown how cerebral BCAA metabolism is regulated in HD. Here we investigate the metabolism of leucine and isoleucine in the R6/2 mouse model of HD. Acutely isolated cerebral cortical and striatal slices of control and R6/2 mice were incubated in media containing 15N- or 13C-labeled leucine or isoleucine and slice extracts were analyzed by gas chromatography-mass spectrometry (GC-MS) to determine isotopic enrichment of derived metabolites. Elevated BCAA transamination was found from incubations with [15N]leucine and [15N]isoleucine, in both cerebral cortical and striatal slices of R6/2 mice compared to controls. Metabolism of [U-13C]leucine and [U-13C]isoleucine, entering oxidative metabolism as acetyl CoA, was maintained in R6/2 mice. However, metabolism of [U-13C]isoleucine, entering the TCA cycle as succinyl CoA, was elevated in both cerebral cortical and striatal slices of R6/2 mice, suggesting enhanced metabolic flux via this anaplerotic pathway. To support the metabolic studies, expression of enzymes in the BCAA metabolic pathway was assessed from a proteomic resource. Several enzymes related to BCAA metabolism were found to exhibit augmented expression in the R6/2 brain, particularly related to isoleucine metabolism, suggesting an increase in the BCAA metabolic machinery. Our results show that the capacity for cerebral BCAA metabolism, predominantly of isoleucine, is amplified in the R6/2 brain and indicates that perturbations in cerebral BCAA homeostasis could have functional consequences for HD pathology.

Background The mechanisms underlying the association between immune activation and postpartum depression remained elusive. Although Ω-3 fatty acids possess anti-inflammatory properties, there is limited evidence directly linking the modulating effects of Ω-3 fatty acids on neuroimmune and neurochemistry to the antidepressant actions. Methods A between-groups design was used to assess the effects of reproductive status (virgin or parous) and Ω-3 fatty acids content (control and supplementary). Serum inflammatory cytokine levels (IL-1a, IL-1β, IL-2, IL-6, IL-12, TNF-a, IFN-γ) were evaluated using the Bio-Plex Luminex System. Moreover, we also measured the protein levels of Purinergic type 2X7 receptor (P2X7R), NOD-like receptor pyrin domain containing 3 (NLRP3) and Nuclear factor-kappaB (NF-κB). Lastly, we assessed the function of various neurotransmitter systems to link the inflammatory response and neurotransmitter metabolism. Results Pro-inflammatory cyrokines, including IL-1a, IL-6, TNF-a and IFN-γ were markedly induced in the serum of parous rats, although no significantly depressive-like behavior was found. Meanwhile, NLRP3 and NF-κB were decreased in certain brain areas. Moreover, gestational stress significantly induced neurochemical disturbance, which is partly restored by Ω-3 fatty acids supplementation. Conclusions These findings strengthen the link between inflammation, neurochemistry and postpartum depression, and further provide novel insights into the antidepressant effect of Ω-3 fatty acids.

Disruptions in methyl group metabolism have been associated with a number of disease states, including birth defects, cardiovascular disease, and neurological disorders. Therefore, characterization of the factors that regulate folate and methyl group supply is essential for the development of disease treatments and prevention. Glycine N-methyltransferase (GNMT), an enzyme essential to methyl group balance, is markedly increased by retinoic acid treatment. Furthermore, retinoid therapy has been shown to impact neurotransmitter metabolism, thereby contributing to the development of major depressive disorder. Recently, it has been shown that depressed patients have low levels of folate, other B-vitamins, and S-adenosyl methionine (SAM), all compounds essential for maintaining effective methyl group metabolism. The following studies were conducted to further characterize the impact of oral retinoic acid administration, and to investigate the potential prevention of any detrimental effects by administering oral SAM. In the preliminary study (Chapter 2), as expected, GNMT activity was significantly increased in rats receiving all-trans retinoic acid (ATRA). Additionally, whole brain serotonin levels were decreased by 46% in rats receiving ATRA, an effect that was partially attenuated by oral

SCOPE Vitamin B6 plays crucial roles on brain development and its maternal deficiency impacts the gamma-aminobutyric acid (GABA)ergic, serotonergic, glutamatergic, and dopaminergic systems in offspring. However, the molecular mechanisms underlying these neurological changes are not well understood. Thus, we aimed at evaluating which components of those neurotransmitter metabolism and signaling pathways can be modulated by maternal vitamin B6 -deficient or B6 -supplementated diets in the hippocampus of rat dams and their offspring. METHODS AND RESULTS Female Wistar rats were fed three different diets: control (6 mg vitamin B6 /kg), supplemented (30 mg vitamin B6 /kg) or deficient diet (0 mg vitamin B6 /kg), from 4 weeks before pregnancy through lactation. Newborn pups (10 days old) from rat dams fed vitamin B6 -deficient diet presented hyperhomocysteinemia and had a significant increase in mRNA levels of glutamate decarboxylase 1 (Gad1), fibroblast growth factor 2 (Fgf2), and glutamate-ammonia ligase (Glul), while glutaminase (Gls) and tryptophan hydroxylase 1 (Tph1) mRNAs were downregulated. Vitamin B6 supplementation or deficiency did not change hippocampal global DNA methylation. CONCLUSION A maternal vitamin B6 -deficient diet affects the expression of genes related to GABA, glutamate, and serotonin metabolisms in offspring by regulating Gad1, Glul, Gls, and Tph1 mRNA expression.

Background The manifestation of chronic pain and psychological impairments are related to alterations of neurotransmitter metabolism in cerebral pain processing regions, e.g., anterior cingular cortex (ACC), insula. Magnetic resonance spectroscopy ((1)H-MRS) enables in vivo quantification of neurotransmitters in the brain and was applied in this study to examine the hypothesized chronic pain-related imbalance between excitatory (glutamatergic) and inhibitory (GABA-ergic) neurotransmitter turnovers in the brain of patients with nonspecific chronic pain. Materials and methods A total of 19 patients with nonspecific chronic (> 3 months) back pain and 19 age- and gender-matched healthy subjects participated in this study. Glutamate and GABA as well as glutamate/GABA ratios were determined in the ACC and insula using (1)H-MRS. Sociodemographic, psychological, and pain-related features were measured with standardized questionnaires. Results There was a strong variance of glutamate/GABA ratios for both patients and healthy subjects with no significant difference between the two groups. Regression analysis revealed certain significant predictors, such as anxiety as causal variable for reduced glutamate and depression and age as predictors for reduced GABA in ACC. In the patient group, intensity of pain was a significant predictor for glutamate and GABA levels in the insula. Conclusions Despite the uniform diagnosis of nonspecific chronic back pain, we observed a strong variance of neurotransmitters in cerebral pain processing regions. It is necessary to include psychological as well as clinical parameters (e.g., intensity of pain or depression) for a proper interpretation of neurotransmitter turnovers.

Depression may result in far reaching adverse health outcomes in addition to impaired sociooccupational or quality of life. Depression is commonly associated with greater cardiovascular morbidity and mortality. Dysregulated inflammation has been suggested as one of the plausible underlying mechanism relating the two. Several studies have reported elevated levels of proinflammatory cytokines and acute phase proteins in depression patients. The proinflammatory cytokines have been shown to alter various signaling pathway relevant to depression such as neurotransmitter metabolism, neuroendocrine dysfunction, and synaptic plasticity after reaching the brain. Potential pathways which have been implicated in mediating the depression and inflammation include the tryptophan-kynurenine pathway, hypothalamic-pituitary-adrenal axis dysregulation, and neuronal plasticity. Inflammation appears to play a pivotal role in the pathophysiology of depression but only in subset of depressive patients. It may prove to be an effective target to develop several treatment modalities and thus open avenues for development of potential therapeutic strategies in vulnerable at risk depressive patients.

Polymorphisms in ApoE are highly correlated with the progression of neurodegenerative disease, in particular Alzheimer’s disease. Little is known, however, about the role of ApoE or cholesterol metabolism on brain neurochemistry in general. To better understand the role of lipoprotein and cholesterol metabolism in the brain, we profiled 6-week and 12-week old Apoe KO and Ldlr KO mouse models via unbiased metabolomics to determine which metabolites were affected at an early age to identify those that may play a role in triggering pathology later in life. Steady-state metabolomics revealed only subtle differences among Apoe KO, Ldlr KO and WT mouse brains. Ldlr KO mice exhibited alterations in metabolites involved in neurotransmitter, amino acid and cholesterol metabolism. In contrast, Apoe KO mice only showed subtle changes in amino acid and neurotransmitter metabolism. These subtle changes in a broad range of metabolites indicate that ApoE and Ldl-R alone may not play a significant role in these mouse models at an early age, but instead require the cumulative effect from different pathways that lead to dysfunction at a much later stage of life.

Ferdinando Squitieri,1 Justo Garcia de Yebenes2 1IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo and Mendel Institute of Human Genetics, Rome, Italy; 2Fundación para Investigaciones Neurológicas, Madrid, Spain Abstract: Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia), impaired voluntary movements (ie, incoordination and gait balance), progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt). The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpiperidines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl-piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl-phenyl]-1-propyl-piperidine) are members of a new class of pharmacologic agents known as “dopamine stabilizers”. Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice) highlighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and σ-1 receptor binding and modulation). These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD. Keywords: Huntington disease, dopamine, neuroprotection, pridopidine

We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.

Rationale: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. Objective: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. Methods and Results: As in dopamine β-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 ( CYB561 ); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561 (− /− ) mice compared with wild-type mice ( P P l -dihydroxyphenylserine, which can be converted directly to norepinephrine. Conclusions: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.

Acupuncture and moxibustion proved to be very effective in chronic atrophic gastritis (CAG). According to the Chinese traditional medicine theory, chronic diseases have an influence on the function of liver and kidney. However, there is little research to demonstrate this theory. This study is aimed at assessing the1H NMR-based metabolic profiling in liver and kidney of CAG rats and comparing the difference between electroacupuncture and moxibustion treatment. Male SD rats were subjected to CAG modeling by intragastric administration of mixture of 2% sodium salicylate and 30% alcohol coupled with compulsive sporting and irregular fasting for 12 weeks and then treated by electroacupuncture or moxibustion at Liangmen (ST 21) and Zusanli (ST 36) acupoints for 2 weeks. A1H NMR analysis of liver and kidney samples along with histopathological examination and molecular biological assay was employed to assess and compare the therapeutic effects of electroacupuncture and moxibustion. CAG brought characterization of metabolomic signatures in liver and kidney of rats. Both electroacupuncture and moxibustion treatment were found to normalize the CAG-induced changes by restoring energy metabolism, neurotransmitter metabolism, antioxidation metabolism, and other metabolism, while the moxibustion treatment reversed more metabolites related to energy metabolism in liver than electroacupuncture treatment. CAG did have influence on liver and kidney of rats. Both of these treatments had good effects on CAG by reversing the CAG-induced perturbation in liver and kidney. For regulating the energy metabolism in liver, the moxibustion played more important role than electroacupuncture treatment.

l -homoarginine ( l -hArg) is an endogenous non-proteinogenic amino acid. Low l -hArg concentrations are associated with increased all-cause mortality, fatal strokes, and worse outcome after stroke. On the other hand, oral supplementation with l -hArg in mice improved neurological deficits and preserved cardiac function in experimental models of stroke and heart failure, respectively. Recently, oral supplementation with 125 mg daily l -hArg capsules in healthy volunteers demonstrated increased l -hArg plasma levels. Therefore, oral l -hArg supplementation could represent a potential treatment for patients with cerebrovascular disease. In addition to vascular physiology, animal studies have suggested that l -hArg might play a role in synapse function, neurotransmitter metabolism and cognitive training. However the direct influence of l -hArg on cognitive function has not been studied so far. In this study, cognitive performance in healthy humans was analyzed concerning memory, learning, and attention following supplementation with placebo or l -hArg for 4 weeks. Our results did not reveal any effects on cognition, neither impairment nor improvement, upon l -hArg supplementation. Therefore, potential l -hArg treatment is not expected to cause any acute neurocognitive or behavioral side effects.