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The extent of damage to the nervous, vascular and microcirculatory systems in diabetic patients determine the regulation of physiological events that lead to the formation of chronic wounds, reduction of patient quality of life and increase of the financial value of medical care. Successful physiological repair is impossible without the successive phases of inflammation, proliferation and wound healing. Keratinocytes are the major cellular barrier components of the epidermis. These cells play an important role in physiological repair, as suggested by recent research, with many cells able to secrete steroid hormones de novo. Damage to the integrity of the skin leads to keratinocyte activation, triggering a cascade of reactions that contribute to changes in epidermal cell phenotype and lead to their proliferation and migration, analogous to changes in cellular adhesion and configuration of the cytoskeleton. An open question remains as to how the keratinocyte cell cycle, which is altered under conditions of hyperglycemia, and neurotransmitter metabolism during different stages of physiological repair are regulated. Understanding these processes will provide a scientific basis for the development of new targets for pharmacotherapies.

Published data describing the current status and prospects for the development of clinical diagnostics of a number of neurodegenerative and neuroendocrine diseases associated with neurotransmitter balance disorders in a human body are generalized, systematized, and assessed in the review. Characteristics, advantages, and limitations of neuroimaging techniques and different diagnostic methods based on measuring concentrations of protein markers, catecholamines, and their metabolites are discussed. Prospects of the application of optical methods, such as fluorimetry and surface-enhanced Raman spectroscopy, to the development of sensor systems for the diagnosis of these diseases by the concentration of catecholamines and their metabolites in biological fluids are demonstrated.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

Inherited neurotransmitter disorders are rare neurometabolic conditions which encompass genetic disorders of neurotransmitter metabolism or transport. The clinical manifestations of these rare disorders are often nonspecific, ranging from encephalopathies and seizures to movement disorders. As a consequence, neurotransmitter disorders are underrecognized and often misdiagnosed. Accurate and timely diagnosis is, however, of utmost importance, given the availability of therapeutic strategies. A high index of clinical suspicion and familiarity with the neuroimaging phenotypes is therefore crucial. While the imaging features of various neurotransmitter disorders often overlap and are nonspecific, imaging can be helpful in providing useful clues to guide the diagnostic algorithm for uncommon conditions in a neonate presenting with nonspecific neurological symptoms. In this review paper, we aim to bring together current knowledge of neuroimaging phenotypes associated with inherited (primary) disorders of neurotransmitter biosynthesis. Magnetic resonance imaging phenotypes of disorders of monoamine biosynthesis, primary cerebral folate deficiency, disorders of pyridoxine metabolism, disorders of gamma-aminobutyric acid metabolism, nonketotic hyperglycinemia (glycine encephalopathy), disorders of serine biosynthesis, and cerebral creatine deficiency syndrome will be discussed and illustrated with case examples.

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.

Mast cells are rare tissue-resident cells of importance to human allergies. To understand the structural basis of principle mast cell functions, we analyzed the proteome of primary human and mouse mast cells by quantitative mass spectrometry. We identified a mast-cell-specific proteome signature, indicative of a unique lineage, only distantly related to other immune cell types, including innate immune cells. Proteome comparison between human and mouse suggested evolutionary conservation of core mast cell functions. In addition to specific proteases and proteins associated with degranulation and proteoglycan biosynthesis, mast cells expressed proteins potentially involved in interactions with neurons and neurotransmitter metabolism, including cell adhesion molecules, ion channels, and G protein coupled receptors. Toward targeted cell ablation in severe allergic diseases, we used MRGPRX2 for mast cell depletion in human skin biopsies. These proteome analyses suggest a unique role of mast cells in the immune system, probably intertwined with the nervous system.

Chemotherapeutics can induce oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, and abnormalities in neurotransmitter metabolism leading to toxicity. Because there have been no therapeutic strategies developed to target inflammation and oxidative stress, there is a continuing need for new and improved therapy. As a result, there has been increasing interest in complementary and alternative medicine with anticancer potential. Studies have shown that the antioxidant activities and anti-inflammatory effects of citrus fruits are promising natural phytochemicals in the development of new anticancer agents. Tangeretin is a naturally polymethoxylated flavone compound extracted from the citrus peel that has shown significant intestinal absorption and adequate bioavailability, with the added benefit of promoting longevity. In addition, tangeretin is known to exhibit considerable selective toxicity to many types of cancer cell proliferation such as ovarian, brain, blood, and skin cancer. Evidence indicates that tangeretin acts through several mechanisms including growth inhibition, induction of apoptosis, autophagy, antiangiogenesis, and estrogenic-like effects. Furthermore, tangeretin works through mitigating levels of inflammatory mediators in the immune system. Using tangeretin in combination with clinically applied anticancer drugs could be a good strategy for increasing the efficiency of these agents and protecting noncancerous cells from damage caused by chemotherapy. The purpose of this review is to highlight the protective effects of a novel natural product, tangeretin against chemotherapeutic-induced toxicity. The development of chemoprevention strategies can lead to significant health care improvement in cancer survivors. Thus, study outcomes may attract more investigators to conduct tangeretin-related research and find out potentially significant impacts on health care of cancer patients and decreased health problems associated with chemotherapeutics-induced toxicity.

Background: Fibromyalgia is a complex, relatively unknown disease characterised by chronic, widespread musculoskeletal pain. The gut-brain axis connects the gut microbiome with the brain through the enteric nervous system (ENS); its disruption has been associated with psychiatric and gastrointestinal disorders. To gain an insight into the pathogenesis of fibromyalgia and identify diagnostic biomarkers, we combined different omits techniques to analyse microbiome and serum composition. Methods: We collected faeces and blood samples to study the microbiome, the serum metabolome and circulating cytokines and miRNAs from a cohort of 105 fibromyalgia patients and 54 age- and environment-matched healthy individuals. We sequenced the V3 and V4 regions of the 16S rDNA gene from faeces samples. UPLC-MS metabolomics and custom multiplex cytokine and miRNA analysis (FirePlex (TM) technology) were used to examine sera samples. Finally, we combined the different data types to search for potential biomarkers. Results: We found that the diversity of bacteria is reduced in fibromyalgia patients. The abundance of the Bifidobacterium and Eubacterium genera (bacteria participating in the metabolism of neurotransmitters in the host) in these patients was significantly reduced. The serum metabolome analysis revealed altered levels of glutamate and serine, suggesting changes in neurotransmitter metabolism. The combined serum metabolomics and gut microbiome datasets showed a certain degree of correlation. reflecting the effect of the microbiome on metabolic activity. We also examined the microbiome and serum metabolites, cytokines and miRNAs as potential sources of molecular biomarkers of fibromyalgia. Conclusions: Our results show that the microbiome analysis provides more significant biomarkers than the other techniques employed in the work. Gut microbiome analysis combined with serum metabolomics can shed new light onto the pathogenesis of fibromyalgia. We provide a list of bacteria whose abundance changes in this disease and propose several molecules as potential biomarkers that can be used to evaluate the current diagnostic criteria. This project was funded by the Basque Government's Health Department (ref. 2015111149 (2016-2018)).

Neurotransmitters are conventionally viewed as nerve-secreted substances that mediate the stimulatory or inhibitory neuronal functions through binding to their respective receptors. In the past decades, many novel discoveries come to light elucidating the regulatory roles of neurotransmitters in the physiological and pathological functions of tissues and organs. Notably, emerging data suggest that cancer cells take advantage of the neurotransmitters-initiated signaling pathway to activate uncontrolled proliferation and dissemination. In addition, neurotransmitters can affect immune cells and endothelial cells in the tumor microenvironment to promote tumor progression. Therefore, a better understanding of the mechanisms underlying neurotransmitter function in tumorigenesis, angiogenesis, and inflammation is expected to enable the development of the next generation of antitumor therapies. Here, we summarize the recent important studies on the different neurotransmitters, their respective receptors, target cells, as well as pro/antitumor activity of specific neurotransmitter/receptor axis in cancers and provide perspectives and insights regarding the rationales and strategies of targeting neurotransmitter system to cancer treatment.

Postpartum depression affects about 10-20% of newly delivered women, which is harmful for both mothers and infants. However, the current diagnosis of postpartum depression depends on the subjective judgment of a practitioner, which may lead to misdiagnosis. Hence, an appended objective diagnosis index may help the practitioner to improve diagnosis. A metabolomic study can find biomarkers as an objective index to facilitate disease diagnosis. Forty-nine postpartum depressed patients and 50 healthy controls were recruited into this study. The metabolites in urine were scanned with LC-Q-TOF-MS. The metabolomic data were analyzed with a multivariate statistical analysis method. Data from 40 patients and 40 controls were used for partial least square-discriminate analysis (PLS-DA). The urine metabolomic profiles of patients were different from those of controls. The PLS-DA model was validated by a permutation test, and the model could accurately classify the other 9 patients and 10 controls in T-prediction. Ten differentiating metabolites were found as main contributors to this difference, which are involved in amino acid metabolism, neurotransmitter metabolism, bacteria population, etc. Some of these potential biomarkers, such as 4-hydroxyhippuric acid, homocysteine, and tyrosine, showed relatively high sensitivities and specificities. The metabolic profile alteration induced by postpartum depression was found, and some of the differentiating metabolites may serve as biomarkers to facilitate the diagnosis of postpartum depression.

Brain iron plays key roles in catecholaminergic neurotransmitter synthesis and early life brain development. It is also central to cellular energetics and neurotransmitter metabolism throughout the lifespan. Disturbances in brain iron have been implicated in a growing number of psychiatric and late-life neurodegenerative disorders. Additionally, brain iron accumulations are thought to play a deleterious role in neuroinflammatory processes in later life. Despite its importance, the role of brain iron in development, aging, and psychiatric disorders remains comparatively understudied. This is partly due to technical challenges inherent in implementation and analysis of formal iron imaging protocols and practical constraints on scan session durations. Here, we introduce a method to estimate relative brain iron concentrations that is 1) computationally simple, 2) shows excellent correspondence with formal iron imaging in-vivo, 3) replicates clinically-relevant findings from formal iron imaging, 4) yields novel insights into brain iron and cognition across the lifespan, and 5) leverages a widely available and frequently shared brain imaging modality: functional MRI. The computationally simple nature of the measure, coupled with the availability of fMRI datasets across the lifespan and disorders, has the potential to transform our understanding of the complex and critical relationship between iron and brain health.

A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here we show that opioid peptide receptors, GPCRs which mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR - effector coupling.

Iron is a crucial cofactor for several physiological functions in the brain including transport of oxygen, DNA synthesis, mitochondrial respiration, synthesis of myelin, and neurotransmitter metabolism. If iron concentration exceeds the capacity of cellular sequestration, excessive labile iron will be harmful by generating oxidative stress that leads to cell death. In patients suffering from Parkinson disease, the total amount of iron in the substantia nigra was reported to increase with disease severity. High concentrations of iron were also found in the amyloid plaques and neurofibrillary tangles of human Alzheimer disease brains. Besides iron, nitric oxide (NO) produced in high concentration has been associated with neurodegeneration. NO is produced as a co-product when the enzyme NO synthase converts L-arginine to citrulline, and NO has a role to support normal physiological functions. When NO is produced in a high concentration under pathological conditions such as inflammation, aberrantly S-nitrosylated proteins can initiate neurodegeneration. Interestingly, NO is closely related with iron homeostasis. Firstly, it regulates iron-related gene expression through a system involving iron regulatory protein and its cognate iron responsive element (IRP-IRE). Secondly, it modified the function of iron-related protein directly via S-nitrosylation. In this review, we examine the recent advances about the potential role of dysregulated iron homeostasis in neurodegeneration, with an emphasis on AD and PD, and we discuss iron chelation as a potential therapy. This review also highlights the changes in iron homeostasis caused by NO. An understanding of these mechanisms will help us formulate strategies to reverse or ameliorate iron-related neurodegeneration in diseases such as AD and PD.

Predation risk induces broad behavioral and physiological responses that have traditionally been considered acute and transitory. However, prolonged or frequent exposure to predators and the sensory cues of their presence they broadcast to the environment impact long-term prey physiology and demographics. Though several studies have assessed acute and chronic stress responses in varied taxa, these attempts have often involved a priori expectations of the molecular pathways involved in physiological responses, such as glucocorticoid pathways and neurohormone production in vertebrates. While relatively little is known about physiological and molecular predator-induced stress in insects, many dramatic insect defensive behaviors have evolved to combat selection by predators. For instance, several moth families, such as Noctuidae, include members equipped with tympanic organs that allow the perception of ultrasonic bat calls and facilitate predation avoidance by eliciting evasive aerial flight maneuvers. In this study, we exposed adult male fall armyworm (Spodoptera frugiperda) moths to recorded ultrasonic bat foraging and attack calls for a prolonged period and constructed a de novo transcriptome based on brain tissue from predator cue-exposed relative to control moths kept in silence. Differential expression analysis revealed that 290 transcripts were highly up- or down-regulated among treatment tissues, with many annotating to noteworthy proteins, including a heat shock protein and an antioxidant enzyme involved in cellular stress. Though nearly 50% of differentially expressed transcripts were unannotated, those that were are implied in a broad range of cellular functions within the insect brain, including neurotransmitter metabolism, ionotropic receptor expression, mitochondrial metabolism, heat shock protein activity, antioxidant enzyme activity, actin cytoskeleton dynamics, chromatin binding, methylation, axonal guidance, cilia development, and several signaling pathways. The five most significantly overrepresented Gene Ontology terms included chromatin binding, macromolecular complex binding, glutamate synthase activity, glutamate metabolic process, and glutamate biosynthetic process. As a first assessment of transcriptional responses to ecologically relevant auditory predator cues in the brain of moth prey, this study lays the foundation for examining the influence of these differentially expressed transcripts on insect behavior, physiology, and life history within the framework of predation risk, as observed in ultrasound-sensitive Lepidoptera and other ‘eared’ insects.

Oxidative stress in depression is a prime cause of neurotransmitter metabolism dysfunction in the brain. Acetylcholinesterase (AChE), a key hydrolase in the cholinergic system, directly determines the degradation of neurotransmitters. However, due to the complexity of the brain and lack of appropriate in situ imaging tools, the mechanism underlying the changes in AChE activity in depression remains unclear. Hence, we generated a two-photon fluorescence probe (MCYN) for real-time visualization of AChE with excellent sensitivity and selectivity. AChE can specifically recognize and cleave the carbamic acid ester bond in MCYN, and MCYN emits bright fluorescence at 560 nm by two-photon excitation at 800 nm. By utilizing MCYN to monitor AChE, we discovered a significant increase in AChE activity in the brains of mice with depression phenotypes. Notably, with the assistance of a two-photon fluorescence imaging probe of the superoxide anion radical (O2•–), in vivo visualization for the first time revealed the pos...

Nutritional reduction of omega-3 polyunsaturated fatty acids (n-3 PUFAs) and increased ratio of omega-6 (n-6) to n-3 PUFAs in neural tissues and blood component may have adverse effects on the brain development and neuropsychological outcomes. The PUFAs have many biological functions that influence cell and tissue metabolism, regulation, and responsiveness to hormonal and other signals. The decreased content of PUFAs in the developing brain leads to deficits in neurogenesis, neurotransmitter metabolism, and altered learning and visual function in experimental research. Epidemiological and intervention studies have linked low plasma and blood cell lipid docosahexaenoic acid (DHA) to increased risk of poor visual and neural development in infants and children, especially for those individuals born after exposure to fetal adversity (e.g., small for gestational age and preterm infants). Here we review current knowledge of PUFAs metabolism and function in the nervous system and present the role of n-3 PUFAs during critical periods and their effects on the children’s neurodevelopment, nutrition, and growth. We also summarize clinical and experimental studies of n-3 PUFAs effects proposing some current therapeutic perspectives for brain protection and repair.

Sexuality is an important component of human personality and behavior. Its development follows a multifactorial model, since psychological, biological, and sociocultural characteristics play a major role. The majority of basic research mainly comes from animals, while epigenetic, cognitive, and sociocultural factors play an important role in humans. The hypothalamus seems to be the main brain structure involved in sexual behavior, while various of its areas such as the sexually dimorphic nucleus of the preoptic area, the median preoptic area, the ventromedial nucleus, the bed nucleus of the stria terminalis, etc. are sexually differentiated in humans. Androgenization is mainly based on steroid action during the sensitive period of brain development in the fetus, while also other factors (e.g., hormone and neurotransmitter metabolism) play a role in the development of sexual identity and orientation. Central nervous system dimorphisms regarding the regions that modulate sexual function are also a biological basis for the differences in sexual desire, arousal, and orgasm. Hypothalamic structures, limbic and cortical areas, are activated and deactivated during all the phases of the sexual response cycle, while the role of hormones, neurotransmitters, and its receptors is crucial.

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.

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.

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.

Krabbe disease (KD) is caused by mutations in the galactosylceramidase (GALC) gene, which encodes a lysosomal enzyme that degrades galactolipids, including galactosylceramide and galactosylsphingosine (psychosine). GALC deficiency results in progressive intracellular accumulation of psychosine, which is believed to be the main cause for the demyelinating neurodegeneration in KD pathology. Umbilical cord blood transplantation slows disease progression when performed presymptomatically but carries a significant risk of morbidity and mortality. Accurate presymptomatic diagnosis is therefore critical to facilitate the efficacy of existing transplant approaches and to avoid unnecessary treatment of children who will not develop KD. Unfortunately, current diagnostic criteria, including GALC activity, genetic analysis, and psychosine measurement, are insufficient for secure presymptomatic diagnosis. This study performs a global metabolomic analysis to identify pathogenetic metabolic pathways and novel biomarkers implicated in the authentic mouse model of KD known as twitcher. At a time point before onset of signs of disease, twitcher hindbrains had metabolic profiles similar to WT, with the exception of a decrease in metabolites related to glucose energy metabolism. Many metabolic pathways were altered after early signs of disease in the twitcher, including decreased phospholipid turnover, restricted mitochondrial metabolism of branched-chain amino acids, increased inflammation, and changes in neurotransmitter metabolism and osmolytes. Hypoxanthine, a purine derivative, is increased before signs of disease appear, suggesting its potential as a biomarker for early diagnosis of KD. Additionally, given the early changes in glucose metabolism in the pathogenesis of KD, diagnostic modalities that report metabolic function, such as positron emission tomography, may be useful in KD. © 2016 Wiley Periodicals, Inc.

Volatile anesthetics (VAs) have been in clinical use for a very long time. Their mechanism of action is yet to be fully delineated, but multiple ion channels have been reported as targets for VAs (canonical VA targets). It is increasingly recognized that VAs also manifest effects outside the central nervous system, including on immune cells. However, the literature related to how VAs affect the behavior of immune cells is very limited, but it is of interest that some canonical VA targets are reportedly expressed in immune cells. Here, we review the current literature and describe canonical VA targets expressed in leukocytes and their known roles. In addition, we introduce adhesion molecules called β2 integrins as noncanonical VA targets in leukocytes. Finally, we propose a model for how VAs affect the function of neutrophils, macrophages, and natural killer cells via concerted effects on multiple targets as examples.

INTRODUCTION: \ud \ud Fibromyalgia (FM) is a common, complex chronic widespread pain condition is characterized by fatigue, sleep disturbance and cognitive dysfunction. Treatment of FM is difficult, requiring both pharmacological and non-pharmacological approaches, with an empiric approach to drug therapy focused toward individual symptoms, particularly pain. The effectiveness of current medications is limited with many patients discontinuing use.\ud \ud AREAS COVERED: \ud \ud A systemic database search has identified 26 molecular entities as potential emerging drug therapies. Advances in the understanding of the pathophysiology of FM provides clues to targets for new medications. Investigation of bioamine modulation and α2δ ligands and novel targets such as dopamine receptors, NMDA receptors, cannabinoid receptors, melatonin receptors and potassium channels has identified potential drug therapies.\ud \ud EXPERT OPINION: \ud \ud Modest improvement of health status in patients with FM has been observed with drugs targeting a diverse range of molecular mechanisms. No single drug, however, offered substantial efficacy against all the symptoms characteristic of FM. Identification of new and improved therapies for FM needs to address the heterogeneity of the condition, which suggests existence of patient subgroups, the relationship of central and peripheral aspects of the pathophysiology and a requirement of combination therapy with drugs targeting multiple molecular mechanisms.

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.

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.

Genetic polymorphisms are major determinants of individual variability in a drug's efficacy and safety, which is one of the main challenges in current clinical practice and drug development. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict changes in the PK parameters associated with genetic polymorphisms and the impact of these changes on drugs' PD effect.We developed PBPK models for two central nervous system (CNS) medications, namely quetiapine and fluvoxamine that are substrates for polymorphic enzymes by incorporating the corresponding alterations in the enzyme activity and/or abundance. Then, the PBPK models were linked to PD models to predict the influence of these changes on the drugs' PD effect.Application of the PBPK models for prediction of phenotypic differences in the PKs compared favorably with reported clinical data. In addition, the PBPK/PD models were able to describe the relationship between the drugs' PD effect and their unbound fractions in the brain and predict changes in receptor/transporter occupancy percentages, obtained from positron emission tomography occupancy studies, associated with genetic variations.This work provides a simplified approach to predict the influence of genetic polymorphisms on the PK parameters and associated PD effect for CNS drugs. The impact of these polymorphisms on the drugs' PD requires further in vivo validation.

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.

The principle in the accounting of a weak neurotransmitter component is considered as one of the most specific and promising ones for the study and practical introduction of therapy for postcomatous states. The paper outlines problems in the accurate determination of the lack and excess of neurotransmitters by up-to-date techniques (biochemical and neurophysiological tests, magnetic resonance spectroscopy). It gives the reasons for clinical doubts and difficulties in the practical use of ideas about the relationship of the clinical picture to one or another disorder of neurotransmitter metabolism and to the feasibilities of its effective correction. It is concluded that the main method for the individualized therapy of postcomatous states is the clinical analysis of neurological and psychiatric symptoms, only upon its completion, the consideration of a weak neurotransmitter component can be taken into account. The main possible and currently preferable ways to correct cholinergic and GABAergic deficiency and redundancy and deficiency in glutamate and dopamine are considered.

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.

Catecholamines (CAs) play critical roles in regulating physiological and immunological homeostasis in invertebrates and vertebrates under stressful environments. DOPA decarboxylase (DDC), an enzyme responsible for the decarboxylation step of dopamine synthesis, participates in neurotransmitter metabolism and innate immunity. In shrimp, two genes encoding CA-related enzymes, tyrosine hydroxylase and dopamine beta-hydroxylase, were further identified and characterized as neuroendocrine-immune regulators. In this study, full-length complementary DNA of DDC cloned from the thoracic ganglia of shrimp, Litopenaeus vannamei, (LvDDC) was predicted to encode a 452-amino acid protein with a pyridoxal-dependent decarboxylase-conserved domain, and this deduced protein of LvDDC was phylogenetically closely related to insect DDC. LvDDC messenger RNA expression was analyzed by a semiquantitative RT-PCR and a real-time quantitative RT-PCR and found to be abundant in the hepatopancreas and nervous system but at low levels in haemocytes, heart, stomach, and gills. To determine the role of LvDDC, double-stranded (ds)RNA was used for in vivo assessments. LvDDC-depleted shrimp revealed significant increases in the total haemocyte count, hyaline cells, granular cells, phenoloxidase activity, and respiratory bursts of haemocytes per unit of haemolymph, and phagocytic activity and clearance efficiency toward Vibrio alginolyticus. Further, decreased LvDDC mRNA expression was accompanied by decreases in dopamine, glucose, and lactate levels in haemolymph. In shrimp that received LvDDC-dsRNA for 3 days and were then challenged with V. alginolyticus, the survival rate of LvDDC-depleted shrimp was significantly higher than that of shrimp that received diethyl pyrocarbonate-water or non-targeted dsRNA. In conclusion, the cloned LvDDC was responsible for controlling dopamine synthesis, which then regulated physiological and immune responses in L. vannamei.

Some long noncoding RNAs (lncRNAs) are specifically expressed in brain cells, implying their neural and behavioural functions. However, how lncRNAs contribute to neural regulatory networks governing the precise behaviour of animals is less explored. Here, we report the regulatory mechanism of the nuclear-enriched lncRNA PAHAL for dopamine biosynthesis and behavioural adjustment in migratory locusts (Locusta migratoria), a species with extreme behavioral plasticity. PAHAL is transcribed from the sense (coding) strand of the gene encoding phenylalanine hydroxylase (PAH), which is responsible for the synthesis of dopamine from phenylalanine. PAHAL positively regulates PAH expression resulting in dopamine production in the brain. In addition, PAHAL modulates locust behavioral aggregation in a population density-dependent manner. Mechanistically, PAHAL mediates PAH transcriptional activation by recruiting serine/arginine-rich splicing factor 2 (SRSF2), a transcription/splicing factor, to the PAH proximal promoter. The co-activation effect of PAHAL requires the interaction of the PAHAL/SRSF2 complex with the promoter-associated nascent RNA of PAH. Thus, the data support a model of feedback modulation of animal behavioural plasticity by an lncRNA. In this model, the lncRNA mediates neurotransmitter metabolism through orchestrating a local transcriptional loop., Author summary The neurotransmitter dopamine is crucial for the neuronal and behavioral response in animals. Phenylalanine hydroxylase (PAH) is involved in dopamine biosynthesis and behavioral regulation in the migratory locust. However, the molecular mechanism for the fine tuning of PAH expression in behavioral response remains ambiguous. Here we discovered a nuclear-enriched lncRNA PAHAL that is transcribed from the coding strand of the PAH gene in the locust (i.e., sense lncRNA). PAHAL positively regulated PAH expression and dopamine production in the brain. In addition, PAHAL modulated behavioral aggregation of the locust. Mechanistically, PAHAL mediated the transcriptional activation of PAH by recruiting SRSF2, a transcription/splicing factor, to the promoter-associated nascent RNA of PAH. These data support a model of feedback modulation of dopamine biosynthesis and behavioral plasticity via a sense lncRNA in the catecholamine metabolic pathway.

Major depressive disorder (MDD), which is a leading psychiatric illness across the world, severely affects quality of life and causes an increased incidence of suicide. Evidence from animal as well as clinical studies have indicated that increased peripheral or central cytokine interleukin-6 (IL-6) levels play an important role in stress reaction and depressive disorder, especially physical disorders comorbid with depression. Increased release of IL-6 in MDD has been found to be a factor associated with MDD prognosis and therapeutic response, and may affect a wide range of depressive symptomatology. However, study results of the IL6 genetic effects in MDD are controversial. Increased IL-6 activity may cause depression through activation of hypothalamic-pituitary-adrenal axis or influence of the neurotransmitter metabolism. The important role of neuroinflammation in MDD pathogenesis has created a new perspective that the combining of blood IL-6 and other depression-related cytokine levels may help to classify MDD biological subtypes, which may allow physicians to identify the optimal treatment for MDD patients. To modulate the IL-6 activity by IL-6-related agents, current antidepressive agents, herb medication, pre-/probiotics or non-pharmacological interventions may hold great promise for the MDD patients with inflammatory features.

We have analysed post-mortem samples of prefrontal cortex from control and alcoholic human brains by the technique of Western blotting to estimate and compare the expressions of glutamate transporter GLAST (Excitatory Amino Acid Transporter One; EAAT1). Furthermore, using the non-alcoholic prefrontal cortex and custom-made GLAST (EAAT1) antibody we determined GLAST (EAAT1) "interactome" i.e. the set of proteins selectively bound by GLAST (EAAT1). We found that GLAST (EAAT1) was significantly more abundant (about 1.6-fold) in the cortical tissue from alcoholic brains compared to that from non-alcoholic controls. The greatest increase in the level of GLAST (EAAT1) was found in plasma membrane fraction (2.2-fold). Additionally, using the prefrontal cortical tissue from control brains, we identified 38 proteins specifically interacting with GLAST (EAAT1). These can be classified as contributing to the cell structure (6 proteins; 16%), energy and general metabolism (18 proteins; 47%), neurotransmitter metabolism (three proteins; 8%), signalling (6 proteins: 16%), neurotransmitter storage/release at synapses (three proteins; 8%) and calcium buffering (two proteins; 5%). We discuss possible consequences of the increased expression of GLAST (EAAT1) in alcoholic brain tissue and whether or how this could disturb the function of the proteins potentially interacting with GLAST (EAAT1) in vivo. The data represent an extension of our previous proteomic and metabolomic studies of human alcoholism revealing another aspect of the complexity of changes imposed on brain by chronic long-term consumption of ethanol.

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

Depresio nagusia asaldura neuropsikiatriko ohikoenen artean dago. Gaixotasun mental honen etiologia eta oinarri fisiopatologikoak azaltzeko hainbat teoria proposatu dira, hala nola teoría monoaminergikoa edo neurotrofikoa. Hala ere, oinarri neurobiologikoak oraindik ez dira ezagutzen, sistema ezberdinen parte-hartzea izanik proposatzen dena. Depresioan hanturaren eta funtzio neuralaren arteko elkarrekintza dagoela frogatzen duten entsegu prekliniko eta klinikoetako emaitzak gero eta pisu handiagoa hartzen ari dira, teoría neuroinflamatorioa indartuz. Horrek proposatzen du depresioan sistema ezberdinetan asaldurak gertatuko liratekeela: ardatz hipotalamiko-hipofisiario-adrenalaren (HPA) hiperaktibazioa (igotako glukokortikoide-mailak eraginez) bai eta sistema immunearen hiperaktibazioa ere, periferiako eta nerbio-sistema zentraleko (NSZ) hanturaren markatzaileen, hau da, zitokina proinflamatorioen mailak handituz. Gainera, depresiodun pazienteetan aurkitu diren periferiako gehiegizko zitokinak garunera igarotzeko gai direla eta depresioan ezagunak diren bide fisiopatologiko gehienei eragiten dietela deskribatu da. Horien artean neurotransmisoreen metabolismoa, funtzio neuroendokrinoa eta plastikotasun edo moldatze neurala daude. Hain zuzen ere, garuneko hanturaren aktibazioak depresioan gertatzen diren asaldura fisiopatologikoen antzeko moldaketak eragiten ditu, faktore neurotrofikoen gutxipena, eszitotoxikotasuna eta horren ondorio den estres oxidatiboa, adibidez. Areagotutako zitokinen kalte kronikoak iraupen luzeko aldaketak dakartza garunaren anatomian eta funtzionamenduan, eta kalteok umorean, kognizioan edo portaeran eragin zuzena izango dute. Hortaz, garunaren endekapen hau sintoma depresiboekin lotzea funtsezkoa da tratamendua aukeratzeko orduan. Izan ere, gaixotasun inflamatorioak dituzten pazienteetan lortutako emaitzen arabera, zitokina proinflamatorioak inhibitzeak gaixoek pairatzen dituzten sintoma depresiboak hobetzen eta pazientearen ohiko tratamendu antidepresiboaren erantzuna hobetzen lagundu dezake. Beraz, garunean gertatzen den hantura eta sistema immunea itu dituzten tratamenduak garatzea aukera bat izan daiteke hantura duten depresiodun pazienteen sintomatologia hobetzeko.

Increasing evidence suggests that infection and persistent low-grade inflammation in peripheral tissues are important pathogenic factors in major depression. Major depression is frequently comorbid with systemic inflammatory diseases/conditions such as rheumatoid arthritis, allergies of different types, multiple sclerosis, cardiovascular disease, inflammatory bowel disease, chronic liver disease, diabetes, and cancer, in which pro-inflammatory cytokines are overexpressed. A number of animal studies demonstrate that systemic inflammation induced by peripheral administration of lipopolysaccharide increases the expression of pro-inflammatory cytokines in both the periphery and brain and causes abnormal behavior similar to major depression. Systemic inflammation can cause an increase in CNS levels of pro-inflammatory cytokines associated with glial activation, namely, neuroinflammation, through several postulated pathways. Such neuroinflammation can in turn induce depressive moods and behavioral changes by affecting brain functions relevant to major depression, especially neurotransmitter metabolism. Although various clinical studies imply a causal relationship between periodontitis, which is one of the most common chronic inflammatory disorders in adults, and major depression, the notion that periodontitis is a risk factor for major depression is still unproven. Additional population-based cohort studies or prospective clinical studies on the relationship between periodontitis and major depression are needed to substantiate the causal link of periodontitis to major depression. If such a link is established, periodontitis may be a modifiable risk factor for major depression by simple preventive oral treatment.

The exceptional toxicity of botulinum neurotoxins (BoNTs) is mediated by high avidity binding to complex polysialogangliosides and intraluminal segments of synaptic vesicle proteins embedded in the presynaptic membrane. One peculiarity is an exposed hydrophobic loop in the toxin’s cell binding domain HC, which is located between the ganglioside- and protein receptor-binding sites, and that is particularly pronounced in the serotypes BoNT/B, DC, and G sharing synaptotagmin as protein receptor. Here, we provide evidence that this HC loop is a critical component of their tripartite receptor recognition complex. Binding to nanodisc-embedded receptors and toxicity were virtually abolished in BoNT mutants lacking residues at the tip of the HC loop. Surface plasmon resonance experiments revealed that only insertion of the HC loop into the lipid-bilayer compensates for the entropic penalty inflicted by the dual-receptor binding. Our results represent a new paradigm of how BoNT/B, DC, and G employ ternary interactions with a protein, ganglioside, and lipids to mediate their extraordinary neurotoxicity., Author summary Botulinum neurotoxins are Janus-faced molecules: due to their exquisite toxicity, botulinum neurotoxins are considered as biological weapons, but they are also highly effective medicines for numerous neurological indications. However, what mediates their exquisite toxicity? The exclusive binding to neurons and the subsequent paralysis cuts off the host’s communication networks. The neurospecific binding is ensured by anchoring to two receptor molecules both embedded in the membrane: a complex ganglioside and a synaptic vesicle protein. Here, we reveal a third interaction between a hydrophobic so-called HC loop protruding from the surface of the serotypes BoNT/B, DC, and G into the lipid membrane. Only this HC loop ensures their high-affinity binding to the neuronal receptors also at physiological temperature (37°C). Hereby, BoNT/B, DC, and G prevent untimely dissociation prior to uptake into the neuron. Therefore, our study provides the mechanistic basis for the development of inhibitors to combat botulism, but it also has implications for engineering toxin—membrane interactions yielding optimized BoNT-based therapeutics to treat neuromuscular dysfunctions successfully. Intriguingly, a broadly neutralizing anti-HIV-1 antibody shares a similar strategy, emphasizing the general relevance of our results for host—pathogen interactions.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition that impairs quality of life in social, academic, and occupational contexts for both children and adults. Although a strong neurobiological basis has been demonstrated, the pathophysiology of ADHD is still poorly understood. Among the proposed mechanisms are glial activation, neuronal damage and degeneration, increased oxidative stress, reduced neurotrophic support, altered neurotransmitter metabolism, and blood-brain barrier disruption. In this way, a potential role of inflammation has been increasingly researched. However, evidence for the involvement of inflammation in ADHD is still scarce and comes mainly from (1) observational studies showing a strong comorbidity of ADHD with inflammatory and autoimmune disorders; (2) studies evaluating serum inflammatory markers; and (3) genetic studies. A co-occurrence of ADHD with inflammatory disorders has been demonstrated in a large number of subjects, suggesting a range of underlying mechanisms such as an altered immune response, common genetics, and environmental links. The evaluation of serum inflammatory markers has provided mixed results, likely due to the small sample sizes and high heterogeneity between biomarkers. However, there is evidence that increased inflammation during the early development may be a risk factor for ADHD symptoms. Although genetic studies have demonstrated a potential role for inflammation in this disorder, there is no clear evidence. To sum up, inflammation may be an important mechanism in ADHD pathophysiology, but more studies are still needed for a more precise conclusion.

Peroxisomal β-oxidation (pβo) is a highly conserved fat metabolism pathway involved in the biosynthesis of diverse signaling molecules in animals and plants. In Caenorhabditis elegans, pβo is required for the biosynthesis of the ascarosides, signaling molecules that control development, lifespan, and behavior in this model organism. Via comparative mass spectrometric analysis of pβo mutants and wildtype, we show that pβo in C. elegans and the satellite model P. pacificus contributes to life stage-specific biosynthesis of several hundred previously unknown metabolites. The pβo-dependent portion of the metabolome is unexpectedly diverse, e.g., intersecting with nucleoside and neurotransmitter metabolism. Cell type-specific restoration of pβo in pβo-defective mutants further revealed that pβo-dependent submetabolomes differ between tissues. These results suggest that interactions of fat, nucleoside, and other primary metabolism pathways can generate structural diversity reminiscent of that arising from combinatorial strategies in microbial natural product biosynthesis.

Background Assessing neurotransmitter metabolism in the brain is essential in studying the effects of drugs, dietary modification and characterizing transgenic mouse models of human neurodegenerative diseases. Regional brain concentrations of parent neurotransmitters and related metabolites are informative and provide a snap shot of the steady-state levels. The choice in method of sacrificing mice may differ from one laboratory to another, and the technique in removal of brain may have limitations depending on speed in which tissue can be dissected and frozen to prevent post-mortem changes. New methods In order to better assess neurotransmitter metabolism in an effective and standardized manner we evaluated microwave irradiation as a method of sacrificing mice. Mice were sacrificed by CO2 asphyxiation followed by cervical dislocation or microwave irradiation at 4 Kw for 1.1 s. Brain tissue was harvested into five regions and stored at −80 °C until analysis by either LC–MS/MS for acetylcholine, choline and GABA, or HPLC-EC for dopamine, serotonin and norepinephrine and related metabolites. Results The results of our study showed considerable differences in the levels of neurotransmitters between the two methods of sacrifice. Overall, the concentrations of neurotransmitters were higher in mice sacrificed by microwave irradiation, except for GABA, which was lower. Comparison with existing method(s) Previous microwave irradiation studies employed presently outdated equipment and neurotransmitter analysis methods, and were not as comprehensive. Conclusions The combination of microwave irradiation with LC–MS/MS and HPLC-EC detection allows accurate and sensitive measurement of several neurotransmitter systems in discrete mouse brain regions.

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.

Neuromodulatory systems, including the noradrenergic, serotonergic, dopaminergic, and cholinergic systems, track environmental signals, such as risks, rewards, novelty, effort, and social cooperation. These systems provide a foundation for cognitive function in higher organisms; attention, emotion, goal-directed behavior, and decision-making derive from the interaction between the neuromodulatory systems and brain areas, such as the amygdala, frontal cortex, hippocampus, and sensory cortices. Given their strong influence on behavior and cognition, these systems also play a key role in disease states and are the primary target of many current treatment strategies. The fact that these systems interact with each other either directly or indirectly, however, makes it difficult to understand how a failure in one or more systems can lead to a particular symptom or pathology. In this review, we explore experimental evidence, as well as focus on computational and theoretical models of neuromodulation. Better understanding of neuromodulatory systems may lead to the development of novel treatment strategies for a number of brain disorders.

Regular overconsumption of sugar is associated with obesity and type-2 diabetes, but how genetic factors contribute to variable sugar preferences and intake levels remains mostly unclear. Here we provide evidence for the usefulness of a Drosophila larva model to investigate genetic influence on vulnerability to sugar overconsumption. Using genetic and RNA interference approaches, we show that the activity of the Oamb gene, which encodes a receptor for octopamine (OA, the invertebrate homologue of norepinephrine), plays a major role in controlled sugar consumption. Furthermore, Oamb appears to suppress sugar food intake in fed larvae in an acute manner, and neurons expressing this Oamb receptor do not overlap with neurons expressing Octβ3R, another OA receptor previously implicated in hunger-driven exuberant sugar intake. Together, these results suggest that two separate sub-circuits, defined by Oamb and Octβ3R respectively, co-regulate sugar consumption according to changes in energy needs. We propose that the noradrenergic-like system defines an ancient regulatory mechanism for prevention of sugar overload.