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1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360837

RESUMO

Skin pigmentation can occur due to increased melanin, including melanocyte proliferation, melanin biosynthesis, or melanocyte migration. There are many factors that influence the melanin production process, but the role of neurotransmitters in this process is still unclear. We found that histamine and serotonin influence the different stages of melanogenesis and melanogenesis, which increase melanogenesis. Since then, several related papers have been published, and from these papers, it has been recognised that the role of neurotransmitters in skin-pigment-related diseases needs to be summarised. By introducing the role of neurotransmitters in the regulation of various pigment disorders, including vitiligo and melasma, through this review, many researchers can be expected to try to apply neurotransmitter-related agonists and antagonists as treatments for skin pigment disorders.


Assuntos
Neurotransmissores/metabolismo , Transtornos da Pigmentação/metabolismo , Receptores de Neurotransmissores/metabolismo , Pigmentação da Pele , Animais , Humanos , Melaninas/metabolismo , Melanócitos/metabolismo , Melanócitos/fisiologia , Melanose , Neurotransmissores/fisiologia , Transtornos da Pigmentação/fisiopatologia , Receptores de Neurotransmissores/fisiologia , Vitiligo
2.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445312

RESUMO

"Neuroplasticity" is often evoked to explain adaptation and compensation after acute lesions of the Central Nervous System (CNS). In this study, we investigated the modification of 80 genes involved in synaptic plasticity at different times (24 h, 8 and 45 days) from the traumatic spinal cord injury (SCI), adopting a bioinformatic analysis. mRNA expression levels were analyzed in the motor cortex, basal ganglia, cerebellum and in the spinal segments rostral and caudal to the lesion. The main results are: (i) a different gene expression regulation is observed in the Spinal Cord (SC) segments rostral and caudal to the lesion; (ii) long lasting changes in the SC includes the extracellular matrix (ECM) enzymes Timp1, transcription regulators (Egr, Nr4a1), second messenger associated proteins (Gna1, Ywhaq); (iii) long-lasting changes in the Motor Cortex includes transcription regulators (Cebpd), neurotransmitters/neuromodulators and receptors (Cnr1, Gria1, Nos1), growth factors and related receptors (Igf1, Ntf3, Ntrk2), second messenger associated proteins (Mapk1); long lasting changes in Basal Ganglia and Cerebellum include ECM protein (Reln), growth factors (Ngf, Bdnf), transcription regulators (Egr, Cebpd), neurotransmitter receptors (Grin2c). These data suggest the molecular mapping as a useful tool to investigate the brain and SC reorganization after SCI.


Assuntos
Encéfalo/metabolismo , Plasticidade Neuronal/genética , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Transcriptoma , Animais , Feminino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurotransmissores/genética , Neurotransmissores/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Biochemistry (Mosc) ; 86(6): 729-736, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225595

RESUMO

Comparative analysis of available literature data on the pathogenetic neuroendocrine mechanisms of depression and post-traumatic stress disorder (PTSD) is provided in this review to identify their common features and differences. We discuss the multidirectional modifications of the activity of cortical and subcortical structures of the brain, levels of neurotransmitters and their receptors, and functions of the hypothalamic-pituitary-adrenocortical axis in depression and PTSD. The analysis shows that these disorders are examples of opposite failures in the system of adaptive stress response of the body to stressful psychotraumatic events. On this basis, it is concluded that the currently widespread use of similar approaches to treat these disorders is not justified, despite the significant similarity of their anxiety-depressive symptoms; development of differential therapeutic strategies is required.


Assuntos
Encéfalo/metabolismo , Transtorno Depressivo Maior/metabolismo , Glucocorticoides/metabolismo , Neurotransmissores/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtorno Depressivo Maior/etiologia , Humanos , Transtornos de Estresse Pós-Traumáticos/etiologia , Estresse Psicológico
4.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208199

RESUMO

Thus far, many hypotheses have been proposed explaining the cause of depression. Among the most popular of these are: monoamine, neurogenesis, neurobiology, inflammation and stress hypotheses. Many studies have proven that neurogenesis in the brains of adult mammals occurs throughout life. The generation of new neurons persists throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. For this reason, the search for drugs acting in this mechanism seems to be a priority for modern pharmacotherapy. Paroxetine is one of the most commonly used antidepressants. However, the exact mechanism of its action is not fully understood. The fact that the therapeutic effect after the administration of paroxetine occurs after a few weeks, even if the levels of monoamine are rapidly increased (within a few minutes), allows us to assume a neurogenic mechanism of action. Due to the confirmed dependence of depression on serotonin, norepinephrine, dopamine and γ-aminobutyric acid levels, studies have been undertaken into paroxetine interactions with these primary neurotransmitters using in silico and in vitro methods. We confirmed that paroxetine interacts most strongly with monoamine transporters and shows some interaction with γ-aminobutyric acid transporters. However, studies of the potency inhibitors and binding affinity values indicate that the neurogenic mechanism of paroxetine's action may be determined mainly by its interactions with serotonin transporters.


Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Paroxetina/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Sítios de Ligação , Células CHO , Cricetulus , Humanos , Simulação de Acoplamento Molecular , Neurotransmissores/química , Neurotransmissores/metabolismo , Paroxetina/química
5.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202125

RESUMO

Alzheimer's disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, which may result from the accumulation of amyloid plaques and neurofibrillary tangles. Preclinical studies showed that melatonin, a monoaminergic neurotransmitter released from the pineal gland, is able to ameliorate AD pathologies and restore cognitive impairments. Theoretically, inhibition of the pathological progression of AD by melatonin treatment should also restore the impaired neurotransmission. This review aims to explore the impact of AD on neurotransmission, and whether and how melatonin can enhance neurotransmission via improving AD pathology.


Assuntos
Doença de Alzheimer/metabolismo , Melatonina/metabolismo , Neurotransmissores/metabolismo , Transmissão Sináptica , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Monoaminas Biogênicas/metabolismo , Suscetibilidade a Doenças , Humanos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Proteínas tau/metabolismo
6.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204780

RESUMO

The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced industrial use. Inhaled Br2 damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br2 in Sprague Dawley rats. Rats were exposed to Br2 (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholamines and their metabolites. TyrH was found to be increased in a time-dependent manner. TrpH1 and TrpH2 were significantly decreased upon Br2 exposure in the brainstem. The neurotransmitter content evaluation indicated an increase in 5-HT and dopamine at early timepoints after exposure; however, other metabolites were not significantly altered. Taken together, our results predict brain damage and autonomic dysfunction upon Br2 exposure.


Assuntos
Comportamento Animal , Tronco Encefálico/patologia , Bromo/administração & dosagem , Bromo/efeitos adversos , Neurônios/patologia , Estresse Oxidativo , Administração por Inalação , Animais , Biomarcadores/metabolismo , Lesões Encefálicas/patologia , Catecolaminas/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Metaboloma , Neurônios/efeitos dos fármacos , Neurotransmissores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
7.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207264

RESUMO

Despite not being utilized as considerably as other antidepressants in the therapy of depression, the monoamine oxidase inhibitors (MAOIs) proceed to hold a place in neurodegeneration and to have a somewhat broad spectrum in respect of the treatment of neurological and psychiatric conditions. Preclinical and clinical studies on MAOIs have been developing in recent times, especially on account of rousing discoveries manifesting that these drugs possess neuroprotective activities. The altered brain levels of monoamine neurotransmitters due to monoamine oxidase (MAO) are directly associated with various neuropsychiatric conditions like Alzheimer's disease (AD). Activated MAO induces the amyloid-beta (Aß) deposition via abnormal cleavage of the amyloid precursor protein (APP). Additionally, activated MAO contributes to the generation of neurofibrillary tangles and cognitive impairment due to neuronal loss. No matter the attention of researchers on the participation of MAOIs in neuroprotection has been on monoamine oxidase-B (MAO-B) inhibitors, there is a developing frame of proof indicating that monoamine oxidase-A (MAO-A) inhibitors may also play a role in neuroprotection. The therapeutic potential of MAOIs alongside the complete understanding of the enzyme's physiology may lead to the future advancement of these drugs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Neurotransmissores/metabolismo
8.
Nat Commun ; 12(1): 4251, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253733

RESUMO

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Descarboxilases de Aminoácido-L-Aromático/deficiência , Dependovirus/genética , Neurônios Dopaminérgicos/metabolismo , Técnicas de Transferência de Genes , Terapia Genética , Imageamento por Ressonância Magnética , Mesencéfalo/patologia , Erros Inatos do Metabolismo dos Aminoácidos/líquido cefalorraquidiano , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Descarboxilases de Aminoácido-L-Aromático/líquido cefalorraquidiano , Descarboxilases de Aminoácido-L-Aromático/genética , Criança , Pré-Escolar , Discinesias/fisiopatologia , Feminino , Terapia Genética/efeitos adversos , Humanos , Masculino , Metaboloma , Atividade Motora , Neurotransmissores/líquido cefalorraquidiano , Neurotransmissores/metabolismo , Fatores de Tempo
9.
Biomed Pharmacother ; 140: 111556, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34087694

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. In addition to motor symptoms, a variety of non-motor symptoms seriously affect the life quality of PD patients. Baicalein, a flavonoid extracted from the herb Scutellaria baicalensis Georgi, exhibits anti-PD activity through alleviation of its motor symptoms. However, its effects on non-motor symptoms were barely reported. This study aimed to investigate the therapeutic effects of baicalein on PD-related depression. METHODS: After a 2-week injection of rotenone, mice with PD-related depression behavior were selected, divided into three groups, and administrated saline, baicalein, or madopar orally for four weeks. Behavior, neuroinflammation, neurotransmitters, and synaptic plasticity were evaluated. RESULTS: Our results showed that 4-week baicalein treatment significantly alleviated the depression-like behavior in the rotenone-induced mice model. Repeated baicalein treatment reduced α-synuclein aggregation, inhibited neuroinflammation, and maintained neurotransmitters homeostasis. Moreover, we found that baicalein treatment could remarkably protect the synaptic plasticity and activate the BDNF/TrkB/CREB pathway in the PD-related depression mice model. As traditional dopamine replacement therapy unleashed few effects on depression-like symptom amelioration and synaptic function protection, baicalein might be a more appropriate choice for PD-related depression. CONCLUSIONS: The current results suggested that baicalein could act as a treatment for PD-related depression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Flavanonas/farmacologia , Glicoproteínas de Membrana/metabolismo , Doença de Parkinson/tratamento farmacológico , Proteínas Tirosina Quinases/metabolismo , Rotenona/efeitos adversos , Animais , Depressão/metabolismo , Modelos Animais de Doenças , Flavonoides/farmacologia , Homeostase/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Ecotoxicol Environ Saf ; 220: 112391, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34090107

RESUMO

BACKGROUND: Exposure to heavy metals has been considered harmful and can cause cognitive deficits in preschool children. OBJECTIVE: To investigate the possible mediation effect of neurotransmitters on the relationship of heavy metal exposure with neurobehaviour. METHODS: The levels of blood heavy metals and neurotransmitters, along with the neurobehavioural scores, were determined in preschool children. Multiple linear regression was used to assess the relationship between heavy metals, neurotransmitters, and neurobehavioural scores. Furthermore, the mediating role of neurotransmitters was investigated. RESULTS: An interquartile range (IQR) increase in lead (6.10 µg/L) was associated with a decrease of 8.52%, 30.06%, and 20.10% for Glutamic acid (Glu), Glycine (Gly), and gamma-aminobutyric acid (GABA), respectively. An IQR increase in arsenic (19.37 µg/L) was associated with an increase of 6.32% and 2.09% for Gly and GABA, respectively. Further, an IQR increase in zinc (15.58 µg/L) was associated with an increase of 1.44% for Ser, whereas the IQR increase was associated with a decrease of 2.14%, 2.24%, and 1.89% for Glu, Gly, and GABA, respectively. An IQR increase in selenium (38.75 µg/L) was associated with an increase of 1.88% for GABA. Moreover, both Glu and Gly decreased by 2.87% for an IQR increase in manganese (16.92 µg/L). An IQR increase in mercury (15.22 µg/L) was associated with a decrease of 2.43% for Ser, but the IQR increase was associated with an increase of 4.99% and 3.09% for Gly and GABA, respectively. It was found that Glu and Serine (Ser) have a significant linear relationship with conduct score and impulsivity-hyperactivity index, and that there was a significant linear relationship between Ser and the learning disability index. GABA and conduct score and attention-deficit hyperactivity disorder (ADHD) index have a significant linear relationship. There is a significant linear relationship between Gly and conduct, anxiety, ADHD, and impulsivity-hyperactivity index. The results of the mediating effect analysis indicated that Ser, Glu, Gly, and GABA have a specific mediating effect between blood heavy metals and neurobehaviour. CONCLUSION: We showed the mediating effect of neurotransmitters. The current study may provide valuable information regarding the prevention and management of metal-related neurological disorders in preschool children.


Assuntos
Doenças do Sistema Nervoso Central/induzido quimicamente , Poluentes Ambientais/toxicidade , Metais Pesados/toxicidade , Neurotransmissores/metabolismo , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Estudos Transversais , Humanos , Masculino
11.
Nat Protoc ; 16(7): 3298-3321, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34075230

RESUMO

Molecule-specific techniques such as MALDI and desorption electrospray ionization mass spectrometry imaging enable direct and simultaneous mapping of biomolecules in tissue sections in a single experiment. However, neurotransmitter imaging in the complex environment of biological samples remains challenging. Our covalent charge-tagging approach using on-tissue chemical derivatization of primary and secondary amines and phenolic hydroxyls enables comprehensive mapping of neurotransmitter networks. Here, we present robust and easy-to-use chemical derivatization protocols that facilitate quantitative and simultaneous molecular imaging of complete neurotransmitter systems and drugs in diverse biological tissue sections with high lateral resolution. This is currently not possible with any other imaging technique. The protocol, using fluoromethylpyridinium and pyrylium reagents, describes all steps from tissue preparation (~1 h), chemical derivatization (1-2 h), data collection (timing depends on the number of samples and lateral resolution) and data analysis and interpretation. The specificity of the chemical reaction can also help users identify unknown chemical identities. Our protocol can reveal the cellular locations in which signaling molecules act and thus shed light on the complex responses that occur after the administration of drugs or during the course of a disease.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neurotransmissores/metabolismo , Imagem Óptica , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Limite de Detecção , Masculino , Ratos Sprague-Dawley , Padrões de Referência , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071460

RESUMO

Nausea and vomiting are common gastrointestinal complaints that can be triggered by diverse emetic stimuli through central and/or peripheral nervous systems. Both nausea and vomiting are considered as defense mechanisms when threatening toxins/drugs/bacteria/viruses/fungi enter the body either via the enteral (e.g., the gastrointestinal tract) or parenteral routes, including the blood, skin, and respiratory systems. While vomiting is the act of forceful removal of gastrointestinal contents, nausea is believed to be a subjective sensation that is more difficult to study in nonhuman species. In this review, the authors discuss the anatomical structures, neurotransmitters/mediators, and corresponding receptors, as well as intracellular emetic signaling pathways involved in the processes of nausea and vomiting in diverse animal models as well as humans. While blockade of emetic receptors in the prevention of vomiting is fairly well understood, the potential of new classes of antiemetics altering postreceptor signal transduction mechanisms is currently evolving, which is also reviewed. Finally, future directions within the field will be discussed in terms of important questions that remain to be resolved and advances in technology that may help provide potential answers.


Assuntos
Antieméticos/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Vômito/fisiopatologia , Animais , Eméticos/efeitos adversos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/fisiopatologia , Humanos , Náusea/etiologia , Náusea/fisiopatologia , Neurotransmissores/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vômito/etiologia
13.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064670

RESUMO

Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Transmissão Sináptica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/metabolismo , Transmissão Sináptica/efeitos dos fármacos
14.
Nat Microbiol ; 6(6): 792-805, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846627

RESUMO

Human physiology is regulated by endogenous signalling compounds, including fatty acid amides (FAAs), chemical mimics of which are made by bacteria. The molecules produced by human-associated microbes are difficult to identify because they may only be made in a local niche or they require a substrate sourced from the host, diet or other microbes. We identified a set of uncharacterized gene clusters in metagenomics data from the human gut microbiome. These clusters were discovered to make FAAs by fusing exogenous fatty acids with amines. Using an in vitro assay, we tested their ability to incorporate 25 fatty acids and 53 amines known to be present in the human gut, from which the production of six FAAs was deduced (oleoyl dopamine, oleoyl tyramine, lauroyl tryptamine, oleoyl aminovaleric acid, α-linolenoyl phenylethylamine and caproyl tryptamine). These molecules were screened against panels of human G-protein-coupled receptors to deduce their putative human targets. Lauroyl tryptamine is found to be an antagonist to the immunomodulatory receptor EBI2 against its native oxysterol ligand (0.98 µM half-maximal inhibitory concentration), is produced in culture by Eubacterium rectale and is present in human faecal samples. FAAs produced by Clostridia may serve as a mechanism to modulate their host by mimicking human signalling molecules.


Assuntos
Aminas/metabolismo , Ácidos Graxos/metabolismo , Firmicutes/metabolismo , Microbioma Gastrointestinal , Neurotransmissores/metabolismo , Aminas/química , Dieta , Ácidos Graxos/química , Firmicutes/classificação , Firmicutes/genética , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Neurotransmissores/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
15.
Nat Commun ; 12(1): 2073, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824313

RESUMO

Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.


Assuntos
Amiloide/metabolismo , Fígado/enzimologia , Mutação/genética , Estresse Oxidativo , Fenilalanina Hidroxilase/genética , Agregados Proteicos , Animais , Autofagia , Biomarcadores/metabolismo , Peso Corporal , Cruzamento , Feminino , Regulação da Expressão Gênica , Genótipo , Metabolismo dos Lipídeos , Fígado/patologia , Masculino , Metaboloma , Camundongos , Proteínas Mutantes/metabolismo , Neurotransmissores/metabolismo , Estresse Oxidativo/genética , Fenilalanina/metabolismo , Fenilalanina Hidroxilase/metabolismo , Fenilcetonúrias/enzimologia , Pterinas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Respiração , Ubiquitina/metabolismo , Ubiquitinação
16.
Am J Physiol Regul Integr Comp Physiol ; 320(6): R791-R799, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33825506

RESUMO

Astrocyte glycogen is dynamically remodeled during metabolic stability and provides oxidizable l-lactate equivalents during neuroglucopenia. Current research investigated the hypothesis that ventromedial hypothalamic nucleus (VMN) glycogen metabolism controls glucostimulatory nitric oxide (NO) and/or glucoinhibitory gamma-aminobutyric acid (GABA) neuron 5'-AMP-activated protein kinase (AMPK) and transmitter marker, e.g., neuronal nitric oxide synthase (nNOS), and glutamate decarboxylase65/67 (GAD) protein expression. Adult ovariectomized estradiol-implanted female rats were injected into the VMN with the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) before vehicle or l-lactate infusion. Western blot analysis of laser-catapult-microdissected nitrergic and GABAergic neurons showed that DAB caused lactate-reversible upregulation of nNOS and GAD proteins. DAB suppressed or increased total AMPK content of NO and GABA neurons, respectively, by lactate-independent mechanisms, but lactate prevented drug enhancement of pAMPK expression in nitrergic neurons. Inhibition of VMN glycogen disassembly caused divergent changes in counter-regulatory hormone, e.g. corticosterone (increased) and glucagon (decreased) secretion. Outcomes show that VMN glycogen metabolism controls local glucoregulatory transmission by means of lactate signal volume. Results implicate glycogen-derived lactate deficiency as a physiological stimulus of corticosterone release. Concurrent normalization of nitrergic neuron nNOS and pAMPK protein and corticosterone secretory response to DAB by lactate infers that the hypothalamic-pituitary-adrenal axis may be activated by VMN NO-mediated signals of cellular energy imbalance.


Assuntos
Ácido Láctico/metabolismo , Norepinefrina/farmacologia , Células Receptoras Sensoriais/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Estradiol/farmacologia , Neurotransmissores/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Ratos Sprague-Dawley , Receptores de Estrogênio/efeitos dos fármacos , Rombencéfalo/metabolismo
17.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802338

RESUMO

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiologia , Neurotransmissores/metabolismo , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/fisiopatologia , Animais , Animais Recém-Nascidos/metabolismo , Animais Recém-Nascidos/fisiologia , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Depressão/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Masculino , Privação Materna , Aprendizagem em Labirinto/fisiologia , Imagem Molecular/métodos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Natação/fisiologia
18.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802343

RESUMO

Potassium homeostasis is fundamental for brain function. Therefore, effective removal of excessive K+ from the synaptic cleft during neuronal activity is paramount. Astrocytes play a key role in K+ clearance from the extracellular milieu using various mechanisms, including uptake via Kir channels and the Na+-K+ ATPase, and spatial buffering through the astrocytic gap-junction coupled network. Recently we showed that alterations in the concentrations of extracellular potassium ([K+]o) or impairments of the astrocytic clearance mechanism affect the resonance and oscillatory behavior of both the individual and networks of neurons. These results indicate that astrocytes have the potential to modulate neuronal network activity, however, the cellular effectors that may affect the astrocytic K+ clearance process are still unknown. In this study, we have investigated the impact of neuromodulators, which are known to mediate changes in network oscillatory behavior, on the astrocytic clearance process. Our results suggest that while some neuromodulators (5-HT; NA) might affect astrocytic spatial buffering via gap-junctions, others (DA; Histamine) primarily affect the uptake mechanism via Kir channels. These results suggest that neuromodulators can affect network oscillatory activity through parallel activation of both neurons and astrocytes, establishing a synergistic mechanism to maximize the synchronous network activity.


Assuntos
Astrócitos/metabolismo , Neurotransmissores/metabolismo , Potássio/metabolismo , Animais , Junções Comunicantes/metabolismo , Homeostase/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo
19.
Cell Mol Life Sci ; 78(11): 4973-4992, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33864480

RESUMO

Amyloid beta (Aß) is linked to the pathology of Alzheimer's disease (AD). At physiological concentrations, Aß was proposed to enhance neuroplasticity and memory formation by increasing the neurotransmitter release from presynapse. However, the exact mechanisms underlying this presynaptic effect as well as specific contribution of endogenously occurring Aß isoforms remain unclear. Here, we demonstrate that Aß1-42 and Aß1-16, but not Aß17-42, increased size of the recycling pool of synaptic vesicles (SV). This presynaptic effect was driven by enhancement of endogenous cholinergic signalling via α7 nicotinic acetylcholine receptors, which led to activation of calcineurin, dephosphorylation of synapsin 1 and consequently resulted in reorganization of functional pools of SV increasing their availability for sustained neurotransmission. Our results identify synapsin 1 as a molecular target of Aß and reveal an effect of physiological concentrations of Aß on cholinergic modulation of glutamatergic neurotransmission. These findings provide new mechanistic insights in cholinergic dysfunction observed in AD.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Fragmentos de Peptídeos/farmacologia , Sinapses/metabolismo , Sinapsinas/metabolismo , Vesículas Sinápticas/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Cálcio/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Knockout , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurotransmissores/metabolismo , Nicotina/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vesículas Sinápticas/fisiologia , Receptor Nicotínico de Acetilcolina alfa7/deficiência , Receptor Nicotínico de Acetilcolina alfa7/genética
20.
Yakugaku Zasshi ; 141(4): 447-462, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33790111

RESUMO

The blood-brain barrier (BBB) consists of brain capillary endothelial cells linked by tight junctions and serves to regulate the transfer of endogenous compounds and xenobiotics between the circulating blood and brain interstitial fluid. We have developed a methodology to characterize brain-to-blood efflux transport in vivo, using the Brain Efflux Index and an in vitro culture model of the BBB, i.e., a conditionally immortalized cell line of the neurovascular unit. Employing these methods, we showed that the BBB plays an important role in protecting the brain by transporting neurotransmitters, neuromodulators, metabolites, uremic toxins, and xenobiotics together with atrial natriuretic peptide from the brain interstitial fluid to the circulating blood. We also developed a highly selective, sensitive LC-MS/MS method for simultaneous protein quantification. We found significant species differences in the expression amounts of various BBB transporter proteins among mice, rats, marmosets, cynomolgus monkeys, and humans. Among transporter proteins at the BBB, multidrug resistance protein 1 (Mdr1/Abcb1) is known to generate a concentration gradient of unbound substrate drugs between the blood and brain. Based on measurements of the intrinsic efflux transport rate of Mdr1 and the protein expression amounts of Mdr1 in mouse brain capillaries and Mdr1-expressing cell lines, we predicted the unbound drug concentration gradients of 7 drugs in the mouse brain in vivo. This was the first successful prediction of in vivo drug transport activity from in vitro experimental data and transporter protein concentration in tissues. This methodology and findings should greatly advance central nervous system barrier research.


Assuntos
Transporte Biológico/fisiologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Proteômica/métodos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Cromatografia Líquida/métodos , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Neurotransmissores/metabolismo , Proteômica/tendências , Ratos , Espectrometria de Massas em Tandem/métodos , Xenobióticos/metabolismo
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