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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 1738-1741, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018333

RESUMO

Ventromedial prefrontal cortex (vmPFC) is an important brain region involved in many psychological functions. Previous neuroimaging studies have shown disrupted function and altered metabolic level within vmPFC of schizophrenia (SCZ) patients. However, the linkage between the functional connectivity and its underlying neurobiological mechanism in SCZ remains unclear. In this study, we aimed to investigate the altered relationship between the functional connectivity strength (FCS) and metabolic concentrations within vmPFC in drug-naïve first-episode psychosis (FEP) patients using a combined functional magnetic resonance imaging (fMRI) and single-voxel proton magnetic resonance spectroscopy (1H- MRS) technique. There were 26 drug-naïve FEP patients and 27 matched healthy controls participated this study. We have found altered correlation between FCS and N-acetylaspartate (NAA) in drug-naïve FEP patients. In addition, the glutamate and glutamine compounds (Glx) and NAA concentrations were positively correlated with Positive and Negative Symptoms Scale (PANSS) total scores. Our findings revealed the disrupted functional-metabolic coupling within vmPFC in drug-naïve FEP patients and provided useful insights in understanding the etiology of SCZ.


Assuntos
Ácido Aspártico , Psicoses Induzidas por Substâncias , Ácido Aspártico/análogos & derivados , Ácido Glutâmico , Humanos , Córtex Pré-Frontal/diagnóstico por imagem
2.
Yakugaku Zasshi ; 140(10): 1235-1242, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999202

RESUMO

The central nervous system (CNS) is segregated from the circulating blood and peripheral tissues by endothelial and epithelial barriers. To overcome refractory CNS diseases, it is important to understand the membrane transport systems of drugs and the endogenous compounds that relate to the pathogenesis of CNS diseases at these barriers. The endothelial barrier in the brain is the blood-brain barrier (BBB). Our studies clarified the efflux transport of prostaglandin E2 (PGE2), a modulator of neural excitation and inflammatory responses, across the BBB via plasma membrane transporters such as organic anion transporter 3 (Oat3) and multidrug resistance-associated protein 4 (Mrp4). This efflux transport was attenuated by peripheral inflammation or cerebral treatment with neuroexcitatory l-glutamate, suggesting that BBB-mediated PGE2 elimination was altered under several pathological conditions. We also examined excitatory amino acid transporter (EAAT) 1 and 3 as l-glutamate efflux transporters of the inner blood-retinal barrier (BRB) and blood-cerebrospinal barrier. It was considered that these efflux membrane transporters participated in the homeostasis of neuroexcitatory and neuroinflammatory responses in the brain and retina. Moreover, we identified connexin 43 (Cx43) hemichannels as a new membrane transport system that is activated under pathological conditions and recognizes several monocarboxylate drugs, such as valproate. As it is expected that the action of these membrane transporters across the CNS barriers is of great importance in understanding the pathology of various neuroexcitatory diseases, our studies should contribute to the establishment of therapeutic strategies for refractory CNS diseases.


Assuntos
Transporte Biológico , Barreira Hematoencefálica/metabolismo , Barreira Hematorretiniana/metabolismo , Encéfalo/metabolismo , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/metabolismo , Desenvolvimento de Medicamentos , Proteínas de Membrana Transportadoras/metabolismo , Retina/metabolismo , Animais , Doenças do Sistema Nervoso Central/tratamento farmacológico , Conexina 43/metabolismo , Dinoprostona/metabolismo , Transportador 1 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Camundongos , Terapia de Alvo Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
3.
Nat Commun ; 11(1): 5038, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028830

RESUMO

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.


Assuntos
Epilepsia Resistente a Medicamentos/genética , Epilepsia do Lobo Temporal/genética , Neurônios/patologia , Lobo Temporal/patologia , Transcriptoma/genética , Adolescente , Adulto , Biópsia , Estudos de Casos e Controles , Núcleo Celular/genética , Núcleo Celular/metabolismo , Conjuntos de Dados como Assunto , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Ácido Glutâmico/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Microdissecção , Pessoa de Meia-Idade , Modelos Genéticos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neurônios/citologia , Neurônios/metabolismo , RNA-Seq , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Transdução de Sinais/genética , Análise de Célula Única , Lobo Temporal/citologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/cirurgia , Transcrição Genética , Regulação para Cima , Adulto Jovem
4.
Science ; 370(6514): 364-368, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33060364

RESUMO

The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown. Both heart and leg consumed ketones, glutamate, and acetate in direct proportionality to circulating levels, indicating that availability is a key driver for consumption of these substrates. The failing heart consumed more ketones and lactate and had higher rates of proteolysis. These data provide a comprehensive and quantitative picture of human cardiac fuel use.


Assuntos
Ácidos Graxos/metabolismo , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Acetatos/metabolismo , Idoso , Glicemia/metabolismo , Ciclo do Ácido Cítrico , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Cetonas/metabolismo , Perna (Membro)/irrigação sanguínea , Masculino , Metabolômica , Pessoa de Meia-Idade , Contração Miocárdica , Proteólise
5.
Huan Jing Ke Xue ; 41(8): 3862-3869, 2020 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-33124364

RESUMO

In order to clarify the effects of chelate tetrasodium glutamate diacetate (GLDA) on the remediation of cadmium (Cd) contaminated farmland by Pennisetum purpureum Schum, GLDA was applied in different methods within 60 days:total application doses of 585, 1170, and 2340 kg·hm-2 were equally divided into 1-4 applications, respectively, and the time intervals of 2-4 applications were 30, 20, and 15 days, respectively. The biomass, Cd content, and amount of Cd extracted from aboveground parts of Pennisetum purpureum Schum, in addition to the pH, dissolved organic carbon (DOC) mass concentration, and other indicators in soil were analyzed. The results showed that the biomass and Cd content of the aboveground parts of Pennisetum purpureum Schum increased significantly when GLDA was applied many times at a low application dose. The number of applications and the total dose were the key factors influencing the biomass and Cd content, respectively. The highest amount of Cd extracted was 16.78 g·hm-2 at 585 kg·hm-2 (applied four times), which was 275.39% higher than the CK treatment (i.e., no GLDA was applied). There was significant positive correlations between the pH, mass concentration of DOC, and content of DTPA-Cd, and the total dose and number of applications. The mass concentration of DOC was the main factor affecting the DTPA-Cd content. The total Cd content in the soil (after at 585 kg·hm-2 was applied four times) decreased by 3.23% compared with that of the soil before planting Pennisetum purpureum Schum. Therefore, the application of GLDA is of great significance for the remediation of Cd contaminated farmland by Pennisetum purpureum Schum, and the application method should be selected reasonably.


Assuntos
Pennisetum , Poluentes do Solo , Biodegradação Ambiental , Cádmio/análise , Fazendas , Ácido Glutâmico , Solo , Poluentes do Solo/análise
6.
Zhen Ci Yan Jiu ; 45(8): 623-7, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32869571

RESUMO

OBJECTIVE: To observe the effect of wrist-ankle acupuncture (WA) stimulation at "R4"- "R5" - "R6" on the expression of glutamate (Glu) and phosphorylated protein NMDAR1(p-NMDAR1) of the spinal dorsal horn in spared nerve injury (SNI) rats, so as to explore its mechanism underlying improvement of SNI. METHODS: A total of 36 SD rats were randomly divi-ded into sham operation, model and WA groups, with 12 rats in each group. The SNI procedure comprised an axotomy and ligation of the tibial and common peroneal nerves leaving the sural nerve intact. Rats of the WA group were treated by acupuncture at "R4"-"R5"-"R6" points from the 5th day to the 14th day after modeling. The mechanical pain thresholds were measured before and 5, 10 and 14 d after SNI, respectively. The cold allodynia was dectected by Acetone solution dropped onto the lateral plantar surface of the paw. Glu content and p-NMDAR1 expression of spinal dorsal horn were detected by 1H-MRS, ELISA and immunohistochemistry Methods. RESULTS: Compared with the sham operation group, the mechanical pain threshold of the model group was significantly decreased (P<0.01), the duration of cold stimulation foot contraction was increased (P<0.01), and the Glu content and p-NMDAR1 expression in the spinal dorsal horn were significantly increased (P<0.05, P<0.01). After WA intervention, the mechanical pain threshold was significantly increased (P<0.01), the duration of cold stimulation was significantly shortened (P<0.01), and Glu content and p-NMDAR1 protein expression of spinal dorsal horn were decreased significantly (P<0.05, P<0.01) in the WA group compared with the model group. CONCLUSION: WA can reduce pain sensitivity in rats with neuropathic pain, possibly by inhibiting the expression of Glu and p-NMDAR1 in the spinal dorsal horn.


Assuntos
Terapia por Acupuntura , Neuralgia , Animais , Ácido Glutâmico , Extremidade Inferior , N-Metilaspartato , Ratos , Ratos Sprague-Dawley , Medula Espinal , Corno Dorsal da Medula Espinal , Extremidade Superior
7.
PLoS Biol ; 18(8): e3000820, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866173

RESUMO

Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.


Assuntos
Ácido Glutâmico/metabolismo , Cinesina/metabolismo , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo , Neurônios/metabolismo , Espastina/deficiência , Tubulina (Proteína)/metabolismo , Potenciais de Ação , Animais , Membrana Celular/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Potenciais Pós-Sinápticos Excitadores , Hipocampo/patologia , Hipocampo/fisiopatologia , Camundongos Knockout , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Atividade Motora , Neurônios/patologia , Neurônios/ultraestrutura , Transporte Proteico , Espastina/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura , Vesículas Sinápticas/metabolismo
8.
Nat Commun ; 11(1): 4614, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929069

RESUMO

The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours.


Assuntos
Adaptação Ocular , Escuridão , Canais de Potássio/metabolismo , Núcleo Supraquiasmático/fisiologia , Animais , Comportamento Animal , Cálcio/metabolismo , Ácido Glutâmico/metabolismo , Luz , Potenciais da Membrana/efeitos da radiação , Camundongos Endogâmicos C57BL , Canais de Potássio/deficiência , Transdução de Sinais/efeitos da radiação , Núcleo Supraquiasmático/efeitos da radiação
9.
Nat Commun ; 11(1): 4388, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873805

RESUMO

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found that the protocol that induced t-LTD induced t-LTP. We characterized this form of t-LTP and the mechanisms involved in its induction, as well as that driving this switch from t-LTD to t-LTP. We found that this t-LTP is expressed presynaptically at CA3-CA1 synapses, as witnessed by coefficient of variation, number of failures, paired-pulse ratio and miniature responses analysis. Additionally, this form of presynaptic t-LTP does not require NMDARs but the activation of mGluRs and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels and the release of Ca2+ from intracellular stores. Nitric oxide is also required as a messenger from the postsynaptic neuron. Crucially, the release of adenosine and glutamate by astrocytes is required for t-LTP induction and for the switch from t-LTD to t-LTP. Thus, we have discovered a developmental switch of synaptic transmission from t-LTD to t-LTP at hippocampal CA3-CA1 synapses in which astrocytes play a central role and revealed a form of presynaptic LTP and the rules for its induction.


Assuntos
Astrócitos/metabolismo , Hipocampo/crescimento & desenvolvimento , Potenciação de Longa Duração/fisiologia , Transmissão Sináptica/fisiologia , Adenosina/metabolismo , Animais , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Masculino , Camundongos , Técnicas de Patch-Clamp , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
10.
Neuron ; 107(5): 765-767, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32910888

RESUMO

Dopamine release guides reward encoding, but the contribution of glutamate remains unclear. In this issue of Neuron, Zell et al. leverage the genetic ablation of dopamine synthesis from midbrain VGluT2 neurons to assess how glutamate shapes positive reinforcement.


Assuntos
Dopamina , Ácido Glutâmico , Mesencéfalo/metabolismo , Neurônios/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
11.
Biol Res ; 53(1): 36, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32843088

RESUMO

BACKGROUND: To investigate the thalamic neurotransmitters and functional connections in the development of chronic constriction injury (CCI)-induced neuropathic pain. METHODS: The paw withdrawal threshold was measured by mechanical stimulation the right hind paw with the von frey hair in the rats of CCI-induced neuropathic pain. The N-acetylaspartate (NAA) and Glutamate (Glu) in thalamus were detected by magnetic resonance spectrum (MRS) process. The thalamic functional connectivity with other brain regions was scanned by functional magnetic resonance image (fMRI). RESULTS: The paw withdrawal threshold of the ipsilateral side showed a noticeable decline during the pathological process. Increased concentrations of Glu and decreased levels of NAA in the thalamus were significantly correlated with mechanical allodynia in the neuropathic pain states. The thalamic regional homogeneity (ReHo) decreased during the process of neuropathic pain. The functional connectivity among the thalamus with the insula and somatosensory cortex were significantly increased at different time points (7, 14, 21 days) after CCI surgery. CONCLUSION: Our study suggests that dynamic changes in thalamic NAA and Glu levels contribute to the thalamic functional connection hyper-excitation during CCI-induced neuropathic pain. Enhanced thalamus-insula functional connection might have a significant effect on the occurrence of neuropathic pain.


Assuntos
Neuralgia , Neurotransmissores/metabolismo , Tálamo/metabolismo , Ferimentos e Lesões/fisiopatologia , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Constrição , Ácido Glutâmico/metabolismo , Hiperalgesia , Ratos , Tálamo/fisiopatologia
12.
Am J Physiol Cell Physiol ; 319(3): C605-C610, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783655

RESUMO

Epileptic seizures are the manifestation of hypersynchronous and excessive neuronal excitation. While the glutamatergic and GABAergic neurons play major roles in shaping fast neuronal excitation/inhibition homeostasis, it is well illustrated that astrocytes profoundly regulate neuronal excitation by controlling glutamate, GABA, cannabinoids, adenosine, and concentration of K+ around neurons. However, little is known about whether microglia take part in the regulation of acute neuronal excitation and ongoing epileptic behaviors. We proposed that if microglia are innately ready to respond to epileptic overexcitation, depletion of microglia might alter neuronal excitability and severity of acute epileptic seizures. We found that microglia depletion by plx3397, an inhibitor of CSF1R, exacerbates seizure severity and excitotoxicity-induced neuronal degeneration, indicating that microglia are rapidly responsive to the change of excitation/inhibition homeostasis and participate in the protection of neurons from overexcitation.


Assuntos
Astrócitos/metabolismo , Hipocampo/fisiologia , Microglia/fisiologia , Convulsões/fisiopatologia , Animais , Ácido Glutâmico/metabolismo , Camundongos , Neurônios/fisiologia , Convulsões/metabolismo
13.
J Oleo Sci ; 69(9): 1095-1105, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32788523

RESUMO

Ayu sweetfish (Plecoglossus altivelis) is a diurnal freshwater fish that are surface swimmers and active under broad and short wavelength-dominated light. Biochemical analyses have shown that the ayu fish have abundant carotenoids including zeaxanthin in their integuments. Although zeaxanthin plays an important role in the physiological function of the retina, the amount and location of zeaxanthin in the ayu eye have not been accurately determined. In this study, circular dichroism spectral data and chiral high-performance liquid chromatography analysis showed that zeaxanthin was the primary carotenoid in the ayu eye, and the eye had the highest carotenoid content compared to those in the integuments, subcutaneous fat, and digestive tract. Interestingly, zeaxanthin in the ayu eyeball was expressed in the photoreceptor layer and near the retinal pigmented epithelium. In vitro assays showed that zeaxanthin could protect photoreceptors and retinal pigmented epithelial cell lines against the oxidative stress induced by exposure to L-buthionine-(S,R)-sulfoximine/glutamate. These findings indicate that zeaxanthin plays protective roles against oxidative stress in the vision of wild ayu.


Assuntos
Antioxidantes , Olho/metabolismo , Osmeriformes/metabolismo , Células Fotorreceptoras/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Zeaxantinas/metabolismo , Zeaxantinas/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ácido Glutâmico/efeitos adversos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Zeaxantinas/fisiologia
14.
PLoS One ; 15(8): e0237371, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845904

RESUMO

The neurotransmitter gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the human brain; however, it is becoming more evident that this non-proteinogenic amino acid plays multiple physiological roles in biology. In the present study, the transport and function of GABA is studied in the highly infectious intracellular bacterium Brucella abortus. The data show that 3H-GABA is imported by B. abortus under nutrient limiting conditions and that the small RNAs AbcR1 and AbcR2 negatively regulate this transport. A specific transport system, gts, is responsible for the transport of GABA as determined by measuring 3H-GABA transport in isogenic deletion strains of known AbcR1/2 regulatory targets; however, this locus is unnecessary for Brucella infection in BALB/c mice. Similar assays revealed that 3H-GABA transport is uninhibited by the 20 standard proteinogenic amino acids, representing preference for the transport of 3H-GABA. Metabolic studies did not show any potential metabolic utilization of GABA by B. abortus as a carbon or nitrogen source, and RNA sequencing analysis revealed limited transcriptional differences between B. abortus 2308 with or without exposure to GABA. While this study provides evidence for GABA transport by B. abortus, questions remain as to why and when this transport is utilized during Brucella pathogenesis.


Assuntos
Brucella abortus/metabolismo , Neurotransmissores/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Brucella abortus/efeitos dos fármacos , Brucella abortus/fisiologia , Ácido Glutâmico/farmacologia , Camundongos , Camundongos Endogâmicos BALB C
15.
Nat Commun ; 11(1): 4218, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839452

RESUMO

Exposure to social stress and dysregulated serotonergic neurotransmission have both been implicated in the etiology of psychiatric disorders. However, the serotonergic circuit involved in stress vulnerability is still unknown. Here, we explored whether a serotonergic input from the dorsal raphe (DR) to ventral tegmental area (VTA) influences vulnerability to social stress. We identified a distinct, anatomically and functionally defined serotonergic subpopulation in the DR that projects to the VTA (5-HTDR→VTA neurons). Moreover, we found that susceptibility to social stress decreased the firing activity of 5-HTDR→VTA neurons. Importantly, the bidirectional manipulation of 5-HTDR→VTA neurons could modulate susceptibility to social stress. Our findings reveal that the activity of 5-HTDR→VTA neurons may be an essential factor in determining individual levels of susceptibility to social stress and suggest that targeting specific serotonergic circuits may aid the development of therapies for the treatment of stress-related disorders.


Assuntos
Núcleo Dorsal da Rafe/fisiologia , Vias Neurais/fisiologia , Neurônios Serotoninérgicos/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Núcleo Dorsal da Rafe/citologia , Núcleo Dorsal da Rafe/metabolismo , Ácido Glutâmico/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neurônios Serotoninérgicos/citologia , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/metabolismo
16.
J Pharmacol Sci ; 144(3): 151-164, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32807662

RESUMO

Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamate transmission efficiency depends on the correct functionality and expression of a plethora of receptors and transporters, located both on neurons and glial cells. Of note, glutamate reuptake by dedicated transporters prevents its accumulation at the synapse as well as non-physiological spillover. Indeed, extracellular glutamate increase causes aberrant synaptic signaling leading to neuronal excitotoxicity and death. Moreover, extrasynaptic glutamate diffusion is strongly associated with glia reaction and neuroinflammation. Glutamate-induced excitotoxicity is mainly linked to an impaired ability of glial cells to reuptake and respond to glutamate, then this is considered a common hallmark in many neurodegenerative diseases, including Parkinson's disease (PD). In this review, we discuss the function of astrocytes and microglia in glutamate homeostasis, focusing on how glial dysfunction causes glutamate-induced excitotoxicity leading to neurodegeneration in PD.


Assuntos
Ácido Glutâmico/metabolismo , Ácido Glutâmico/toxicidade , Neuroglia/metabolismo , Neurotransmissores/metabolismo , Neurotransmissores/toxicidade , Doença de Parkinson/etiologia , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Homeostase , Humanos , Inflamação , Doença de Parkinson/metabolismo , Receptores de Glutamato/metabolismo
17.
Adv Pharmacol ; 89: 103-129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616204

RESUMO

Depression represents one of the most common and debilitating mental illnesses in the world today. Despite this pressing issue, the majority treatments for depression give patients therapeutic response only approximately half of the time, with many not responding at all. In part, this stagnation has been due to the dominance of the monoamine hypothesis that guides the current approach to understanding and treating depression. While therapies that increase levels of monoamines have been useful, clearly a more complete understanding of the neural circuits and treatments is needed to better help patients. Recent work that exploits the glutamatergic system within the brain has demonstrated a functional role for glutamate in combatting depression. While more research is required to understand the specific glutamatergic pathophysiological mechanisms within depression, emerging clinical work has already demonstrated promising results. Current treatments that target the glutamatergic system, especially NMDA receptor antagonists have already shown efficacy in several clinical trials. In this chapter we briefly introduce a mechanistic basis for a role of glutamate in the pathophysiology of depression. We further review basic and translational studies that describes potential mechanisms and roles for glutamate. A discussion of the first promising NMDA receptor antagonist for depression, ketamine, follows afterward. The development of NMDA receptor antagonists for treatment of depression is chronicled, from initial studies up through the recent FDA approval of intranasal esketamine as well as other newer compounds that have shown recent promise in clinical trials.


Assuntos
Padrões de Prática Médica , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ácido Glutâmico/uso terapêutico , Humanos , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo
18.
PLoS One ; 15(7): e0236478, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716967

RESUMO

CaMKII is an important mediator of forms of synaptic plasticity that are thought to underly learning and memory. The CaMKII mutants K42M and K42R have been used interchangeably as research tools, although some reported phenotypic differences suggest that they may differ in the extent to which they impair ATP binding. Here, we directly compared the two mutations at the high ATP concentrations that exist within cells (~4 mM). We found that both mutations equally blocked GluA1 phosphorylation in vitro and GluN2B binding within cells. Both mutations also reduced but did not completely abolish CaMKII T286 autophosphorylation in vitro or CaMKII movement to excitatory synapses in neurons. Thus, despite previously suggested differences, both mutations appear to interfere with ATP binding to the same extent.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Mutação/genética , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Células Cultivadas , Feminino , Ácido Glutâmico/farmacologia , Células HEK293 , Hipocampo/citologia , Humanos , Masculino , Movimento , Fosforilação , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo
19.
J Stroke Cerebrovasc Dis ; 29(8): 104848, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689584

RESUMO

BACKGROUND: Dapsone prevents ischemic injury, inhibits apoptosis and shows functional improvement post-ischemia. However, its effect on proapoptotic or survival proteins in delayed ischemia remains unclear. METHODS: Male adult Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by 24 h of ischemic reperfusion (I/R). Dapsone [9.375 or 12.5 mg/kg, intraperitoneally (IP)] was administered at 3, 6 and 12 h of I/R followed by behavioural assessment, brain infarction, histological alteration and cell viability study. Further, dapsone (25 and 50 µM) was added at 3, 6 and 12 h after L-glutamate (100 µM) in primary cortical culture (DIV 14) and cell viability, cytotoxicity, apoptosis was observed. Proteins expression were observed using immunocytochemistry. All experiments were performed after 24 h of I/R (In-Vivo) and 24 h of recovery post glutamate insult (In-Vitro). RESULTS: Reduced brain infarction, improved neurobehavioural functions in addition to reduction in abnormal morphological structures of ischemic brain and improvement in cell viability was observed with treatment of dapsone (12.5 mg/kg) administered upto 6 h. Similarly, dapsone (25, 50 µM) increased cell survival post glutamate insult in cortical culture (In-vitro). Further, dapsone treatment at delayed hours (6 h) reduced apoptotic nuclei and proapoptotic proteins JNK, PTEN, Calpain, Caspase 3 expression along with activation of prosurvival protein BDNF expression post-glutamate insult. CONCLUSION: Our results suggest that dapsone has the potential to limit the neuronal damage post-glutamate insult in delayed hours (6 h) through repressing proapoptotic proteins JNK, PTEN, Calpain, Caspase-3 of cerebral ischemia along with activation of pro-survival protein BDNF.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Dapsona/farmacologia , Ácido Glutâmico/toxicidade , Infarto da Artéria Cerebral Média/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
20.
J Clin Pediatr Dent ; 44(3): 174-179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32644890

RESUMO

Objective: The aim of the present study was to evaluate the reduction in bacterial loading using Papacarie and Carisolv as an irrigating solution in pulpectomized primary molars. Study design: A controlled, randomized clinical trial involving 120 necrotic canals from both genders between 3 and 7 years old children were included, 30 irrigated with Papacarie [ group I], Carisolv [ group II], 1% NaOCl gel [ group III] and 1% Na0Cl solution [group IV ] each; in all cases, 2 microbiological samples from within the canals were taken with sterile paper points, the first after the canal opening and before the first irrigation, and the second after instrumentation and final irrigation, before obturation. All samples were evaluated by Agar plate method. Results: The results were statistically analyzed by ANOVA. After analyzing samples before and after irrigation in all the groups, a strong significant decrease in bacterial load [ p = < 0.001 ] was found with Papacarie and Carisolv. Conclusion: Papacarie and Carisolv can be suggested as an alternative irrigant for pulpectomy of necrotic teeth.


Assuntos
Dente Molar , Irrigantes do Canal Radicular , Criança , Pré-Escolar , Cavidade Pulpar , Feminino , Ácido Glutâmico , Humanos , Leucina , Lisina , Masculino , Papaína , Preparo de Canal Radicular , Hipoclorito de Sódio
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