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1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802338

RESUMEN

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.


Asunto(s)
Encéfalo/metabolismo , Encéfalo/fisiología , Neurotransmisores/metabolismo , Heridas y Traumatismos/metabolismo , Heridas y Traumatismos/fisiopatología , Animales , Animales Recién Nacidos/metabolismo , Animales Recién Nacidos/fisiología , Ansiedad/metabolismo , Ansiedad/fisiopatología , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Conducta Animal/fisiología , Depresión/metabolismo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Femenino , Masculino , Privación Materna , Aprendizaje por Laberinto/fisiología , Imagen Molecular/métodos , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Natación/fisiología
2.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802343

RESUMEN

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.


Asunto(s)
Astrocitos/metabolismo , Neurotransmisores/metabolismo , Potasio/metabolismo , Animales , Uniones Comunicantes/metabolismo , Homeostasis/fisiología , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo
3.
Nat Commun ; 12(1): 2073, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824313

RESUMEN

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.


Asunto(s)
Amiloide/metabolismo , Hígado/enzimología , Mutación/genética , Estrés Oxidativo , Fenilalanina Hidroxilasa/genética , Agregado de Proteínas , Animales , Autofagia , Biomarcadores/metabolismo , Peso Corporal , Cruzamiento , Femenino , Regulación de la Expresión Génica , Genotipo , Metabolismo de los Lípidos , Hígado/patología , Masculino , Metaboloma , Ratones , Proteínas Mutantes/metabolismo , Neurotransmisores/metabolismo , Estrés Oxidativo/genética , Fenilalanina/metabolismo , Fenilalanina Hidroxilasa/metabolismo , Fenilcetonurias/enzimología , Pterinas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Respiración , Ubiquitina/metabolismo , Ubiquitinación
4.
Nat Commun ; 12(1): 2107, 2021 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-33833240

RESUMEN

Vacuolar H+-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1R741Q) and A512P (Atp6v0a1A512P) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1A512P/A512P mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.


Asunto(s)
Encefalopatías/genética , Encéfalo/crecimiento & desarrollo , Neuronas/fisiología , Neurotransmisores/metabolismo , ATPasas de Translocación de Protón Vacuolares/genética , Animales , Autofagosomas/patología , Mapeo Encefálico/métodos , Catepsina D/metabolismo , Línea Celular , Células HEK293 , Humanos , Mutación con Pérdida de Función/genética , Lisosomas/patología , Imagen por Resonancia Magnética/métodos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Mutación Missense/genética , Neuronas/citología , Vesículas Sinápticas/patología
5.
Adv Pharmacol ; 90: 19-37, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33706933

RESUMEN

More than a scientific paper or a review article, this is a remembrance of a unique time of science and life that the authors spent in Paul Greengard's laboratory at the Rockefeller University in New York in the 1980s and 1990s, forming the so-called synaptic vesicle group. It was a time in which the molecular mechanisms of synaptic transmission and the nature of the organelles in charge of storing and releasing neurotransmitter were just beginning to be understood. It was an exciting time in which the protein composition of synaptic vesicles started to be identified. It turned out that the interactions of synaptic vesicle proteins with the cytoskeleton and the presynaptic membrane and their modulation by protein phosphorylation represented an essential network regulating the efficiency of neurotransmitter release and thereby synaptic strength and plasticity. This is also a description of the distinct scientific journeys that the three authors took on going back to Europe and how they were strongly influenced by the generous and outstanding mentorship of Paul Greengard, his genuine interest in their lives and careers and the life-long friendship with him.


Asunto(s)
Plasticidad Neuronal/fisiología , Transmisión Sináptica/fisiología , Vesículas Sinápticas/fisiología , Animales , Investigación Biomédica , Humanos , Neuronas/fisiología , Neurotransmisores/metabolismo
6.
Adv Pharmacol ; 90: 67-87, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33706939

RESUMEN

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein with an apparent Mr of 32,000), now also known as phosphoprotein phosphatase 1 regulatory subunit 1B (PPP1R1B), is a potent inhibitor of protein phosphatase 1 (PP1, also known as PPP1) when phosphorylated at Thr34 by cAMP-dependent protein kinase (PKA). DARPP-32 exhibits a remarkable regional distribution in brain, roughly similar to that of dopamine innervation. Its discovery was a culmination of the long-standing effort of Paul Greengard to understand the mechanisms through which neurotransmitters such as dopamine exert their effects on target neurons. DARPP-32 is particularly enriched in striatal projection neurons where it is regulated by numerous signals through which it integrates and amplifies responses to many stimuli. Molecular studies of DARPP-32 have revealed that its regulation and function are more complex than anticipated. It is phosphorylated on multiple sites by several protein kinases that modulate DARPP-32 properties. Primarily, when phosphorylated at Thr34 DARPP-32 is a potent inhibitor of PP1, whereas when phosphorylated at Thr75 by Cdk5 it inhibits PKA. Phosphorylation at serine residues by CK1 and CK2 modulates its intracellular localization and its sensitivity to kinases or phosphatases. Modeling studies provide evidence that the signaling pathways including DARPP-32 are endowed of strong robustness and bistable properties favoring switch-like responses. Thus DARPP-32 combined with a set of other distinct signaling molecules enriched in striatal projection neurons plays a key role in the characteristic properties and physiological function of these neurons.


Asunto(s)
Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Animales , Ganglios Basales/metabolismo , Fosfoproteína 32 Regulada por Dopamina y AMPc/química , Humanos , Enfermedades del Sistema Nervioso/metabolismo , Neurotransmisores/metabolismo , Fosforilación
7.
Int J Nanomedicine ; 16: 2203-2217, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33762821

RESUMEN

Background: It is well known that smoking is harmful to health; however, it can also ameliorate anxiety. To date, it is unclear whether any nanoparticles found in cigarette mainstream smoke (CS) contribute to this effect. Aim: The aim of this study was to assess the particle composition of CS to identify novel anti-anxiety components. Methods: Carbon dots (CDs) from CS (CS-CDs) were characterised using high-resolution transmission electron microscopy, Fourier-transform infrared, ultraviolet, fluorescence, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. The anti-anxiety effects of CS-CDs in mouse models were evaluated and confirmed with the elevated plus maze and open-field tests. Results: The quantum yield of CS-CDs was 13.74%, with a composition of C, O, and N. In addition, the surface groups contained O-H, C-H, C=O, C-N, N-H, C-O-C, and COO- bonds. Acute toxicity testing revealed that CS-CDs had low in vitro and in vivo toxicity within a certain concentration range. The results of the elevated plus maze and open-field tests showed that CS-CDs had a significant anti-anxiety effect and a certain sedative effect in mice. The mechanism of these effects may be related to the decrease in glutamate levels and promotion of norepinephrine production in the mouse brain, and the decrease in dopamine in mouse serum due to CS-CDs. Conclusion: CS-CDs may have anti-anxiety and certain sedative effects. This study provides a new perspective for a more comprehensive understanding of the components, properties, and functions of CS. Furthermore, it offers a novel target for the development of smoking cessation treatments, such as nicotine replacement therapy.


Asunto(s)
Conducta Animal , Carbono/química , Fumar Cigarrillos/efectos adversos , Sistema Endocrino/metabolismo , Neurotransmisores/metabolismo , Puntos Cuánticos/química , Agua/química , Hormona Adrenocorticotrópica/sangre , Animales , Ansiedad/sangre , Ansiedad/patología , Encéfalo/metabolismo , Encéfalo/patología , Cromatografía Líquida de Alta Presión , Corticosterona/sangre , Hormona Liberadora de Corticotropina/sangre , Dopamina/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Espectroscopía de Fotoelectrones , Puntos Cuánticos/ultraestructura , Células RAW 264.7 , Espectrometría de Fluorescencia , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Pruebas de Toxicidad Aguda , Difracción de Rayos X
8.
Int J Nanomedicine ; 16: 2013-2044, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727812

RESUMEN

Background: Sulpiride (SUL), is a selective antidopaminergic drug that had extensive biological activities. However, its sparingly aqueous solubility and limited gastrointestinal permeability lead to scanty oral bioavailability which hinders its clinical efficacy. Objective: SUL-loaded lipospheres (SUL-LPS) were designed to serve as an oral biocompatible nanovector for improving SUL permeability as well as conquering its low oral absorption and then in turn enhancing its antidepressant action. Methods: SUL-LPS were fabricated via two processing techniques namely, melt emulsification and solvent evaporation. The impact of different lipid cores, phospholipid shells together with various surfactant concentrations and types on the lipospheres properties were screened. Detailed physicochemical elucidations were performed followed by ex vivo permeation appraisal using the non-everted intestine model. The pharmacokinetic parameters of SUL-LPS, free SUL and marketed product were assessed following oral administration to healthy rats. Reserpine-induced depression rat model was used to assess the antidepressant action of SUL-LPS on which full behavioural and biochemical analysis was conducted. Safety attributes of nanoencapsulated SUL on the brain and other internal organs were evaluated. Results: The optimum LPS revealed an excellent nanosize with a narrow PdI, negative zeta potential and acceptable entrapment efficiency of 68.62 nm, 0.242, -30.4 mV and 84.12%, respectively. SUL-LPS showed a sustained release pattern and 2.1-fold enhancement in the intestinal permeation parameters with low mucin interaction. Oral pharmacokinetic appraisal exhibited that LPS provided 3.4-fold improvement in SUL oral bioavailability together with long-circulating properties, relative to the free drug. Pharmacodynamic study confirmed the superior antidepressant action of SUL-LPS as evident by 1.6 and 1.25-fold elevation in the serotonin and dopamine expressions, respectively. Meanwhile, nanotoxicological appraisal proved the biocompatibility of SUL-LPS upon repetitive oral administration. Conclusion: Rationally designed lipospheres hold promising in vitro and in vivo characteristics for efficient delivery of SUL with high oral bioavailability, antidepressant activity together with a good safety profile.


Asunto(s)
Antidepresivos/farmacología , Lípidos/química , Nanopartículas/química , Sulpirida/administración & dosificación , Sulpirida/farmacología , Administración Oral , Animales , Materiales Biocompatibles/química , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Composición de Medicamentos , Liberación de Fármacos , Liofilización , Masculino , Mucinas/química , Nanopartículas/ultraestructura , Neurotransmisores/metabolismo , Especificidad de Órganos/efectos de los fármacos , Tamaño de la Partícula , Permeabilidad , Ratas Sprague-Dawley , Ratas Wistar , Sulpirida/química , Sulpirida/farmacocinética , Porcinos
9.
Nat Commun ; 12(1): 761, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536412

RESUMEN

Synaptotagmin 1 is a vesicle-anchored membrane protein that functions as the Ca2+ sensor for synchronous neurotransmitter release. In this work, an arginine containing region in the second C2 domain of synaptotagmin 1 (C2B) is shown to control the expansion of the fusion pore and thereby the concentration of neurotransmitter released. This arginine apex, which is opposite the Ca2+ binding sites, interacts with membranes or membrane reconstituted SNAREs; however, only the membrane interactions occur under the conditions in which fusion takes place. Other regions of C2B influence the fusion probability and kinetics but do not control the expansion of the fusion pore. These data indicate that the C2B domain has at least two distinct molecular roles in the fusion event, and the data are consistent with a model where the arginine apex of C2B positions the domain at the curved membrane surface of the expanding fusion pore.


Asunto(s)
Arginina/metabolismo , Membrana Celular/metabolismo , Fusión de Membrana , Proteínas SNARE/metabolismo , Sinaptotagmina I/metabolismo , Animales , Arginina/química , Sitios de Unión , Calcio/metabolismo , Neurotransmisores/metabolismo , Unión Proteica , Dominios Proteicos , Ratas , Proteínas SNARE/química , Sinaptotagmina I/química
10.
Nature ; 591(7848): 111-116, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33442056

RESUMEN

In 1986, electron microscopy was used to reconstruct by hand the entire nervous system of a roundworm, the nematode Caenorhabditis elegans1. Since this landmark study, high-throughput electron-microscopic techniques have enabled reconstructions of much larger mammalian brain circuits at synaptic resolution2,3. Nevertheless, it remains unknown how the structure of a synapse relates to its physiological transmission strength-a key limitation for inferring brain function from neuronal wiring diagrams. Here we combine slice electrophysiology of synaptically connected pyramidal neurons in the mouse somatosensory cortex with correlated light microscopy and high-resolution electron microscopy of all putative synaptic contacts between the recorded neurons. We find a linear relationship between synapse size and strength, providing the missing link in assigning physiological weights to synapses reconstructed from electron microscopy. Quantal analysis also reveals that synapses contain at least 2.7 neurotransmitter-release sites on average. This challenges existing release models and provides further evidence that neocortical synapses operate with multivesicular release4-6, suggesting that they are more complex computational devices than thought, and therefore expanding the computational power of the canonical cortical microcircuitry.


Asunto(s)
Neocórtex/citología , Neocórtex/ultraestructura , Sinapsis/fisiología , Sinapsis/ultraestructura , Transmisión Sináptica , Animales , Tamaño de la Célula , Fenómenos Electrofisiológicos , Masculino , Ratones , Microscopía , Microscopía Electrónica , Neurotransmisores/metabolismo , Células Piramidales/citología , Células Piramidales/metabolismo , Células Piramidales/ultraestructura , Corteza Somatosensorial/citología , Corteza Somatosensorial/ultraestructura
11.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33466562

RESUMEN

Given the pharmacological properti es and the potential role of kynurenic acid (KYNA) in human physiology and the pleiotropic activity of the neurohormone melatonin (MEL) involved in physiological and immunological functions and as regulator of antioxidant enzymes, this study aimed at evaluating the capability of Saccharomyces cerevisiae EC1118 to release tryptophan derivatives (dTRPs) from the kynurenine (KYN) and melatonin pathways. The setting up of the spectroscopic and chromatographic conditions for the quantification of the dTRPs in LC-MS/MS system, the optimization of dTRPs' production in fermentative and whole-cell biotransformation approaches and the production of dTRPs in a soybean-based cultural medium naturally enriched in tryptophan, as a case of study, were included in the experimental plan. Variable amounts of dTRPs, with a prevalence of metabolites of the KYN pathway, were detected. The LC-MS/MS analysis showed that the compound synthesized at highest concentration is KYNA that reached 9.146 ± 0.585 mg/L in fermentation trials in a chemically defined medium at 400 mg/L TRP. Further experiments in a soybean-based medium confirm KYNA as the main dTRPs, whereas the other dTRPs reached very lower concentrations. While detectable quantities of melatonin were never observed, two MEL isomers were successfully measured in laboratory media.


Asunto(s)
Medios de Cultivo/metabolismo , Saccharomyces cerevisiae/metabolismo , Soja/metabolismo , Triptófano/metabolismo , Cromatografía Liquida/métodos , Fermentación/fisiología , Humanos , Ácido Quinurénico/metabolismo , Quinurenina/metabolismo , Melatonina/metabolismo , Neurotransmisores/metabolismo , Transducción de Señal/fisiología , Espectrometría de Masas en Tándem/métodos
12.
Nat Commun ; 12(1): 431, 2021 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-33462204

RESUMEN

Neuronal exocytosis facilitates the propagation of information through the nervous system pertaining to bodily function, memory, and emotions. Using amperometry, the sub-millisecond dynamics of exocytosis can be monitored and the modulation of exocytosis due to drug treatment or neurodegenerative diseases can be studied. Traditional single-cell amperometry is a powerful technique for studying the molecular mechanisms of exocytosis, but it is both costly and labor-intensive to accumulate statistically significant data. To surmount these limitations, we have developed a silicon-based electrode array with 1024 on-chip electrodes that measures oxidative signal in 0.1 millisecond intervals. Using the developed device, we are able to capture the modulation of exocytosis due to Parkinson's disease treatment (L-Dopa), with statistical significance, within 30 total minutes of recording. The validation study proves our device's capability to accelerate the study of many pharmaceutical treatments for various neurodegenerative disorders that affect neurotransmitter secretion to a matter of minutes.


Asunto(s)
Técnicas Biosensibles/instrumentación , Exocitosis/fisiología , Vesículas Extracelulares/metabolismo , Neurotransmisores/metabolismo , Línea Celular Tumoral , Humanos , Microelectrodos , Semiconductores
13.
J Ethnopharmacol ; 264: 113265, 2021 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-32858198

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Luffa operculata (L.) Cogn (Cucurbitaceae) is a traditional plant popularly used in the abortion induction, against sinusitis and is toxic. AIM OF THE STUDY: To verify the influence of the aqueous extract obtained from the dry fruit of L. operculata (BNE) on the male rats vertically exposed to a subabortive dose of BNE, by evaluating alterations in behavior and neurochemical features in hypothalamus, striatum and frontal cortex, at a juvenile age, after receiving a stress challenge given by the use of the "New York subway stress" technique (NYS). MATERIALS AND METHODS: Pregnant female rats (F0 generation) received 1.0 mg/kg BNE, or distilled water (100 mL/kg), by gavage, between gestation days GD17 and GD21. The pups were weaned at PND21 and were kept up to PND60 (juvenile age) in controlled environmental conditions. Four groups were obtained: control (CG), experimental (EG), stress control (SCG) and stress experimental (SEG) After being stressed, the animals were behavioral screened for in the open field (OF) and in light-dark box (LDB) apparatuses. They were euthanized, and the liver, kidneys and brain were removed for both macroscopic and microscopic analyses, and for quantification of vanillylmandelic acid (VMA), norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the serotonin (5-HT) and its metabolite 5-hydroxyindolylacetic acid (5-HIAA) were accessed in the hypothalamus, frontal cortex and striatum. RESULTS AND DISCUSSION: although most of the behavior changes were due to the stress challenge, the rats spent more time in the dark side of the LDB and were less likely to explore the light side, indicating that the treatment with BNE induced to fear. Interferences of BNE over behavior were due to impairment of VMA, NE, 5-HT and DA and increasing of DOPAC in the hypothalamus, and an increase of 5-HIAA in the frontal cortex, indicating alterations in the hypothalamic-hypophysis-adrenal axis (HHAA). No macroscopic or histopathological changes were observed in the liver, kidneys, or brain, although GFAP was diminished in the SCG, as expected for stressed rats. CONCLUSION: the vertical exposition of juvenile rats to BNE led to the manifestation of fear and to a down regulation of the hypothalamic-hypophysis-adrenal axis.


Asunto(s)
Miedo/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Luffa , Neurotransmisores/metabolismo , Extractos Vegetales/administración & dosificación , Efectos Tardíos de la Exposición Prenatal/metabolismo , Factores de Edad , Animales , Dopamina/metabolismo , Miedo/fisiología , Miedo/psicología , Femenino , Ácido Hidroxiindolacético/metabolismo , Masculino , Extractos Vegetales/aislamiento & purificación , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas Wistar , Serotonina/metabolismo
14.
Aquat Toxicol ; 231: 105715, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33341507

RESUMEN

This study was conceptualized in order to assess the 96-h LC50 of bifenthrin (BF) in O. niloticus and also to measure the biochemical, behavioral, and molecular responses of the fish suchronically exposed to a sub-lethal concentration of the insecticide. The role of Petroselinum crispum essential oil (PEO) supplementation in mitigating the resulted neurotoxic insult was also investigated. The acute toxicity study revealed that the 96-h LC50 of BF is 6.81 µg/L, and varying degrees of behavioral changes were recorded in a dose-dependent manner. The subchronic study revealed reduction of dissolved oxygen and increased ammonia in aquaria of BF-exposed fish. Clinical signs revealed high degree of discomfort and aggressiveness together with reductions in survival rate and body weight gain. The levels of monoamines in brain, and GABA and amino acids in serum were reduced, together with decreased activities of Na+/K+-ATPase and acetylcholine esterases (AchE). The activities of antioxidant enzymes were also diminshed in the brain while oxdative damage and DNA breaks were elevated. Myeloperoxidase (MPO) activity in serum increased with overexpression of the pro-inflammatory cytokines in the brain tissue. BF also upregulated the expression of brain-stress related genes HSP70, Caspase-3 and P53. Supplemention of PEO to BF markedly abrogated the toxic impacts of the insecticide, specially at the high level. These findings demonstrate neuroprotective, antioxidant, genoprotective, anti-inflammatory and antiapoptic effects of PEO in BF-intoxicated fish. Based on these mechanistic insights of PEO, we recommend its use as an invaluable supplement in the fish feed.


Asunto(s)
Encéfalo/patología , Cíclidos/fisiología , Suplementos Dietéticos , Inflamación/patología , Aceites Volátiles/farmacología , Petroselinum/química , Piretrinas/toxicidad , Acetilcolinesterasa/metabolismo , Aminoácidos/metabolismo , Animales , Antioxidantes/metabolismo , Conducta Animal , Biomarcadores/metabolismo , Encéfalo/efectos de los fármacos , Cíclidos/crecimiento & desarrollo , Citocinas/metabolismo , Daño del ADN , Regulación de la Expresión Génica/efectos de los fármacos , Insecticidas/metabolismo , Dosificación Letal Mediana , Neurotoxinas/toxicidad , Neurotransmisores/metabolismo , Estrés Oxidativo/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Análisis de Supervivencia , Contaminantes Químicos del Agua/toxicidad , Calidad del Agua , Ácido gamma-Aminobutírico/metabolismo
15.
Adv Exp Med Biol ; 1264: 15-28, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33332001

RESUMEN

Most of our current understanding of the neuromolecular mechanisms of Cannabis action focusses on two plant cannabinoids, THC and CBD. THC acts primarily through presynaptic CB cannabinoid receptors to regulate neurotransmitter release in the brain, spinal cord and peripheral nerves. CBD action, on the other hand, is probably mediated through multiple molecular targets.


Asunto(s)
Cannabinoides/farmacología , Cannabis/química , Transmisión Sináptica/efectos de los fármacos , Cannabidiol/farmacología , Dronabinol/farmacología , Humanos , Neurotransmisores/metabolismo , Receptores de Cannabinoides/metabolismo
16.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-33322180

RESUMEN

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.


Asunto(s)
Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Mycobacterium tuberculosis/metabolismo , Neuronas/patología , Tuberculosis Pulmonar/metabolismo , Animales , Ansiedad/metabolismo , Ansiedad/microbiología , Síntomas Conductuales/microbiología , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/citología , Encéfalo/enzimología , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Disfunción Cognitiva/microbiología , Depresión/metabolismo , Depresión/microbiología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hipocampo/citología , Hipocampo/inmunología , Hipocampo/metabolismo , Hipocampo/patología , Quinasas Janus/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/patogenicidad , Neuronas/citología , Neurotransmisores/metabolismo , Tuberculosis Pulmonar/enzimología , Tuberculosis Pulmonar/patología , Tuberculosis Pulmonar/psicología , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
18.
Nat Commun ; 11(1): 5516, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139696

RESUMEN

Assembly of SNARE complexes that mediate neurotransmitter release requires opening of a 'closed' conformation of UNC-64/syntaxin. Rescue of unc-13/Munc13 mutant phenotypes by overexpressed open UNC-64/syntaxin suggested a specific function of UNC-13/Munc13 in opening UNC-64/ syntaxin. Here, we revisit the effects of open unc-64/syntaxin by generating knockin (KI) worms. The KI animals exhibit enhanced spontaneous and evoked exocytosis compared to WT animals. Unexpectedly, the open syntaxin KI partially suppresses exocytosis defects of various mutants, including snt-1/synaptotagmin, unc-2/P/Q/N-type Ca2+ channel alpha-subunit and unc-31/CAPS, in addition to unc-13/Munc13 and unc-10/RIM, and enhanced exocytosis in tom-1/Tomosyn mutants. However, open syntaxin aggravates the defects of unc-18/Munc18 mutants. Correspondingly, open syntaxin partially bypasses the requirement of Munc13 but not Munc18 for liposome fusion. Our results show that facilitating opening of syntaxin enhances exocytosis in a wide range of genetic backgrounds, and may provide a general means to enhance synaptic transmission in normal and disease states.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Exocitosis/genética , Liposomas/metabolismo , Transmisión Sináptica/genética , Sintaxina 1/metabolismo , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Técnicas de Sustitución del Gen , Mutación , Neurotransmisores/metabolismo , Sintaxina 1/genética
19.
Neuron ; 108(1): 17-32, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33058762

RESUMEN

The actions of neuromodulation are thought to mediate the ability of the mammalian brain to dynamically adjust its functional state in response to changes in the environment. Altered neurotransmitter (NT) and neuromodulator (NM) signaling is central to the pathogenesis or treatment of many human neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, depression, and addiction. To reveal the precise mechanisms by which these neurochemicals regulate healthy and diseased neural circuitry, one needs to measure their spatiotemporal dynamics in the living brain with great precision. Here, we discuss recent development, optimization, and applications of optical approaches to measure the spatial and temporal profiles of NT and NM release in the brain using genetically encoded sensors for in vivo studies.


Asunto(s)
Técnicas Biosensibles , Encéfalo/metabolismo , Neuronas/metabolismo , Neurotransmisores/metabolismo , Imagen Óptica , Optogenética , Animales , Encéfalo/diagnóstico por imagen , Humanos , Proteínas de Unión Periplasmáticas/genética , Ingeniería de Proteínas , Receptores Acoplados a Proteínas G/genética
20.
Int J Nanomedicine ; 15: 6339-6353, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32922005

RESUMEN

Introduction: Epilepsy is a chronic neurological condition characterized by behavioral, molecular, and neurochemical alterations. Current antiepileptic drugs are associated with various adverse impacts. The main goal of the current study is to investigate the possible anticonvulsant effect of selenium nanoparticles (SeNPs) against pentylenetetrazole (PTZ)-mediated epileptic seizures in mice hippocampus. Sodium valproate (VPA) was used as a standard anti-epileptic drug. Methods: Mice were assigned into five groups (n=15): control, SeNPs (5 mg/kg, orally), PTZ (60 mg/kg, intraperitoneally), SeNPs+PTZ and VPA (200 mg/kg)+PTZ. All groups were treated for 10 days. Results: PTZ injection triggered a state of oxidative stress in the hippocampal tissue as represented by the elevated lipoperoxidation, heat shock protein 70 level, and nitric oxide formation while decreased glutathione level and antioxidant enzymes activity. Additionally, the blotting analysis showed downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the epileptic mice. A state of neuroinflammation was recorded following the developed seizures represented by the increased pro-inflammatory cytokines. Moreover, neuronal apoptosis was recorded following the development of epileptic convulsions. At the neurochemical level, acetylcholinesterase activity and monoamines content were decreased in the epileptic mice, accompanied by high glutamate and low GABA levels in the hippocampal tissue. However, SeNP supplementation was found to delay the onset and decreased the duration of tonic, myoclonic, and generalized seizures following PTZ injection. Moreover, SeNPs were found to provide neuroprotection through preventing the development of oxidative challenge via the upregulation of Nrf2 and HO-1, inhibiting the inflammatory response and apoptotic cascade. Additionally, SeNPs reversed the changes in the activity and levels of neuromodulators following the development of epileptic seizures. Conclusion: The obtained results suggest that SeNPs could be used as a promising anticonvulsant drug due to its potent antioxidant, anti-inflammatory, and neuromodulatory activities.


Asunto(s)
Nanopartículas/química , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Selenio/uso terapéutico , Aminoácidos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Apoptosis/efectos de los fármacos , Colinérgicos/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Ratones , Nanopartículas/administración & dosificación , Neuronas/efectos de los fármacos , Neurotransmisores/metabolismo , Oxidación-Reducción , Pentilenotetrazol , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Selenio/administración & dosificación , Selenio/farmacología
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