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2.
Toxicol Lett ; 321: 21-31, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830555

RESUMO

Nerve agents inhibit acetylcholinesterase (AChE), leading to a build-up of acetylcholine (ACh) and overstimulation at cholinergic synapses. Current post-exposure nerve agent treatment includes atropine to treat overstimulation at muscarinic synapses, a benzodiazepine anti-convulsant, and an oxime to restore the function of AChE. Aside from the oxime, the components do not act directly to reduce the overstimulation at nicotinic synapses. The false transmitters acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) are analogs of ACh, synthesised similarly at synapses. AMECh and ADECh are partial agonists, with reduced activity compared to ACh, so it was hypothesised the false transmitters could reduce overstimulation. Synthetic routes to AMECh and ADECh, and their precursors, monoethylcholine (MECh) and diethylcholine (DECh), were devised, allowing them to be produced easily on a laboratory-scale. The mechanism of action of the false transmitters was investigated in vitro. AMECh acted as a partial agonist at human muscarinic (M1 and M3) and muscle-type nicotinic receptors, and ADECh was a partial agonist only at certain muscarinic subtypes. Their precursors acted as antagonists at muscle-type nicotinic, but not muscarinic receptors. Administration of MECh and DECh improved neuromuscular function in the soman-exposed guinea-pig hemi-diaphragm preparation. False transmitters may therefore help reduce nerve agent induced overstimulation at cholinergic synapses.


Assuntos
Acetilcolina/análogos & derivados , Antídotos/farmacologia , Colina/análogos & derivados , Inibidores da Colinesterase/envenenamento , Diafragma/inervação , Agentes Neurotóxicos/envenenamento , Neurotransmissores/farmacologia , Intoxicação por Organofosfatos/tratamento farmacológico , Soman/envenenamento , Sinapses/efeitos dos fármacos , Acetilcolina/síntese química , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antídotos/síntese química , Células CHO , Linhagem Celular Tumoral , Colina/síntese química , Colina/farmacologia , Cricetulus , Agonismo Parcial de Drogas , Cobaias , Humanos , Masculino , Neurotransmissores/síntese química , Intoxicação por Organofosfatos/enzimologia , Intoxicação por Organofosfatos/fisiopatologia , Receptores Colinérgicos/efeitos dos fármacos , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Sinapses/enzimologia
3.
Life Sci ; 238: 116969, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628912

RESUMO

AIMS: Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the ß-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. MATERIALS AND METHODS: Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 µl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. KEY FINDINGS: Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. SIGNIFICANCE: Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ceftriaxona/farmacologia , Giro Denteado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Antibacterianos/farmacologia , Carcinógenos/toxicidade , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/patologia , Ácido Okadáico/toxicidade , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
4.
Nat Commun ; 10(1): 4140, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515501

RESUMO

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.


Assuntos
Proteínas dos Microfilamentos/metabolismo , Neuropeptídeos/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Heroína/efeitos adversos , Histona Desacetilase 2/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/genética , Núcleo Accumbens/metabolismo , Alcaloides Opiáceos/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Dor/metabolismo , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
5.
Food Chem Toxicol ; 134: 110824, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31539617

RESUMO

Fisetin, a natural flavonoid found in plants, fruits and vegetables, exerts anti-cancer, anti-oxidant, anti-inflammatory and anti-mitotic effects. The current study instigates the protective effect of fisetin against lead-induced synaptic dysfunction, neuroinflammation and neurodegeneration in mice, and explores its underlying mechanisms. The results indicated fisetin can significantly ameliorated behavioral impairments in Pb-treated mice. Fisetin inhibited Pb-induced the apoptotic neurodegeneration, as indicated by the decreased levels of Bax and cleaved caspase-3. Fisetin suppressed activations of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), NF-κB and subsequently inactivate pro-inflammatory factor including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). It can also decrease the accumulation of p-tau and amyloid-beta (Aß) and increased the expression of the Aß remover neprilysin (NEP) in brains of mice. Fisetin also reversed Pb-induced synaptic dysfunction by increasing the levels of synaptosomal associated protein-25 (SNAP-25), postsynaptic density-95 (PSD-95), cyclic-AMP-response element-binding protein (CREB) phosphorylation and calcium/calmodulin kinase II (CaMKII) phosphorylation. Fisetin promoted Pb-induced autophagy in the brains of mice. Moreover, fisetin can increase levels of the denosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation and SIRT1. Fisetin may be developed as a potential nutritional target for the prevention of Pb-induced neurotoxicity.


Assuntos
Adenilato Quinase/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Flavonoides/uso terapêutico , Inflamação/tratamento farmacológico , Chumbo/toxicidade , Sirtuína 1/metabolismo , Sinapses/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Flavonoides/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fosforilação , Sinapses/fisiologia
6.
Ecotoxicol Environ Saf ; 185: 109686, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31546205

RESUMO

Gestational exposure to PM2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1ß, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.


Assuntos
Poluentes Atmosféricos/toxicidade , Transtorno Autístico/prevenção & controle , Hipocampo/efeitos dos fármacos , Material Particulado/toxicidade , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Complexo Vitamínico B/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Transtorno Autístico/induzido quimicamente , Citocinas/metabolismo , Suplementos Nutricionais , Feminino , Hipocampo/crescimento & desenvolvimento , Hipocampo/imunologia , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Neurogênese/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sinapses/efeitos dos fármacos , Complexo Vitamínico B/administração & dosagem
7.
PLoS Biol ; 17(8): e3000086, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31433818

RESUMO

Lengthy use of general anesthetics (GAs) causes neurobehavioral deficits in the developing brain, which has raised significant clinical concerns such that the United States Food and Drug Administration (FDA) is warning on the use of GAs in children younger than 3 years. However, the molecular and cellular mechanisms for GAs-induced neurotoxicity remain largely unknown. Here, we report that sevoflurane (Sevo), a commonly used GA in pediatrics, caused compromised astrocyte morphogenesis spatiotemporally correlated to synaptic overgrowth, with reduced synaptic function in developing cortex in a regional-, exposure-length-, and age-specific manner. Sevo disrupted astrocyte Ca2+ homeostasis both acutely and chronically, which led to the down-regulation of Ezrin, an actin-binding membrane-bound protein, which we found was critically involved in astrocyte morphogenesis in vivo. Importantly, overexpression of astrocyte Ezrin rescued astrocytic and neuronal dysfunctions and fully corrected deficits in social behaviors in developing mice with lengthy Sevo exposure. Our data uncover that, in addition to neurons, astrocytes may represent important targets for GAs to exert toxic effects and that astrocyte morphological integrity is crucial for synaptogenesis and neurological behaviors.


Assuntos
Astrócitos/efeitos dos fármacos , Sevoflurano/efeitos adversos , Sinapses/efeitos dos fármacos , Anestesia Geral/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Proteínas do Citoesqueleto/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Social
8.
Int J Mol Sci ; 20(13)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284573

RESUMO

Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia.


Assuntos
Demência/tratamento farmacológico , Demência/psicologia , Neurofarmacologia , Dor/tratamento farmacológico , Óleos Vegetais/uso terapêutico , Autofagia/efeitos dos fármacos , Demência/complicações , Humanos , Dor/complicações , Óleos Vegetais/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
10.
Nat Methods ; 16(8): 699-702, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308551

RESUMO

Chemical inhibitors have revealed requirements for protein synthesis that drive cellular plasticity. We developed a genetically encodable protein synthesis inhibitor (gePSI) to achieve cell-type-specific temporal control of protein synthesis. Controlled expression of the gePSI in neurons or glia resulted in rapid, potent and reversible cell-autonomous inhibition of protein synthesis. Moreover, gePSI expression in a single neuron blocked the structural plasticity induced by single-synapse stimulation.


Assuntos
Engenharia Genética , Hipocampo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/farmacologia , Sinapses/metabolismo , Animais , Células Cultivadas , Células HeLa , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Humanos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Inibidores da Síntese de Proteínas/química , Ratos , Sinapses/efeitos dos fármacos
11.
Oxid Med Cell Longev ; 2019: 7593608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191803

RESUMO

Synaptic structural and functional damage is a typical pathological feature of Alzheimer's disease (AD). Normal axonal mitochondrial function and transportation are vital to synaptic function and plasticity because they are necessary for maintaining cellular energy supply and regulating calcium and redox signalling as well as synaptic transmission and vesicle release. Amyloid-ß (Aß) accumulation is another pathological hallmark of AD that mediates synaptic loss and dysfunction by targeting mitochondria. Therefore, it is important to develop strategies to protect against synaptic mitochondrial damage induced by Aß. The present study examined the beneficial effects of berberine, a natural isoquinoline alkaloid extracted from the traditional medicinal plant Coptis chinensis, on Aß-induced mitochondrial and synaptic damage in primary cultured hippocampal neurons. We demonstrate that berberine alleviates axonal mitochondrial abnormalities by preserving the mitochondrial membrane potential and preventing decreases in ATP, increasing axonal mitochondrial density and length, and improving mitochondrial motility and trafficking in cultured hippocampal neurons. Although the underlying protective mechanism remains to be elucidated, the data suggest that the effects of berberine were in part related to its potent antioxidant activity. These findings highlight the neuroprotective and specifically mitoprotective effects of berberine treatment under conditions of Aß enrichment.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Berberina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Masculino , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
12.
Life Sci ; 231: 116566, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201846

RESUMO

AIMS: Diabetes mellitus can cause cognitive impairments, a state between normal aging and dementia. Effective clinical interventions are urgently needed to prevent or treat this complication. Liraglutide as a glucagon-like peptide 1 analog has been shown to exert memory-enhancing and neuroprotective effects on neurodegenerative diseases. This study aims to investigate the neuroprotective effects of liraglutide in streptozotocin (STZ)-induced diabetic mice with cognitive deficits. METHODS: Male C57BL/6J mice were intraperitoneal injected with STZ (65 mg/kg body weight daily for 5 days) to induce type 1 diabetes model. Then the mice were treated with liraglutide (250 mg/kg/day, for 6 weeks) or saline. Weekly changes of body weight and fasting blood glucose were measured. Cognitive performance was evaluated by Morris water maze test. The ultrastructure of hippocampus was observed by transmission electron microscope. The superoxide dismutase activities and malondialdehyde levels in the hippocampus were detected by biochemistry assay. Apoptosis-related proteins and phosphoinositide 3-kinase (PI3K)/protein kinase-B (Akt) signaling were detected by Western blotting. KEY FINDINGS: We found that STZ-induced diabetic mice exhibited impaired learning and memory, ultrastructure damage of hippocampal neurons and synapses, exacerbated oxidative stress and neuronal apoptosis, as compared to the control mice. These effects were attenuated by the treatment with liraglutide. Furthermore, liraglutide reversed diabetes-induced alterations in PI3K/Akt signaling pathway that plays an essential role in modulating neuronal survival, apoptosis and plasticity. SIGNIFICANCE: These data suggest that the neuroprotective effects of liraglutide on diabetes-induced cognitive impairments are associated with the improvements of hippocampal synapses and inhibition of neuronal apoptosis.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Liraglutida/farmacologia , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipoglicemiantes/farmacologia , Liraglutida/metabolismo , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
13.
Biosens Bioelectron ; 140: 111329, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163396

RESUMO

Lab-on-chip platforms, such as microfluidic chips and micro-electrode arrays (MEAs) are powerful tools that allow us to manipulate and study neurons in vitro. Microfluidic chips provide a controlled extracellular environment that structures neural networks and facilitates isolation and manipulation at a sub-cellular level. Furthermore, MEAs enable measurement of extracellular electrophysiological activity from single neurons to entire networks. Here, we demonstrate the design, fabrication and application of a 3-nodal microfluidic chip integrated with MEAs as a versatile study platform for neurobiology and pathophysiology. In this work, we evaluate the use of the microfluidic chip to structure a neural network into three separate nodes, interconnected through tunnels that isolate and guide axons into a channel, thus facilitating synaptic contacts between neurons originating from opposite nodes. Furthermore, we demonstrate the utility of the MEA for monitoring developing activity and intra-/inter nodal connectivity of the structured neural network. Finally, we demonstrate the versatility of the platform in two separate experiments. First, we demonstrate the ability to measure intra- and inter-nodal dynamic responses to a fluidically isolated chemical stimulation. Then, we demonstrate the feature of the microfluidic chip enabling the disruption of functional connectivity between nodes and examination of the immediate activity response of the neural network. The platform enables in vitro modelling of neural networks to study their functional connectomes in the context of neurodegenerative disease and CNS trauma, including spinal cord injury.


Assuntos
Técnicas Biossensoriais/instrumentação , Dispositivos Lab-On-A-Chip , Rede Nervosa/citologia , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Axotomia , Linhagem Celular , Desenho de Equipamento , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
14.
Mol Med Rep ; 19(6): 4897-4905, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059028

RESUMO

Amyloid ß (Aß) has been reported to have an important role in the cognitive deficits of Alzheimer's disease (AD), as oligomeric Aß promotes synaptic dysfunction and triggers neuronal death. Recent evidence has associated an endocytosis protein, endophilin 1, with AD, as endophilin 1 levels have been reported to be markedly increased in the AD brain. The increase in endophilin 1 levels in neurons is associated with an increase in the activation of the stress kinase JNK, with subsequent neuronal death. In the present study, whole­cell patch­clamp recording demonstrated that oligomeric Aß caused synaptic dysfunction and western blotting revealed that endophilin 1 was highly expressed prior to neuronal death of cultured hippocampal neurons. Furthermore, RNA interference and electrophysiological recording techniques in cultured hippocampal neurons demonstrated that knockdown of endophilin 1 prevented synaptic dysfunction induced by Aß. Thus, a potential role for endophilin 1 in Aß­induced postsynaptic dysfunction has been identified, indicating a possible direction for the prevention of postsynaptic dysfunction in cognitive impairment and suggesting that endophilin may be a potential target for the clinical treatment of AD.


Assuntos
Aciltransferases/metabolismo , Peptídeos beta-Amiloides/farmacologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sinapses/efeitos dos fármacos , Aciltransferases/antagonistas & inibidores , Aciltransferases/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Polímeros/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia
15.
Neurosci Lett ; 706: 61-67, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31077740

RESUMO

Estrogens (E2) derived from ovaries and/or local de novo synthesis in the hippocampus profoundly regulate hippocampal structure and function, but the importance of local E2 versus ovarian E2 on hippocampal synaptic plasticity and spatial memory has not been well elucidated. The present study used ovariectomy (OVX) and intraperitoneal injection of an E2 synthase inhibitor, letrozole (LET), in adult female mice to investigate changes in hippocampal steroid receptor coactivator-1 (SRC-1), postsynaptic proteins, and actin polymerization dynamics with these treatments. Changes in the CA1 spine density, synapse density and spatial learning and memory after OVX and LET were also investigated. As a result, OVX and LET showed similar regulation of the expression of GluR1, spinophilin and p-Cofilin, but LET tended to induce more significant changes in SRC-1, PSD95, Rictor, Cofilin and actin depolymerization. More significant decreases in F-actin/G-actin, CA1 spine density and synapse density were also observed after LET than after OVX. Notably, LET-treated mice showed worse learning and memory impairment than OVX mice. Taken together, these results demonstrated that circulating E2 played a limited role and that hippocampus-derived E2 played a more important role in the regulation of hippocampal synaptic plasticity and hippocampus-based spatial learning and memory.


Assuntos
Inibidores da Aromatase/farmacologia , Dendritos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Letrozol/farmacologia , Memória Espacial/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Actinas/metabolismo , Animais , Dendritos/metabolismo , Feminino , Hipocampo/metabolismo , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Ovariectomia , Aprendizagem Espacial/efeitos dos fármacos , Sinapses/metabolismo
16.
Neuroscience ; 410: 1-15, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078686

RESUMO

The contribution of Dopamine (DA) to minimal hepatic encephalopathy (MHE) has been demonstrated. However, recent studies have revealed that cholesterol (CHO) treatment substantially increased the risk of dementia. The objectives of this study were to investigate whether CHO was induced by DA overload and its involvement in DA-induced cognitive impairment in MHE. Our study showed that DA treatment triggered CHO biosynthesis via the activation of JNK3/SREBP2 signaling pathway in primary cultured astrocytes. Conditioned media from DA-treated astrocytes increased CHO uptake by primary cultured neurons and disrupted synaptic formations; at the same time, inhibition of CHO synthesis and transportation from astrocytes diminished the disruption of synaptogenesis, which indicates the involvement of CHO in the perturbation of neural synaptogenesis in vitro. Secondary secretion of DA from primary cultured neurons was stimulated by CHO secreted from astrocytes. DA induced synergistic decreases of PPARγ/pERK/pCREB expressions in the presence of CHO in neurons, leading to synergistic synaptic impairment. Memory impairments were observed in MHE/DA-treated rats, which were partially rescued by atorvastatin (ATVS) treatment, confirming the involvement of CHO burden in vivo. Overall, our study suggests that DA overload triggers obvious CHO production from astrocytes. Excessive CHO in turn triggered neurons to secrete abundant DA and DA burden in combination with CHO overload elicit the cognitive decline and memory loss via PPARγ/ERK/CREB pathway in MHE.


Assuntos
Encéfalo/metabolismo , Colesterol/metabolismo , Dopamina/toxicidade , Encefalopatia Hepática/metabolismo , Neurogênese/fisiologia , Sinapses/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Células Cultivadas , Dopamina/administração & dosagem , Encefalopatia Hepática/patologia , Injeções Intraventriculares , Lipogênese/efeitos dos fármacos , Lipogênese/fisiologia , Neurogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/patologia
17.
Dis Model Mech ; 12(6)2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31142572

RESUMO

The dendrites of retinal ganglion cells (RGCs) synapse with the axon terminals of bipolar cells in the inner plexiform layer (IPL). Changes in the RGC dendrites and synapses between the bipolar cells in the inner retinal layer may critically alter the function of RGCs in glaucoma. The present study attempted to discover changes in the synapse using brain-derived neurotrophic factor (BDNF) after glaucoma induction by chronic intraocular pressure elevation in a rat model. Immunohistochemical staining revealed that the BDNF-injected group had a significant increase in the level of synaptophysin, which is a presynaptic vesicle protein, in the innermost IPL compared with the phosphate-buffered saline (PBS)-injected group. SMI-32, which is a marker of RGCs, was colocalized with synaptophysin in RGC dendrites, and this colocalization significantly increased in the BDNF-injected group. After the induction of glaucoma, the BDNF-injected group exhibited increases in the total number of ribbon synapses, as seen using electron microscopy. Expression of calcium/calmodulin-dependent protein kinase II (CaMKII), cAMP-response element binding protein (CREB) and F-actin, which are key molecules involved in synaptic changes were upregulated after BDNF injection. These initial findings show the capability of BDNF to induce beneficial synaptic changes in glaucoma.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Glaucoma/fisiopatologia , Pressão Intraocular/fisiologia , Plasticidade Neuronal , Sinapses/metabolismo , Actinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Modelos Animais de Doenças , Glaucoma/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Pressão Intraocular/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/ultraestrutura , Sinaptofisina/metabolismo
18.
Elife ; 82019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31099753

RESUMO

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.


Assuntos
Analgésicos Opioides/metabolismo , Corpo Estriado/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Animais , Aprendizagem/efeitos dos fármacos , Camundongos , Dor , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas
19.
J Neuroinflammation ; 16(1): 106, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31103036

RESUMO

BACKGROUND: Systemic inflammation has been linked to synapse loss and cognitive decline in human patients and animal models. A role for microglial release of pro-inflammatory cytokines has been proposed based on in vivo and primary culture studies. However, mechanisms are hard to study in vivo as specific microglial ablation is challenging and the extracellular fluid cannot be sampled without invasive methods. Primary cultures have different limitations as the intricate multicellular architecture in the brain is not fully reproduced. It is essential to confirm proposed brain-specific mechanisms of inflammatory synapse loss directly in brain tissue. Organotypic hippocampal slice cultures (OHSCs) retain much of the in vivo neuronal architecture, synaptic connections and diversity of cell types whilst providing convenient access to manipulate and sample the culture medium and observe cellular reactions. METHODS: OHSCs were generated from P6-P9 C57BL/6 mice. Inflammation was induced via addition of lipopolysaccharide (LPS), and cultures were analysed for changes in synaptic proteins, gene expression and protein secretion. Microglia were selectively depleted using clodronate, and the effect of IL1ß was assessed using a specific neutralising monoclonal antibody. RESULTS: LPS treatment induced loss of the presynaptic protein synaptophysin without altering PSD95 or Aß protein levels. Depletion of microglia prior to LPS application prevented the loss of synaptophysin, whilst microglia depletion after the inflammatory insult was partially effective, although less so than pre-emptive treatment, indicating a time-critical window in which microglia can induce synaptic damage. IL1ß protein and mRNA were increased after LPS addition, with these effects also prevented by microglia depletion. Direct application of IL1ß to OHSCs resulted in synaptophysin loss whilst pre-treatment with IL1ß neutralising antibody prior to LPS addition prevented a significant loss of synaptophysin but may also impact basal synaptic levels. CONCLUSIONS: The loss of synaptophysin in this system confirms LPS can act directly within brain tissue to disrupt synapses, and we show that microglia are the relevant cellular target when all major CNS cell types are present. By overcoming limitations of primary culture and in vivo work, our study strengthens the evidence for a key role of microglia-derived IL1ß in synaptic dysfunction after inflammatory insult.


Assuntos
Encéfalo/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Terminações Pré-Sinápticas/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Terminações Pré-Sinápticas/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
20.
J Neuroinflammation ; 16(1): 104, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31103039

RESUMO

BACKGROUND: Hypoxia-ischemia (HI) during the perinatal period is one of the most common causes of acute mortality and chronic neurologic morbidity. Hydrogen-rich saline (HS) treatment in neonatal mice has been reported to alleviate brain injury following HI, but the mechanisms involved are not known. METHODS: A modified version of the Rice-Vannucci method for the induction of neonatal HI brain injury was performed on postnatal day 7 mouse pups. Animals or BV2-cells received HS and an AMPK inhibitor at indicative time post-injury. RESULTS: In the current study, we show that HS treatment attenuated the accumulation of CD11b+/CD45high cells, suppressed HI-induced neuro-inflammation, induced microglial anti-inflammatory M2 polarization, was associated with promoting AMPK activation, and inhibited nuclear factor-κB activation as demonstrated both in vivo and in vitro. In addition, HS treatment reversed HI-induced neurological disabilities, was associated with improving damaged synapses, and restored the expression levels of synaptophysin and postsynaptic density protein 95 following HI insult. Furthermore, HI insult which increased levels of complement component C1q, C3, and C3aR1 was observed. Importantly, C1q deposited in the infarct core and lesion boundary zone following HI injury, was found to co-localize within regions of synapse loss, whereas HS treatment reversed these effects of HI on synapse loss and complement component levels. Notably, the AMPK inhibitor reversed the beneficial effects of HS as described above. CONCLUSIONS: These results demonstrate that HS restored behavioral deficits after HI in neonatal mice. These beneficial effects, in part, involve promoting microglia M2 polarization and complement-mediated synapse loss via AMPK activation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas do Sistema Complemento/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Microglia/metabolismo , Solução Salina/administração & dosagem , Sinapses/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Feminino , Hidrogênio/administração & dosagem , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Sinapses/efeitos dos fármacos
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