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1.
Mol Biol (Mosk) ; 55(3): 510-518, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34097685

RESUMO

The hormone leptin is produced in adipocytes of white adipose tissue and crosses the blood-brain barrier. Leptin receptors are present in the brain regions that are involved in higher cognitive functions. In particular, leptin directly influences the glutamate receptor trafficking in CA3 → CA1 synapses to increase the phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) level, which is controlled by phosphoinositide 3-kinase (PI3K). It is well recognized that glutamate receptor trafficking involves at least some components of the insulin signaling cascade. However, the effects of leptin and insulin hormones differ at the cell and behavioral levels and often oppose each other. The domain organization of synaptic proteins was analyzed for CA1 field neurons. A molecular mechanism of leptin effects in the hippocampus was assumed to involve a cross-talk of the molecular pathways of the leptin receptors and NMDA-type glutamate receptors. Non-receptor protein kinases of the Src subfamily and, in particular, kinase Fyn are part of glutamate receptor macrocomplexes and are involved in regulating the efficiency of synaptic transmission. Fyn was assumed to utilize its SH2 domain to interact with leptin receptors directly or through other proteins and contribute to leptin signaling through the PI3K signaling pathway. The hypothesis explains experimental findings and sheds further light on the fine tuning of hormone-dependent modulation of hippocampal synaptic processes.


Assuntos
Ácido Glutâmico , Receptores para Leptina , Hipocampo/metabolismo , Leptina/genética , Leptina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Receptores de N-Metil-D-Aspartato , Sinapses/metabolismo
2.
Zhen Ci Yan Jiu ; 46(5): 353-61, 2021 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-34085456

RESUMO

OBJECTIVE: To explore the effect of electroacupuncture (EA) on the ability of spatial learning-memory and the expression of IL-1ß, IL-6 and TNF-α in the hippocampus and spleen tissues and the number of hippocampal neurons and spleen lymphocytes in Alzheimer's disease (AD) mice, so as to study its mechanisms underlying improvement of AD. METHODS: Twenty-four SAMP8 mice were randomly and equally divided into AD model, EA and medication groups, and 8 SAMR1 mice were used as the control group. EA (2 Hz, 0.1 mA) was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 20 min in the EA group, and intragastric administration of donepezil hydrochloride (0.92 mg/kg) was applied in the medication group, once daily for 15 d. The learning-memory ability was determined by Morris water maze task, and the histopathological changes of hippocampus were observed after H.E. staining, followed by determining neurons and the number of splenic lymphocytes. The expression levels of IL-1ß, IL-6 and TNF-α in the hippocampus and spleen were detected by immunohistochemistry and Western blot, respectively. RESULTS: After mode-ling, the escape latency of place navigation test in the Morris water maze, the spleen index, immunoactivity and expression levels of IL-1ß, IL-6 and TNF-α proteins in the hippocampus and spleen tissues were significantly increased (P<0.05, P<0.01). Compared with the model group, the escape latency, spleen index, immunoactivity and expression levels of IL-1ß, IL-6 and TNF-α proteins in both hippocampus and spleen were significantly down-regulated in the medication (except the escape latency) and EA groups (P<0.01, P<0.05). The effect of EA was evidently superior to that of medication in shortening the escape latency, lowering the spleen index, and immunoactivity of hippocampal IL-6 and splenic TNF-α immunoactivity (P<0.01, P<0.05). Outcomes of H.E. staining showed disordered arrangement of neurons with nuclear pyknosis or apoptosis in partial neurons in the hippocampus, and thickened and swollen spleen capsule tissue with loose structure and an increased number of lymphocytes in the model group, which was relatively milder in the EA and medication groups. CONCLUSION: EA can improve the learning-memory ability of AD mice, which may be associated with its effect in relieving the inflammation reaction in the hippocampus and spleen tissues.


Assuntos
Doença de Alzheimer , Eletroacupuntura , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Hipocampo , Interleucina-6/genética , Camundongos , Baço , Fator de Necrose Tumoral alfa/genética
3.
Zhongguo Zhen Jiu ; 41(6): 645-50, 2021 Jun 12.
Artigo em Chinês | MEDLINE | ID: mdl-34085482

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) pretreatment on hippocampal oxidative stress in aged mice with postoperative cognitive dysfunction (POCD) and explore the relevant mechanism of EA pretreatment on the improvement of learning and memory in POCD aged mice. METHODS: A total of 72 healthy male aged mice were randomized into a blank group, a model group, a medication group and an EA group, 18 mice in each one. In each group, 1-day, 3-day and 7-day subgroups were divided separately, 6 mice in each subgroup. In the EA group, "Baihui" (GV 20) and "Dazhui" (GV 14) were selected and stimulated with EA, using continuous wave (15 Hz, 1 mA), continuously for 30 min, once a day, for 5 days consecutively. In the medication group, 10% minocycline was injected intraperitoneally, 40 mg/kg, once a day, consecutively for 5 days. In the blank and the control group, intraperitoneal injection of 0.9% sodium chloride solution was given with equal dosage. Except the blank group, at the end of intervention, partial hepatectomy was conducted to establish POCD model in the rest groups. Morris water maze test was adopted to evaluate the learning and memory ability of the aged mice. ELISA was used to determine the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) in the hippocampal tissue. Western blot method was applied to detect the protein expressions of superoxide dismutase 1 (SOD 1) and superoxide dismutase 2 (SOD 2) in the hippocampal tissue. RESULTS: Compared with the blank group, the percentage of platform quadrant residence time was obviously reduced in the mice in the model group (P<0.01), and those in the medication group and the EA group were larger than the model group (P<0.01). Compared with the model group, the contents of ROS were reduced in each subgroup of the medication group and the 3-day subgroup and the 7-day subgroup of the EA group separately (P<0.01, P<0.05), MDA contents were reduced in the medication group and the EA group (P<0.01, P<0.05), the protein expressions of SOD 1 and SOD 2 were all increased in each subgroup of the medication group and the 3-day subgroup and the 7-day subgroup of the EA group (P<0.05, P<0.01). Compared with the medication group, the contents of ROS and MDA in the 1-day subgroup of the EA group were increased (P<0.05), the hippocampal SOD 1 protein expression was increased in the 7-day group of the EA group (P<0.05) and the hippocampal SOD 2 protein expression was reduced in the 1-day subgroup of the EA group (P<0.05). CONCLUSION: Electroacupuncture pretreatment at "Baihui" (GV 20) and "Dazhui" (GV 14) may increase the learning and memory ability of POCD aged mice, which is probably related to the decrease of oxidative stress and the strengthening of hippocampal antioxidant capacity.


Assuntos
Eletroacupuntura , Complicações Cognitivas Pós-Operatórias , Animais , Hipocampo , Masculino , Memória , Camundongos , Estresse Oxidativo
4.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065959

RESUMO

Brain tissue may be especially sensitive to electromagnetic phenomena provoking signs of neural stress in cerebral activity. Fifty-four adult female Sprague-Dawley rats underwent ELISA and immunohistochemistry testing of four relevant anatomical areas of the cerebrum to measure biomarkers indicating induction of heat shock protein 70 (HSP-70), glucocorticoid receptors (GCR) or glial fibrillary acidic protein (GFAP) after single or repeated exposure to 2.45 GHz radiation in the experimental set-up. Neither radiation regime caused tissue heating, so thermal effects can be ruled out. A progressive decrease in GCR and HSP-70 was observed after acute or repeated irradiation in the somatosensory cortex, hypothalamus and hippocampus. In the limbic cortex; however, values for both biomarkers were significantly higher after repeated exposure to irradiation when compared to control animals. GFAP values in brain tissue after irradiation were not significantly different or were even lower than those of nonirradiated animals in all brain regions studied. Our results suggest that repeated exposure to 2.45 GHz elicited GCR/HSP-70 dysregulation in the brain, triggering a state of stress that could decrease tissue anti-inflammatory action without favoring glial proliferation and make the nervous system more vulnerable.


Assuntos
Cérebro/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Biomarcadores/metabolismo , Cérebro/efeitos da radiação , Feminino , Regulação da Expressão Gênica/efeitos da radiação , Hipocampo/metabolismo , Hipocampo/efeitos da radiação , Hipotálamo/metabolismo , Hipotálamo/efeitos da radiação , Ratos , Ratos Sprague-Dawley , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/efeitos da radiação
5.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064454

RESUMO

The γ-aminobutyric acid type A receptor (GABAAR) plays a major role in fast inhibitory synaptic transmission and is highly regulated by the neuromodulator dopamine. In this aspect, most of the attention has been focused on the classical intracellular signaling cascades following dopamine G-protein-coupled receptor activation. Interestingly, the GABAAR and dopamine D5 receptor (D5R) have been shown to physically interact in the hippocampus, but whether a functional cross-talk occurs is still debated. In the present study, we use a combination of imaging and single nanoparticle tracking in live hippocampal neurons to provide evidence that GABAARs and D5Rs form dynamic surface clusters. Disrupting the GABAAR-D5R interaction with a competing peptide leads to an increase in the diffusion coefficient and the explored area of both receptors, and a drop in immobile synaptic GABAARs. By means of patch-clamp recordings, we show that this fast lateral redistribution of surface GABAARs correlates with a robust depression in the evoked GABAergic currents. Strikingly, it also shifts in time the expression of long-term potentiation at glutamatergic synapses. Together, our data both set the plasma membrane as the primary stage of a functional interplay between GABAAR and D5R, and uncover a non-canonical role in regulating synaptic transmission.


Assuntos
Potenciação de Longa Duração/genética , Neurônios/metabolismo , Receptor Cross-Talk , Receptores de Dopamina D5/genética , Receptores de GABA-A/genética , Transmissão Sináptica/genética , Animais , Ligação Competitiva , Membrana Celular/metabolismo , Embrião de Mamíferos , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Neurônios/citologia , Técnicas de Patch-Clamp , Peptídeos/síntese química , Peptídeos/metabolismo , Cultura Primária de Células , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D5/metabolismo , Receptores de GABA-A/metabolismo , Sinapses/genética , Sinapses/metabolismo
6.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068707

RESUMO

BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT-/-) is one of the animal models used to investigate the underlying molecular mechanisms of depression in humans. They present decreased BDNF levels, and anxiety- and depression-like behavior. To investigate whether upregulating BDNF would ameliorate the phenotype of SERT-/- rats, we overexpressed BDNF locally into the ventral hippocampus and submitted the animals to behavioral testing. The results showed that BDNF overexpression in the vHIP of SERT-/- rats promoted higher sucrose preference and sucrose intake; on the first day of the sucrose consumption test it decreased immobility time in the forced swim test and increased the time spent in the center of a novel environment. Furthermore, BDNF overexpression altered social behavior in SERT-/- rats, which presented increased passive contact with test partner and decreased solitary behavior. Finally, it promoted decrease in plasma corticosterone levels 60 min after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT-/- rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential target to new therapeutic approaches to improve depressive symptoms.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/tratamento farmacológico , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/patologia , Corticosterona/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Plasticidade Neuronal/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ratos , Serotonina/genética , Estresse Psicológico/genética , Estresse Psicológico/patologia
7.
Science ; 372(6546): 1068-1073, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34083484

RESUMO

Mammalian medial and lateral hippocampal networks preferentially process spatial- and object-related information, respectively. However, the mechanisms underlying the assembly of such parallel networks during development remain largely unknown. Our study shows that, in mice, complementary expression of cell surface molecules teneurin-3 (Ten3) and latrophilin-2 (Lphn2) in the medial and lateral hippocampal networks, respectively, guides the precise assembly of CA1-to-subiculum connections in both networks. In the medial network, Ten3-expressing (Ten3+) CA1 axons are repelled by target-derived Lphn2, revealing that Lphn2- and Ten3-mediated heterophilic repulsion and Ten3-mediated homophilic attraction cooperate to control precise target selection of CA1 axons. In the lateral network, Lphn2-expressing (Lphn2+) CA1 axons are confined to Lphn2+ targets via repulsion from Ten3+ targets. Our findings demonstrate that assembly of parallel hippocampal networks follows a "Ten3→Ten3, Lphn2→Lphn2" rule instructed by reciprocal repulsions.


Assuntos
Orientação de Axônios , Axônios/fisiologia , Região CA1 Hipocampal/fisiologia , Hipocampo/fisiologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Peptídeos/metabolismo , Animais , Região CA1 Hipocampal/citologia , Córtex Entorrinal/fisiologia , Feminino , Hipocampo/citologia , Ligantes , Masculino , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Vias Neurais , Receptores de Peptídeos/genética , Transcriptoma
8.
Int J Nanomedicine ; 16: 3661-3678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093011

RESUMO

Introduction: Brain ischemia is a common neurological disorder worldwide that activates a cascade of pathophysiological events involving decreases in oxygen and glucose levels. Despite substantial efforts to explore its pathogenesis, the management of ischemic neuronal injury remains an enormous challenge. Accumulating evidence suggests that VEGF modified nanofiber (NF) materials and the fatty-acid amide hydrolase (FAAH) inhibitor URB597 exert an influence on alleviating ischemic brain damage. We aimed to further investigate their effects on primary hippocampal neurons, as well as the underlying mechanisms following oxygen-glucose deprivation (OGD). Methods: Different layers of VEGF-A loaded polycaprolactone (PCL) nanofibrous membranes were first synthesized by using layer-by-layer (LBL) self-assembly of electrospinning methods. The physicochemical and biological properties of VEGF-A NF membranes, and their morphology, hydrophilicity, and controlled-release of VEGF-A were then estimated. Furthermore, the effects of VEGF-A NF and URB597 on OGD-induced mitochondrial oxidative stress, inflammatory responses, neuronal apoptosis, and endocannabinoid signaling components were assessed. Results: The VEGF-A NF membrane and URB597 can not only promote hippocampal neuron adhesion and viability following OGD but also exhibited antioxidant/anti-inflammatory and mitochondrial membrane potential protection. The VEGF-A NF membrane and URB597 also inhibited OGD-induced cellular apoptosis through activating CB1R signaling. These results indicate that VEGF-A could be controlled-released by LBL self-assembled NF membranes. Discussion: The VEGF-A NF membrane and URB597 displayed positive synergistic neuroprotective effects through the inhibition of mitochondrial oxidative stress and activation of CB1R/PI3K/AKT/BDNF signaling, suggesting that a VEGF-A loaded NF membrane and the FAAH inhibitor URB597 could be of therapeutic value in ischemic cerebrovascular diseases.


Assuntos
Benzamidas/farmacologia , Carbamatos/farmacologia , Nanofibras/química , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Células Cultivadas , Endocanabinoides/metabolismo , Glucose/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Membranas Artificiais , Neurônios/metabolismo , Neurônios/patologia , Oxigênio/metabolismo , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/química
9.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066973

RESUMO

L-methionine, an essential amino acid, plays a critical role in cell physiology. High intake and/or dysregulation in methionine (Met) metabolism results in accumulation of its intermediate(s) or breakdown products in plasma, including homocysteine (Hcy). High level of Hcy in plasma, hyperhomocysteinemia (hHcy), is considered to be an independent risk factor for cerebrovascular diseases, stroke and dementias. To evoke a mild hHcy in adult male Wistar rats we used an enriched Met diet at a dose of 2 g/kg of animal weight/day in duration of 4 weeks. The study contributes to the exploration of the impact of Met enriched diet inducing mild hHcy on nervous tissue by detecting the histo-morphological, metabolomic and behavioural alterations. We found an altered plasma metabolomic profile, modified spatial and learning memory acquisition as well as remarkable histo-morphological changes such as a decrease in neurons' vitality, alterations in the morphology of neurons in the selective vulnerable hippocampal CA 1 area of animals treated with Met enriched diet. Results of these approaches suggest that the mild hHcy alters plasma metabolome and behavioural and histo-morphological patterns in rats, likely due to the potential Met induced changes in "methylation index" of hippocampal brain area, which eventually aggravates the noxious effect of high methionine intake.


Assuntos
Comportamento Animal , Hipocampo/patologia , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/metabolismo , Metabolômica , Animais , Homocisteína/sangue , Hiper-Homocisteinemia/patologia , Marcação In Situ das Extremidades Cortadas , Espectroscopia de Ressonância Magnética , Masculino , Metionina , Ratos Wistar , Coloração e Rotulagem
10.
Food Funct ; 12(9): 3992-4004, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977955

RESUMO

Learning and memory impairment may result from age-related decline in synaptic plasticity-related proteins in the hippocampus. Therefore, exploration of functional foods capable of ameliorating memory and cognition decline is an interesting endeavor in neuroscience research. We report the effects of Anredera cordifolia (AC) extract on learning and memory deficits in a senescence-accelerated mouse-prone 8 (SAMP8) mouse model, which demonstrate age-related memory deficits and related pathological changes in the brain. After 8 weeks of oral administration of AC extract, the mice were trained in the Novel Object Recognition (NOR) task, and after 7 more weeks, in the Morris Water Maze (MWM) task. Following the completion of behavioral testing, the blood biochemistry parameters, the hippocampal levels of brain-derived neurotropic factor (BDNF), PSD95, and NR2A, and the p-cAMP-response element binding (p-CREB)/CREB ratio were measured. The AC-treated group spent more time exploring the novel objects in the NOR task, and showed faster acquisition and better retention in the MWM task than the negative control (CN) group. In addition, AC enhanced the levels of the aforementioned neuronal plasticity-related proteins, and did not affect the blood biochemistry parameters. Therefore, our data suggest that the AC extract may improve learning and memory without causing any noticeable side effects in the body.


Assuntos
Envelhecimento , Aprendizagem/efeitos dos fármacos , Magnoliopsida , Memória/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos , Plasticidade Neuronal
11.
Food Funct ; 12(9): 4142-4151, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977961

RESUMO

Irritable bowel syndrome (IBS) is a common chronic functional bowel disease, associated with a high risk of depression and anxiety. The brain-gut axis plays an important role in the pathophysiological changes involved in IBS; however, an effective treatment for the same is lacking. The natural compound costunolide (COS) has been shown to exert gastroprotective, enteroprotective, and neuroprotective effects, but its therapeutic effects in IBS are unclear. Our study explored the effect of COS on intestinal dysfunction and depressive behaviour in stress-induced IBS mice. Mice were subjected to chronic unpredictable mild stress to trigger IBS, and some were administered COS. Behavioural tests, histochemical assays, western blotting, and measurement of 5-hydroxytryptamine (5-HT) levels in the colon and hippocampus were applied to monitor the physiological and molecular consequences of COS treatment in IBS mice. COS administration relieved intestinal dysfunction and depression-like behaviours in IBS mice. Improvements in low-grade colon inflammation and intestinal mucosal permeability, inhibition of the activation of mast cells, upregulation of colonic Occludin expression, and downregulation of Claudin 2 expression were also observed. COS was also found to upregulate GluN2A, BDNF, p-ERK1/2, and p-CREB expression and 5-HT levels in hippocampal cells but inhibited 5-HT metabolism. Molecular docking showed that COS could form hydrogen bonds with the serotonin transporter (SERT) to affect the reuptake of 5-HT in the intercellular space. In conclusion, COS alleviates intestinal dysfunction and depressive behaviour in stress-induced IBS mice by inhibiting mast cell activation in the colon and regulating 5-HT metabolism in the central nervous system.


Assuntos
Transtorno Depressivo/tratamento farmacológico , Intestinos/fisiopatologia , Síndrome do Intestino Irritável/fisiopatologia , Síndrome do Intestino Irritável/psicologia , Mastócitos/imunologia , Serotonina/metabolismo , Sesquiterpenos/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Colo/imunologia , Hipocampo/metabolismo , Mucosa Intestinal/fisiopatologia , Síndrome do Intestino Irritável/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Receptores de N-Metil-D-Aspartato/metabolismo , Sesquiterpenos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico
12.
Food Funct ; 12(9): 4079-4091, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977962

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a disorder of both the motor and nonmotor systems due to a loss of dopaminergic (DA) neurons. Herein, we aimed to investigate the potential neuroprotective role of Schisandra chinensis (Sch) and to determine the mechanism by which Sch functions to ameliorate PD in a 6-hydroxydopamin (6-OHDA)-induced PD model. The open field test, sucrose preference test, and Y-maze test were utilized to evaluate the motor and nonmotor symptoms. We found that administration of Sch improved both disorders and DA neurodegeneration in 6-OHDA-induced mice. Additional data confirmed that Sch treatment significantly increased BDNF expression and decreased the activity of GSK-3ß in the striatum and hippocampus. Moreover, Sch was able to alleviate the abnormal levels of ROS and increase SOD by boosting Nrf2 expression. The nuclear translocation of NF-κB was inhibited by Sch, which subsequently led to a downregulation of proinflammatory cytokines. Sch effectively suppressed apoptosis by decreasing expressions of caspase 3, caspase 9, and p53 in the PD mouse model. Our findings demonstrate that Sch protects against DA neurodegeneration in 6-OHDA-induced PD mice by suppressing oxidative stress, neuroinflammation and apoptosis through the involvement of the BDNF/Nrf2/NF-κB signaling pathway.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Schisandra , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Fitoterapia , Transdução de Sinais
13.
Zhen Ci Yan Jiu ; 46(4): 301-5, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33931995

RESUMO

OBJECTIVE: To study the effect of blood-letting puncture at "Well-points" of the twelve meridians on hippocampal mitophagy of hypobaric hypoxia-induced brain injury (HHIBI) rats, so as to explore its biological mechanisms underlying improvement of high altitude hypoxia-induced brain injury. METHODS: Male SD rats were randomly divided into normal control group (n=9), and model and blood-letting groups which were further divided into 6, 12, 24, 48 and 72 h subgroups (n=9 in each subgroup). The HHIBI model was established by putting the rats into a hypobaric hypoxia chamber (equivalent to 5 000 m above sea level).The blood-letting groups were given blood-letting therapy at "Shaoshang"(LU11), "Shangyang"(LI1), "Zhongchong"(PC9), "Guanchong"(SJ1), "Shaochong"(HT9), "Shaoze"(SI9), once a day for 7 days. H.E. staining was used to observe the histopatholo-gical changes of hippocampus tissue. Serum hypoxia inducible factor(HIF)-1α and vascular endothelial growth factor(VEGF) contents were assayed using ELISA, and the expression levels of hippocampal Beclin-1 and LC3-Ⅱ proteins detected using Western blot. RESULTS: Compared with the normal control group, the levels of serum HIF-1α and VEGF at each time point, and the expressions of hippocampal Beclin-1 at 12 and 24 h, LC3-Ⅱat each time point were significantly increased in the model group (P<0.05, P<0.01); while in comparison with the model group, the levels of serum HIF-1α and VEGF contents, and the expressions of Beclin-1 at 12 h, LC3-Ⅱ at 24, 48 and 72 h were further significantly up-regulated in the blood-letting group (P<0.01, P<0.05). H.E. staining revealed that the pyramidal cells in the hippocampal CA1 region had a disordered arrangement, and some of them presented swelling with loose and pale cytoplasm or vacuolation at 6, 12 and 24 h, and showed indistinct nucleolus, irregular shape, pyknosis and deep staining and an obvious edema at 48 and 72 h, which was relatively milder in the blood-letting group. CONCLUSION: Blood-letting of "Well-points" can up-regulate serum HIF-1α and VEGF contents and hippocampal Beclin-1 and LC3-Ⅱ (mitophagy related proteins) expressions in HHIBI rats, which may contribute to its effect in reducing hypoxic brain injury.


Assuntos
Lesões Encefálicas , Fator A de Crescimento do Endotélio Vascular , Animais , Hipocampo/metabolismo , Hipóxia/genética , Hipóxia/terapia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Mitofagia , Punções , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Zhen Ci Yan Jiu ; 46(4): 318-25, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33931998

RESUMO

OBJECTIVE: To compare the difference of brain functional connectivity between diarrhea-predominant irritable bowel syndrome (IBS-D) patients and healthy volunteers and changes after acupuncture intervention, so as to investigate the underlying mechanism of acupuncture in regulating functional activities of IBS-D patients by using seed point correlation analysis. METHODS: A total of 25 IBS-D patients and 25 healthy volunteers were recruited in the present study and respectively attributed to acupuncture group and control group. The IBS-D patients received manual acupuncture stimulation of Baihui (GV20), Yintang (EX-HN3), and bilateral Tianshu (ST25), Zusanli (ST36), Shangjuxu (ST37), Sanyinjiao (SP6) and Taichong (LR3) with mind-regulating and spleen-strengthening technique for 30 min, once a day, 3 days a week for 6 weeks. Before and after the intervention, the IBS symptom severity scale (IBS-SSS) was used to assess the patients' state of abdominal pain, distention and defecation, and Hamilton Anxiety Rating Scale (HAMA) employed to evaluate the patients' anxiety severity. The resting state functional magnetic resonance imaging (rs-fMRI) data were acquired and preprocessed by using SPM8 and DPARSE soft-wares. Seeds (bilate-ral hippocampus regions) to whole-brain analysis was performed to obtain the mean time series of the left and right seed regions, followed by making Pearson correlation analysis to obtain the correlation coefficient (time series from each seed region with the rest of the voxels in the brain), and making a multivariate comparative correction to get data of functional connectivity (FC) of bilateral hippocampus regions and to find the related difference in the brain regions. Then, the differences of the FC of brain regions between IBS-D patients and healthy volunteers were compared. RESULTS: Following acupuncture treatment, both the HAMA and IBS-SSS scores were significantly reduced in the acupuncture group compared with its pre-treatment (P<0.01). Compared with the healthy volunteers, there were a reduction in the functional connectivity between the left hippocampus seed region and the right inferior temporal gyrus, left fusiform gyrus and left superior gyrus, and between the right hippocampus region and the right fusiform gyrus, left inferior temporal gyrus, left inferior occipital gyrus, left rectus gyrus, left insula, left precuneus, right angular gyrus, left middle occipital gyrus, right precuneus, and the left superior temporal gyrus, and an increase in the FC between the left hippocampus and left superior temporal gyrus was increased in ISB-D patients. Self-comparison showed that after the treatment, the FC was increased between the left hippocampus seed region and the right inferior temporal gyrus, left fusiform gyrus, bilateral lingual gyrus, left amygdala, right inferior occipital gyrus, right insula, right middle frontal gyrus, left middle frontal gyrus and the left middle occipital gyrus; and between the right hippocampus seed region and the posterior inferior cerebellar lobe, left inferior temporal gyrus, left suboccipital gyrus, right fusiform gyrus, left insula, right inferior frontal gyrus, left superior temporal gyrus, left middle occipital gyrus, right middle frontal gyrus, left supplementary motor area and right supplementary motor area, and decreased between the left hippocampus region and the left anterior cingulate, paracingulate gyrus and the right posterior central gyrus in IBS-D patients. CONCLUSION: Mind-regulating and spleen-strengthening acupuncture intervention may improve the abdominal pain and distension and emotional state in IBS-D patients, which is possibly associated with its effect in enhancing FC between the hippocampus and brain regions.


Assuntos
Síndrome do Intestino Irritável , Encéfalo/diagnóstico por imagem , Diarreia , Emoções , Hipocampo , Humanos , Síndrome do Intestino Irritável/terapia , Imageamento por Ressonância Magnética , Baço
15.
Medicine (Baltimore) ; 100(21): e26078, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032740

RESUMO

ABSTRACT: Based on association studies on amounts of alcohol consumed and cortical and subcortical structural shrinkage, we investigated the effect of chronic alcohol consumption on white matter pathways using probabilistic tractography.Twenty-three alcohol-dependent men (with an average sobriety of 13.1 months) from a mental health hospital and 22 age-matched male healthy social drinkers underwent 3T magnetic resonance imaging. Eighteen major white matter pathways were reconstructed using the TRActs Constrained by UnderLying Anatomy tool (provided by the FreeSurfer). The hippocampal volumes were estimated using an automated procedure. The lifetime drinking history interview, Alcohol Use Disorder Identification Test, Brief Michigan Alcoholism Screening Test, and pack-years of smoking were also evaluated.Analysis of covariance controlling for age, cigarette smoking, total motion index indicated that there was no definite difference of diffusion parameters between the 2 groups after multiple comparison correction. As hippocampal volume decreased, the fractional anisotropy of the right cingulum-angular bundle decreased. Additionally, the axial diffusivity of right cingulum-angular bundle was positively correlated with the alcohol abstinence period.The results imply resilience of white matter in patients with alcohol dependence. Additional longitudinal studies with multimodal methods and neuropsychological tests may improve our findings of the changes in white matter pathways in patients with alcohol dependence.


Assuntos
Alcoolismo/complicações , Hipocampo/patologia , Imageamento por Ressonância Magnética , Substância Branca/fisiopatologia , Adulto , Abstinência de Álcool , Alcoolismo/patologia , Alcoolismo/fisiopatologia , Anisotropia , Hipocampo/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Tamanho do Órgão , Substância Branca/diagnóstico por imagem
16.
Methods Mol Biol ; 2274: 217-235, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34050475

RESUMO

Recent extensive studies revealed that the intracellular concentration of magnesium ions (Mg2+) is one of the important factors to regulate cellular functions. To evaluate the impact of Mg2+ concentration changes on intracellular signals or events, simultaneous imaging of Mg2+ with those phenomena is a powerful technique. The present protocol describes the synthesis and evaluation of near-infrared (NIR) fluorescent Mg2+-selective probes, named KMG-500 series, and the application to simultaneous imaging of the corresponding intracellular signal transductions and molecular events. The present protocol for multicolor imaging using fluorescent probes in the NIR and visible ranges is highly useful to reveal how multiple molecular events are correlated each other in each single cell.


Assuntos
Trifosfato de Adenosina/metabolismo , Corantes Fluorescentes/química , Hipocampo/metabolismo , Magnésio/metabolismo , Imagem Molecular/métodos , Neurônios/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Células Cultivadas , Potencial da Membrana Mitocondrial , Microscopia de Fluorescência/métodos , Ratos , Transdução de Sinais
17.
Science ; 372(6545): 913-914, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34045343
18.
Nat Commun ; 12(1): 2849, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990590

RESUMO

Long-term depression (LTD) of synaptic strength can take multiple forms and contribute to circuit remodeling, memory encoding or erasure. The generic term LTD encompasses various induction pathways, including activation of NMDA, mGlu or P2X receptors. However, the associated specific molecular mechanisms and effects on synaptic physiology are still unclear. We here compare how NMDAR- or P2XR-dependent LTD affect synaptic nanoscale organization and function in rodents. While both LTDs are associated with a loss and reorganization of synaptic AMPARs, only NMDAR-dependent LTD induction triggers a profound reorganization of PSD-95. This modification, which requires the autophagy machinery to remove the T19-phosphorylated form of PSD-95 from synapses, leads to an increase in AMPAR surface mobility. We demonstrate that these post-synaptic changes that occur specifically during NMDAR-dependent LTD result in an increased short-term plasticity improving neuronal responsiveness of depressed synapses. Our results establish that P2XR- and NMDAR-mediated LTD are associated to functionally distinct forms of LTD.


Assuntos
Proteína 4 Homóloga a Disks-Large/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Trifosfato de Adenosina/administração & dosagem , Animais , Autofagia/fisiologia , Células Cultivadas , Proteína 4 Homóloga a Disks-Large/deficiência , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Modelos Neurológicos , N-Metilaspartato/administração & dosagem , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/fisiologia , Receptores Purinérgicos P2X/fisiologia
19.
Neuroscience ; 465: 142-153, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33957205

RESUMO

Among different kinds of dietary energy restriction, intermittent fasting (IF) has been considered a dietary regimen which causes a mild stress to the organism. IF can stimulate proteins and signaling pathways related to cell stress that can culminate in the increase of the body resistance to severe stress conditions. Energy intake reduction induced by IF can induce modulation of receptors, kinases, and phosphatases, which in turn can modulate the activation of transcription factors such as NF-E2-related factor 2 (NRF2) and cAMP response element-binding (CREB) which regulate the transcription of genes related to the translation of proteins such as growth factors: brain-derived neurotrophic factor (BDNF), chaperone proteins: heat shock proteins (HSP), and so on. It has been shown that toll-like receptors (TLRs) are important molecules in innate immune response which are present not only in the periphery but also in neurons and glial cells. In central nervous system, TLRs can exert functions related to set up responses to infection, as well as influence neural progenitor cell proliferation and differentiation, being involved in cognitive parameters such as learning and memory. Little is known about the involvement of TLR4 on the beneficial effects induced by IF protocol. The present work investigated the effects of IF on memory and on the signaling mechanisms associated with NRF2 and CREB in Tlr4 knockout mice. The results suggest that TLR4 participates in the modulatory effects of IF on oxidative stress levels, on the transcription factors CREB and NRF2, and on BDNF and HSP90 expressions in hippocampus.


Assuntos
Jejum , Receptor 4 Toll-Like , Animais , Hipocampo/metabolismo , Memória , Camundongos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(4): 521-528, 2021 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-33963710

RESUMO

OBJECTIVE: To analyze spontaneous activities and energy metabolism in the medial prefrontal cortex (mPFC) of mice with chronic unpredictable mild stress (CUMS) and explore the correlation of these changes with the mTORC1 signaling pathway. OBJECTIVE: Normal C57Bl/6 mice were randomly divided into control group (n=16) and depression model group (n= 16), and the mice in the latter group were subjected to 8 weeks of modeling with CUMS. Behavioral tests including open field test, sucrose consumption test, tail suspension test and forced swimming test were performed, and the changes in prefrontal gray matter volume and the amplitude of low frequency fluctuation (ALFF) in the mice were detected with functional magnetic resonance imaging. The CUMS mice were then randomized into two groups for treatment with ketamine (n=8) or saline (n=8). The mPFC tissues of the mice were collected for detecting the phosphorylation levels of mTORC1-related proteins with Western blotting and ATP level and NADP +/NADPH ratio with ELISA in the 3 groups. OBJECTIVE: Compared with the control mice, CUMS mice exhibited a distinct depressive phenotype with significantly decreased sucrose preference (P < 0.05) and shortened total distances (P < 0.01) and central exercise distances (P < 0.05) in the open field test without obvious changes of immobile time in tail suspension test and forced swimming test (P>0.05). Prefrontal gray matter volume and mALFF increased (P < 0.01), and the phosphorylation level of mTORC1- related proteins, ATP level and NADP +/NADPH ratio all decreased significantly (P < 0.05) in CUMS mice. After ketamine treatment, the phosphorylation level of mTORC1-related proteins and ATP level increased significantly in CUMS mice (P < 0.05), but the increase of NADP +/NADPH ratio was not statistically significant. OBJECTIVE: The mPFC of CUMS mice shows increased spontaneous activities but lowered productivity efficiency, indicating the presence of energy metabolism disorder in the mPFC, which is related with reduced mTORC1 phosphorylation and can be alleviated by activating the mTORC1 pathway with ketamine.


Assuntos
Antidepressivos , Depressão , Animais , Depressão/diagnóstico por imagem , Modelos Animais de Doenças , Metabolismo Energético , Hipocampo , Imageamento por Ressonância Magnética , Camundongos , Córtex Pré-Frontal/diagnóstico por imagem , Estresse Psicológico
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