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Post-traumatic stress disorder (PTSD) is a complex psychological disorder provoked by distressing experiences, and it remains without highly effective intervention strategies. The exploration of PTSD's underlying mechanisms is crucial for advancing diagnostic and therapeutic approaches. Current studies primarily explore PTSD through the lens of the central nervous system, investigating concrete molecular alterations in the cerebral area and neural circuit irregularities. However, the body's response to external stressors, particularly the changes in cardiovascular function, is often pronounced, evidenced by notable cardiac dysfunction. Consequently, examining PTSD with a focus on cardiac function is vital for the early prevention and targeted management of the disorder. This review undertakes a comprehensive literature analysis to detail the alterations in brain and heart structures and functions associated with PTSD. It also synthesizes potential mechanisms of heart-brain axis interactions relevant to the development of PTSD. Ultimately, by considering cardiac function, this review proposes novel perspectives for PTSD's prophylaxis and therapy.
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Encéfalo , Coração , Transtornos de Estresse Pós-Traumáticos , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/terapia , Humanos , Coração/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , AnimaisRESUMO
Electroacupuncture (EA) is well documented to treat irritable bowel syndrome (IBS). However, the mechanism of the central nervous system related to IBS and acupuncture stimulation is still not well known. In this study, a rat model of IBS was established by cold-restraint comprehensive stresses for 15 days, and it was found that the levels of corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral serum were increased; the visceral sensitivity was enhanced; and the intestinal motility was accelerated, specifically, there was an enhancement in the discharge frequency of neurons in the paraventricular nucleus (PVN). EA treatment for 3 days, 20 min/day, alleviated the increase in the levels of CRH, CORT, and ACTH in the peripheral serum of rats, reduced the visceral sensitivity of IBS rats, and inhibited colon movement and discharge frequency of the neurons in the PVN. In addition, EA could reduce the excitability of CRH neurons and the expression of corticotropin-releasing hormone receptor 1 (CRHR1) and corticotropin-releasing hormone receptor 2 (CRHR2) in PVN. At the same time, the expression of CRH, CRHR1, and CRHR2 in the peripheral colon was decreased. Taken together, EA appears to regulate intestinal functional activity through the central CRH nervous system, revealing the central regulation mechanism of EA in IBS rats, and providing a scientific research basis for the correlation among the meridians, viscera, and brain.NEW & NOTEWORTHY The purpose of this research was to determine the central regulatory mechanism of electroacupuncture (EA) in rats with irritable bowel syndrome (IBS). Our results showed that combined with the serum changes in corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH), the improvement of IBS by EA was related to them. Furthermore, EA could regulate intestinal functional activity through the central CRH+ nervous system.
Assuntos
Eletroacupuntura , Síndrome do Intestino Irritável , Ratos , Animais , Hormônio Liberador da Corticotropina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Síndrome do Intestino Irritável/terapia , Corticosterona , Eletroacupuntura/métodos , Ratos Sprague-Dawley , Hormônio Adrenocorticotrópico/metabolismo , Neurônios/metabolismoRESUMO
Acute coronary syndrome (ACS) is the most severe form of ischemic heart disease. Although it is caused by atherosclerotic plaque thrombosis or nonatherosclerotic causes, its pathophysiological mechanism of ACS is not fully understood, and its concept is constantly updated and developed. At present, the main pathophysiological mechanisms include plaque rupture, plaque erosion, calcified nodules (CN) and non-atherosclerotic causes such as coronary vasospasm and myocardial bridging (MB). These mechanisms may overlap and coexist in some ACS patients. Therefore, the pathophysiological mechanism of ACS is complex, and is of great significance for the diagnosis and treatment of ACS. This review will discuss the pathophysiological mechanisms of ACS to provide new thoughts on the pathogenesis, diagnosis and treatment of ACS.
RESUMO
Background: Coronary biomechanical stress contributes to the plaque rupture and subsequent events. This study aimed to investigate the impact of plaque biomechanical stability on the physiological progression of intermediate lesions, as assessed by the radial wall strain (RWS) derived from coronary angiography. Methods: Patients with at least one medically treated intermediate lesion at baseline who underwent follow-up coronary angiography over 6 months were included. The maximal RWS ( RWS max ) of the interrogated lesion was calculated from the baseline angiogram. The primary endpoint was to determine the association between baseline RWS max and the functional progression of coronary lesions, defined as an increase in the lesion-specific â³ quantitative flow ratio (L- â³ QFR, calculated as the absolute change in QFR across the lesion) on serial angiograms. Results: Among 175 lesions in 156 patients, 63 lesions showed an increase in L- â³ QFR during a median follow-up period of 12.4 months. Baseline RWS max values were significantly higher in lesions with increased L- â³ QFR than in those with stabilized or decreased L- â³ QFR (11.8 [10.7, 13.7] vs.10.8 [9.7, 11.7]; p = 0.001). Baseline RWS max presented an area under the curve of 0.658 (95% confidence interval [CI]: 0.572-0.743, p < 0.001) for the prediction of increased L- â³ QFR. After full adjustment for clinical and angiographic factors, a high RWS max ( > 12) was found to be an independent predictor of functional lesion progression (odds ratio: 2.871, 95% CI: 1.343-6.138, p = 0.007). Conclusions: A high RWS max calculated from baseline angiograms was independently associated with the subsequent physiological progression in patients with intermediate coronary lesions.
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Ginseng has been used in China as a superior medicinal material for thousands of years that can nourish the five internal organs, calm the mind and benefit wisdom. Due to its anti-inflammatory, antioxidant and neuroprotective activities, one of the active components of ginseng, ginsenoside Rg1, has been extensively investigated in the remedy of brain disorders, especially dementia and depression. In this review, we summarized the research progress on the action mechanisms of Rg1 ameliorating depression-like behaviors, including inhibition of hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis, regulation of synaptic plasticity and gut flora. Rg1 may alleviate Alzheimer's disease in the early phase, as well as in the middle-late phases through repairing dendrite, axon and microglia- and astrocyte-related inflammations. We also proposed that Rg1 could regulate memory state (the imbalance of working and aversive memory) caused by distinct stimuli. These laboratory studies would further the clinical trials on Rg1. From the prospective of drug development, we discussed the limitations of the present investigations and proposed our ideas to increase permeability and bioavailability of Rg1. Taken together, Rg1 has the potential to treat neuropsychiatric disorders, but a future in-depth investigation of the mechanisms is still required. In addition, drug development will benefit from the clinical trials in one specific neuropsychiatric disorder.
Assuntos
Doença de Alzheimer , Ginsenosídeos , Humanos , Doença de Alzheimer/tratamento farmacológico , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Inflamação/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Depressão/tratamento farmacológico , Encefalopatias/tratamento farmacológicoRESUMO
Polygala tenuifolia was documented to calm the mind and promote wisdom. However, its underlying mechanisms are still unclear. This study aimed to investigate the mechanisms underlying the effects of tenuifolin (Ten) on Alzheimer's disease (AD)-like phenotypes. We first applied bioinformatics methods to screen the mechanisms of P. tenuifolia in the treatment of AD. Thereafter, the d-galactose combined with Aß1-42 (GCA) was applied to model AD-like behaviors and investigate the action mechanisms of Ten, one active component of P. tenuifolia. The data showed that P. tenuifolia actioned through multi-targets and multi-pathways, including regulation of synaptic plasticity, apoptosis, and calcium signaling, and so forth. Furthermore, in vitro experiments demonstrated that Ten prevented intracellular calcium overload, abnormal calpain system, and down-regulation of BDNF/TrkB signaling induced by GCA. Moreover, Ten suppressed oxidative stress and ferroptosis in HT-22 cells induced by GCA. Calpeptin and ferroptosis inhibitor prevented the decrease of cell viability induced by GCA. Interestingly, calpeptin did not interrupt GCA-induced ferroptosis in HT-22 cells but blocked the apoptosis. Animal experiments further demonstrated that Ten prevented GCA-induced memory impairment in mice and increased synaptic protein expression while reducing m-calpain expression. Ten prevents AD-like phenotypes through multiple signaling by inhibiting oxidative stress and ferroptosis, maintaining the stability of calpain system, and suppressing neuronal apoptosis.
Assuntos
Doença de Alzheimer , Saponinas , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Ferroptose , Apoptose , Galactose/química , Estresse Oxidativo , Saponinas/metabolismo , Saponinas/farmacologia , FenótipoRESUMO
Chronic traumatic stress results in various psychiatric disorders, especially posttraumatic stress disorder (PTSD). Previous study demonstrated that curculigoside (CUR) a component of Rhizoma Curculiginis prevented fear extinction and stress-induced depression-like behaviors. However, its effects on PTSD and the mechanisms are still not completely clear. In this study, we observed typical PTSD-like phenotypes, synaptic deficit, and reduction of BDNF/TrkB signaling pathway in mice receiving modified single prolonged stress and electrical stimulation (SPS&S). By contrast, systemic administration of CUR blocked PTSD-like phenotypes and synaptic deficits, including reduction of BDNF/TrkB signaling pathway, GluA1 and Arc expression. Importantly, CUR reversed the impairment of PKA signaling pathway elicited by PTSD. We further confirmed that the effects of CUR on synaptic function were through PKA signaling pathway, as H-89, an inhibitor of PKA blocked the effect of CUR on behavioral changes and BDNF/TrkB signaling pathway. Thereafter, we verified that CUR on synaptic function were through PKA pathway using direct intracerebral injection of CUR and H-89. Direct intracerebral injection of CUR activated PKA/CREB/BDNF/TrkB, which was blocked by H-89. Additionally, the docking results showed high binding energies of CUR with A2AR, AC, PRKACA, and PRKAR1A, which might indicate that CUR functions through regulating PKA signaling pathway. In conclusion, CUR prevented the behavioral changes and hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Camundongos , Animais , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo , Extinção Psicológica , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medo , Hipocampo , Transdução de SinaisRESUMO
Astrocytic functions and brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signaling pathways are impaired in stress-related neuropsychiatric diseases. Previous studies have reported neuroprotective effects of 7,8-dihydroxyflavone (7,8-DHF), a TrkB activator. Here, we investigated the molecular mechanisms underlying pathogenesis of post-traumatic stress disorder (PTSD) using a modified single-prolonged stress (SPS&S) model and the potential beneficial effects of 7,8-DHF. SPS&S reduced the hippocampal expression of glial fibrillary acidic protein (GFAP), a marker of astrocytes, and induced morphological changes in astrocytes. From the perspective of synaptic function, the SPS&S model displayed reduced expression of BDNF, p-TrkB, postsynaptic density protein 95 (PSD95), AMPA receptor subunit GluR1 (GluA1), NMDA receptor subunit N2A/N2B ratio, calpain-1, phosphorylated protein kinase B (Akt) and phosphorylated mammalian target of rapamycin (mTOR) and conversely, higher phosphatase and tension homolog (PTEN) expression in the hippocampus. Acute or continuous intraperitoneal administration of 7,8-DHF (5 mg/kg) after SPS&S procedures prevented SPS&S-induced fear memory generalization and anxiety-like behaviors as well as abnormalities of hippocampal oscillations. Most importantly, 7,8-DHF attenuated SPS&S-induced abnormal BDNF-TrkB signaling and calpain-1-dependent cascade of synaptic deficits. Furthermore, treatment with a TrkB inhibitor completely blocked while an mTOR inhibitor partially blocked the effects of 7,8-DHF on behavioral changes of SPS&S model mice. Our collective findings suggest that 7,8-DHF effectively alleviates PTSD-like symptoms, including fear generalization and anxiety-like behavior, potentially by preventing astrocytic and synaptic deficits in the hippocampus through targeting of TrkB.
Assuntos
Flavonas/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Ansiedade/tratamento farmacológico , Astrócitos/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Flavonas/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Receptor trkB/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Sinapses/efeitos dos fármacosRESUMO
BACKGROUND: Lipid-lowering therapy is important, and the distribution of lipid levels and the incidence of hyperlipidemia may vary in different subgroups of the population. We aimed to explore the distribution of lipid levels and the prevalence of hyperlipidemia in subpopulations with subgroup factors, including age, sex, race, and smoking status. METHODS: Our study used data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018, ultimately enrolling and analyzing 15,499 participants. A cross-sectional analysis was performed to assess the distribution of lipids and prevalence of hyperlipidemia in subpopulations, and multifactorial logistic regression analyses were performed for the prevalence of hyperlipidemia, adjusted for age, sex, race and smoking status. RESULTS: Blacks had significantly lower mean serum total cholesterol and triglycerides and higher serum high-density lipoprotein cholesterol (HDL-C) than whites (P < 0.001). In contrast, Mexican Americans had markedly higher mean serum triglycerides and lower serum HDL-C than whites (P < 0.001). Furthermore, the prevalence of hypercholesterolemia and hypertriglyceridemia was lower in blacks than in whites (P = 0.003 and P < 0.001, respectively), while the prevalence of hypertriglyceridemia was significantly higher in Mexican Americans than in whites (P = 0.002). In addition, total cholesterol and triglyceride levels were significantly higher in women aged 65 years or older and markedly higher than in men in the same age group (P < 0.001). In addition, overall mean total cholesterol, triglyceride, and low-density lipoprotein cholesterol (LDL-C) levels were higher in smokers than in nonsmokers (P = 0.01, P < 0.001, and P = 0.005, respectively). CONCLUSION: Based on NHANES data, the mean lipid levels and prevalence of hyperlipidemia differed by sex, age, race, and smoking status.
Assuntos
Hiperlipidemias , Hipertrigliceridemia , Masculino , Feminino , Humanos , Hiperlipidemias/epidemiologia , Inquéritos Nutricionais , Prevalência , Estudos Transversais , HDL-Colesterol , Triglicerídeos , Hipertrigliceridemia/epidemiologiaRESUMO
Polysaccharide from Polygonatum sibiricum (PSP) possesses antioxidant, antiaging, and neuroprotective activities. However, whether and how the steaming process influences the biological activities of PSP, especially against aging-related memory impairment, is not yet known. In this study, Polygonatum sibiricum rhizome was subjected to a "nine steaming and nine drying" process, then PSPs with different steaming times were abstracted. Thereafter, the physicochemical properties were qualified; the antioxidant activities of PSPs were evaluated in a D-gal-induced HT-22 cell model, and the effects of PSPs (PSP0, PSP5 and PSP9) on memory was evaluated using D-gal-injured mice. Our results showed that while the steamed PSPs had a low pH value and a large negative charge, they shared similar main chains and substituents. Cellular experiments showed that the antioxidant activity of steamed PSPs increased. PSP0, PSP5, and PSP9 could significantly ameliorate the memory impairment of D-gal-injured mice, with PSP5 showing the optimal effect. Meanwhile, PSP5 demonstrated the best effect in terms of preventing cell death and synaptic injury in D-gal-injured mice. Additionally, the steamed PSPs increased anti-oxidative stress-related protein expression and decreased inflammation-related protein expression in D-gal-injured mice. Collectively, the steaming process improves the effects of PSPs against D-gal-induced memory impairment in mice, likely by increasing the antioxidant activity of PSPs.
Assuntos
Polygonatum , Animais , Antioxidantes/química , Carboidratos da Dieta/efeitos adversos , Galactose/efeitos adversos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Polygonatum/química , Polissacarídeos/químicaRESUMO
The activation of Nod-like receptor protein 3 (NLRP3) inflammasome propagates pro-inflammatory signaling cascades linking to depression-like behaviors. However, the signaling pathway contributing to NLRP3 inflammasome activation and depression-like behaviors is still not clear. In this study, we evidenced that lipopolysaccharide (LPS) injection (i.p.) triggered depression-like behaviors, promoted the expression of Kir4.1, p-GluN2B and calpain-1, and activated NLRP3 inflammasome. The blockage of N-methyl-d-aspartate receptors (NMDAR) by memantine reduced LPS-induced depression-like behaviors, NLRP3 inflammasome and astrocyte activation, and calpain-1 expression. Additionally, memantine also inhibited LPS-induced reduction of postsynaptic density protein 95 (PSD-95) and Arc expression. Specific reduction of Kir4.1 in astrocytes attenuated LPS-induced expression of NLRP3 and calpain-1, and phosphorylation of GluN2B. Interestingly, LPS-induced expression of calpain-1 largely co-localized with GFAP, indicating the specific function of calpain-1 in astrocytes. Together, these data indicate that astrocytic Kir4.1 could regulate NMDAR/calpain-1 signaling axis, contributing to depression-like behaviors, likely through regulating NLRP3 inflammasome activation.
Assuntos
Astrócitos/metabolismo , Comportamento Animal , Calpaína/metabolismo , Depressão/metabolismo , Hipocampo/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Antidepressivos/farmacologia , Astrócitos/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Depressão/induzido quimicamente , Depressão/prevenção & controle , Depressão/psicologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Inflamassomos/metabolismo , Lipopolissacarídeos , Masculino , Memantina/farmacologia , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fosforilação , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transdução de SinaisRESUMO
This study is aimed at investigating the potential roles of G protein-coupled estrogen receptor 1 (GPER, also known as GPR30) in the preventive effect of ginsenoside Rg1 against cognitive impairment and hippocampal cell apoptosis in experimental vascular dementia (VD) in mice. The effects of bilateral common carotid artery stenosis (BCAS) on GPR30 expression at mRNA level were evaluated. Thereafter, the BCAS mouse model was utilized to evaluate the protection of Rg1 (0.1, 1, 10 mg/kg, 14 days, ip). Spatial memory was evaluated by water Morris Maze 7 days post BCAS. After behavioral tests, neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and potential mechanisms were determined using western blotting and quantitative real-time PCR. Our results showed that GPR30 expression in the hippocampal region at mRNA level was promoted 30 min, 3 h, 6 h, and 24 h following BCAS. Ginsenoside Rg1 (1 or 10 mg/kg, 14 days, ip) promoted GPR30 expression in the hippocampus of model mice (after behavioral tests) but did not alter GPR30 expression in the hippocampus of control mice. Moreover, treatment of ginsenoside Rg1 (10 mg/kg) or G1 (5 µg/kg), a GPR30 agonist, prevented BCAS-induced memory impairment and hippocampal neuronal loss and apoptosis and promoted the ratio of Bcl-2 to Bax expression in the hippocampus (after behavioral tests). On the contrary, G15 (185 µg/kg), an antagonist of GPR30, aggravated BCAS-induced hippocampal neuronal loss and apoptosis. Finally, drug-target molecular docking pointed that Rg1 had a lower binding energy with GPR30 compared with Bax and Bcl-2. Together, our data implicate that ginsenoside Rg1 prevents cognitive impairment and hippocampal neuronal apoptosis in VD mice, likely through promoting GPR30 expression. These results would provide important implications for the application of Rg1 in the treatment of VD.
Assuntos
Apoptose/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Demência Vascular/metabolismo , Ginsenosídeos/uso terapêutico , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Demência Vascular/complicações , Modelos Animais de Doenças , Ginsenosídeos/farmacologia , Hipocampo/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Quinolinas/farmacologiaRESUMO
Curculigoside (CUR) is the main active component of traditional Chinese medicine Curculigoorchioides Gaertn (Xianmao in Chinese), which exhibits a variety of pharmacological activities. In this study we investigated the effects of CUR on fear extinction and related depression-like behaviors in mice. In fear conditioning task, we found that administration of CUR (1.6, 8, 40 mg·kg-1·d-1, ip, for 7 days) did not affect memory consolidation, but CUR at higher doses (8, 40 mg·kg-1·d-1) significantly facilitated fear extinction, especially on D3 and D4. Moreover, CUR administration significantly ameliorated the fear conditioning-induced depression-like behaviors, likely through promoting fear extinction. We showed that CUR increased the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of tropomyosin receptor kinase B (TrkB) in the hippocampus, and activated protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) signaling pathway. Administration of the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF, 5 mg·kg-1·d-1, ip) also facilitated fear extinction, ameliorated depression-like behaviors. We established a mouse learned helplessness (LH) model to evaluate the antidepressant activity of CUR. The spatial memory was assessed in Morris water maze. We showed that LH-induced depression-like behaviors, including prolonged immobility times in forced swim and tail suspension tests as well as spatial memory impairments; LH also downregulated BDNF expression and the Akt-mTOR signaling pathway in the hippocampus. Administration of CUR (1.6, 8, 40 mg·kg-1·d-1, ip, for 14 days) or 7,8-DHF (5 mg·kg-1·d-1, ip, for 3 days) prevented LH-induced depression-like behaviors and promoted BDNF expression and the Akt-mTOR signaling pathway. In conclusion, CUR can accelerate the fear memory extinction and ameliorate depression-like behaviors in mice via promoting BDNF expression and activating the Akt-mTOR signaling pathway in the hippocampus.
Assuntos
Comportamento Animal/efeitos dos fármacos , Benzoatos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Glucosídeos/farmacologia , Desamparo Aprendido , Hipocampo/efeitos dos fármacos , Animais , Depressão/metabolismo , Hipocampo/metabolismo , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Extinction of fear-memory is essential for emotional and mental changes. However, the mechanisms underlying extinction of fear-memory are largely unknown. Calpain is a type of calcium-dependent protease that plays a critical role in memory consolidation and reconsolidation. Whether calpain functions in extinction of fear-memory is unknown, as are the molecular mechanisms. In this study, we investigated the pivotal role of calpain in extinction of fear-memory in mice, and assessed its mechanism. Conditioned stimulation/unconditioned stimulation-conditioned stimulation paradigms combined with pharmacological methods were employed to evaluate the action of calpain in memory extinction. Our data demonstrated that intraperitoneal or intra-basolateral amygdala (BLA) injection of calpain inhibitors could eliminate extinction of fear-memory in mice. Moreover, extinction of fear-memory paradigm-activated BLA calpain activity, which degraded suprachiasmatic nucleus circadian oscillatory protein (SCOP) and phosphatase and tensin homolog (PTEN), subsequently contributing to activation of a protein kinase B (AKT)-mammalian target of the rapamycin (mTor) signaling pathway. Additionally, cAMP-response element binding protein (CREB) phosphorylation was also augmented following extinction of fear-memory. Calpain inhibitor blocked the signaling pathway activation induced by extinction of fear-memory. Additionally, intra-BLA injection of rapamycin or cycloheximide also blocked the extinction of fear-memory. Conversely, intra-BLA injection of PTEN inhibitor, bpV, reversed the effect of calpeptin on extinction of fear-memory. Together, our data confirmed the function of BLA calpain in extinction of fear-memory, likely via degrading PTEN and activating AKT-mTor-dependent protein synthesis.
Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Calpaína/metabolismo , Extinção Psicológica/fisiologia , Medo/fisiologia , Consolidação da Memória/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Calpaína/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15. Interestingly, a group I metabotropic glutamate receptor (mGluR) agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) in mossy fiber-cornu ammonis 3 (MF-CA3) synapses but not Schaffer collateral-CA1 (SC-CA1) synapses was facilitated in brain slices from G1-treated middle-aged mice. Long-term potentiation (LTP) in SC-CA1 synapses was not affected in slices from G1-treated mice. The effects of GPR30 activation on memory and DHPG-LTD in MF-CA3 synapses were further confirmed by viral expression of GPR30 in the CA3. The regulation of hippocampal synaptic plasticity by G1 treatment might be related to brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, as G15 also blocked G1-induced activation of the BDNF-TrkB pathway. Moreover, we found that DHPG triggered GluA internalization in slices from G1-treated mice but not control mice. Pharmacological experiments showed that G1-mediated facilitation of DHPG-induced LTD in MF-CA3 synapses was dependent on protein kinase B (Akt), mammalian target of rapamycin (mTor), and TrkB signaling. In conclusion, our results indicate that GPR30 activation improves memory in middle-aged mice, likely through facilitating synaptic plasticity in the CA3. This study provides novel evidence that GPR30 activation can improve memory in middle-aged animals.
Assuntos
Região CA3 Hipocampal/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Metoxi-Hidroxifenilglicol/análogos & derivados , Receptores de Estrogênio/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Fatores Etários , Animais , Benzodioxóis/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA3 Hipocampal/metabolismo , Medo/efeitos dos fármacos , Feminino , Masculino , Glicoproteínas de Membrana/metabolismo , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Quinolinas/farmacologia , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismoRESUMO
Deciphering and storing information coded in different firing patterns are important properties of neuronal networks, as they allow organisms to respond and adapt to external and internal events. Here we report that hippocampal CA1 pyramidal neurons respond to brief bursts of high-frequency stimulation (HFS) and θ burst stimulation (TBS) with long-lasting enhanced responses (long-term potentiation [LTP]), albeit by engaging different signaling pathways. TBS induces LTP through calpain-1-mediated suprachiasmatic nucleus circadian oscillatory protein degradation, ERK activation, and actin polymerization, whereas HFS requires adenosine A2 receptors, PKA, and actin polymerization. TBS- but not HFS-induced LTP is impaired in calpain-1 knock-out mice. However, TBS-induced LTP and learning impairment in knock-out mice are restored by activating the HFS pathway. Thus, different patterns of rhythmic activities trigger potentiation by activating different pathways, and cross talks between these can be used to restore LTP and learning when elements of the pathways are impaired.
Assuntos
Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração , Neurônios/fisiologia , Ritmo Teta , Actinas/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Calpaína/genética , Calpaína/metabolismo , Células Cultivadas , Condicionamento Clássico , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Receptores A2 de Adenosina/metabolismoRESUMO
Dendritic protein synthesis and actin cytoskeleton reorganization are important events required for the consolidation of hippocampal LTP and memory. However, the temporal and spatial relationships between these two processes remain unclear. Here, we report that treatment of adult rat hippocampal slices with BDNF or with tetraethylammonium (TEA), which induces a chemical form of LTP, produces a rapid and transient increase in RhoA protein levels. Changes in RhoA were restricted to dendritic spines of CA3 and CA1 and require de novo protein synthesis regulated by mammalian target of rapamycin (mTOR). BDNF-mediated stimulation of RhoA activity, cofilin phosphorylation, and actin polymerization were completely suppressed by protein synthesis inhibitors. Furthermore, intrahippocampal injections of RhoA antisense oligodeoxynucleotides inhibited theta burst stimulation (TBS)-induced RhoA upregulation in dendritic spines and prevented LTP consolidation. Addition of calpain inhibitors after BDNF or TEA treatment maintained RhoA levels elevated and prolonged the effects of BDNF and TEA on actin polymerization. Finally, the use of isoform-selective calpain inhibitors revealed that calpain-2 was involved in RhoA synthesis, whereas calpain-1 mediated RhoA degradation. Overall, this mechanism provides a novel link between dendritic protein synthesis and reorganization of the actin cytoskeleton in hippocampal dendritic spines during LTP consolidation.
Assuntos
Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Potenciação de Longa Duração , Proteína rhoA de Ligação ao GTP/metabolismo , Citoesqueleto de Actina/metabolismo , Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/fisiologia , Calpaína/antagonistas & inibidores , Calpaína/metabolismo , Espinhas Dendríticas/metabolismo , Masculino , Especificidade de Órgãos , Fosforilação , Inibidores da Síntese de Proteínas/farmacologia , Proteólise , Ratos , Ratos Sprague-Dawley , Tetraetilamônio/farmacologia , Proteína rhoA de Ligação ao GTP/genéticaRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a severe decline of memory performance. A widely studied AD mouse model is the APPswe/PSEN1ΔE9 (APP/PS1) strain, as mice exhibit amyloid plaques as well as impaired memory capacities. To test whether restoring synaptic plasticity and decreasing ß-amyloid load by Parkin could represent a potential therapeutic target for AD, we crossed APP/PS1 transgenic mice with transgenic mice overexpressing the ubiquitin ligase Parkin and analyzed offspring properties. Overexpression of Parkin in APP/PS1 transgenic mice restored activity-dependent synaptic plasticity and rescued behavioral abnormalities. Moreover, overexpression of Parkin was associated with down-regulation of APP protein expression, decreased ß-amyloid load and reduced inflammation. Our data suggest that Parkin could be a promising target for AD therapy.
Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração , Ubiquitina-Proteína Ligases/metabolismo , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Hipocampo/metabolismo , Humanos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Sinaptofisina/metabolismo , Transcrição Gênica , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
Ubiquitous classical (typical) calpains, calpain-1 and calpain-2, are Ca(+2)-dependent cysteine proteases, which have been associated with numerous physiological and pathological cellular functions. However, a clear understanding of the role of calpains in the CNS has been hampered by the lack of appropriate deletion paradigms in the brain. In this study, we describe a unique model of conditional deletion of both calpain-1 and calpain-2 activities in mouse brain, which more definitively assesses the role of these ubiquitous proteases in brain development/function and pathology. Surprisingly, we show that these calpains are not critical for gross CNS development. However, calpain-1/calpain-2 loss leads to reduced dendritic branching complexity and spine density deficits associated with major deterioration in hippocampal long-term potentiation and spatial memory. Moreover, calpain-1/calpain-2-deficient neurons were significantly resistant to injury induced by excitotoxic stress or mitochondrial toxicity. Examination of downstream target showed that the conversion of the Cdk5 activator, p35, to pathogenic p25 form, occurred only in the presence of calpain and that it played a major role in calpain-mediated neuronal death. These findings unequivocally establish two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.
Assuntos
Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Encéfalo , Calpaína/deficiência , Potenciação de Longa Duração/fisiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Biofísica , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/fisiopatologia , Bromodesoxiuridina/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Dendritos/metabolismo , Dendritos/patologia , Dendritos/ultraestrutura , Modelos Animais de Doenças , Estimulação Elétrica , Embrião de Mamíferos , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Hipocampo/citologia , Técnicas In Vitro , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Potenciação de Longa Duração/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , N-Metilaspartato/farmacologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nestina , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Fosfotransferases , Desempenho Psicomotor , RNA Mensageiro/metabolismo , Coloração pela Prata , TransfecçãoRESUMO
Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression.