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The kallikrein-kinin system is a versatile regulatory network implicated in various biological processes encompassing inflammation, nociception, blood pressure control, and central nervous system functions. Its physiological impact is mediated through G-protein-coupled transmembrane receptors, specifically the B1 and B2 receptors. Dopamine, a key catecholamine neurotransmitter widely distributed in the CNS, plays a crucial role in diverse physiological functions including motricity, reward, anxiety, fear, feeding, sleep, and arousal. Notably, the potential physical interaction between bradykinin and dopaminergic receptors has been previously documented. In this study, we aimed to explore whether B2R modulation in catecholaminergic neurons influences the dopaminergic pathway, impacting behavioral, metabolic, and motor aspects in both male and female mice. B2R ablation in tyrosine hydroxylase cells reduced the body weight and lean mass without affecting body adiposity, substrate oxidation, locomotor activity, glucose tolerance, or insulin sensitivity in mice. Moreover, a B2R deficiency in TH cells did not alter anxiety levels, exercise performance, or motor coordination in female and male mice. The concentrations of monoamines and their metabolites in the substantia nigra and cortex region were not affected in knockout mice. In essence, B2R deletion in TH cells selectively influenced the body weight and composition, leaving the behavioral and motor aspects largely unaffected.
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Receptor B2 da Bradicinina , Tirosina 3-Mono-Oxigenase , Camundongos , Masculino , Feminino , Animais , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Bradicinina/farmacologia , Receptor B1 da Bradicinina/metabolismo , Peso Corporal , Camundongos KnockoutRESUMO
Anxiety, a state related to anticipatory fear, can be adaptive in the face of environmental threats or stressors. However, anxiety can also become persistent and manifest as anxiety- and stress-related disorders, such as generalized anxiety or post-traumatic stress disorder (PTSD). In rodents, systemic administration of glucocorticoids (GCs) or short-term restraint stress induces anxiety-like behaviors and dendritic branching within the basolateral complex of the amygdala (BLA) ten days later. Additionally, increased arousal-related memory retention mediated by elevated GCs requires concomitant noradrenaline (NE) signaling, both acting in the BLA. It is unknown whether GCs and NE play a role in the delayed acute stress-induced effects on behavior and BLA dendritic plasticity. Here, inhibiting corticosterone (CORT) elevation during 2 h of restraint stress prevents stress-induced increases in delayed anxiety-like behavior and BLA dendritic spine density in rats. Also, we show that the delayed acute stress-induced effects on behavior and morphological alterations are critically dependent on genomic glucocorticoid receptor (GR) actions in the BLA. Unlike CORT, the pharmacological enhancement of NE signaling in the BLA was insufficient to drive delayed anxiety-related behavior. Nonetheless, the delayed anxiety-like behavior ten days after acute stress requires NE signaling in the BLA during stress exposure. Therefore, we define the essential roles of two stress-related hormones for the late stress consequences, acting at two separate times: CORT, via GR, immediately during stress, and NE, via beta-adrenoceptors, during the expression of delayed anxiety.
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Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and other neuropsychiatric diseases. GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of posttraumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence the development of neuropsychiatric diseases. Here, we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SSTΔGHR mice) caused no alterations in energy or glucose metabolism. Notably, SSTΔGHR male mice exhibited increased anxiety-like behavior in the light-dark box and elevated plus maze tests, whereas SSTΔGHR females showed no changes in anxiety. Using auditory Pavlovian fear conditioning, both male and female SSTΔGHR mice exhibited a significant reduction in fear memory. Conversely, GHR ablation in SST neurons did not affect memory in the novel object recognition test. Gene expression was analyzed in a micro punch comprising the central nucleus of the amygdala (CEA) and basolateral (BLA) complex. GHR ablation in SST neurons caused sex-dependent changes in the expression of factors involved in synaptic plasticity and function. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not female mice. GHR ablation in SST neurons also decreases fear memory and affects gene expression in the amygdala, although marked sex differences were observed. Our findings identified for the first time a neurochemically-defined neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases.SIGNIFICANCE STATEMENT Hormone action in the brain regulates different neurological aspects, affecting the predisposition to neuropsychiatric disorders, like depression, anxiety, and posttraumatic stress disorder. Growth hormone (GH) receptor is widely expressed in the brain, but the exact function of neuronal GH action is not fully understood. Here, we showed that mice lacking the GH receptor in a group of neurons that express the neuropeptide somatostatin exhibit increased anxiety. However, this effect is only observed in male mice. In contrast, the absence of the GH receptor in somatostatin-expressing neurons decreases fear memory, a key feature of posttraumatic stress disorder, in males and females. Thus, our study identified a specific group of neurons in which GH acts to affect the predisposition to neuropsychiatric diseases.
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Hormônio do Crescimento , Somatostatina , Feminino , Masculino , Camundongos , Animais , Somatostatina/metabolismo , Hormônio do Crescimento/metabolismo , Ansiedade , Medo , Receptores da Somatotropina/genética , Receptores da Somatotropina/metabolismo , Neurônios/metabolismoRESUMO
Parkinson's Disease (PD) is a neurogenerative disorder characterized by the death of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), leading to motor, cognitive, learning, and respiratory dysfunctions. New evidence revealed that breathing impairment in PD mainly results from oxidative stress (OS) that initiates apoptotic signaling in respiratory neurons. Here, we investigated the role of OS inhibition using apocynin (non-specific NADPH oxidase inhibitor) in a 6-OHDA PD animal model in the neural control of breathing. The PD model was confirmed with a 70% reduction in TH-expressing neurons within the SNpc. After 20 and 40â¯days of PD induction, no differences were observed in superoxide anion levels in any respiratory nuclei. At 30â¯days after PD induction, 6-OHDA animals presented OS that was prevented in all respiratory nuclei by adding apocynin to the drinking water for 10â¯days. Forty days after PD animal model induction, impaired motor and breathing function, reduced Phox2b and NK1 receptors-expressing neurons in the medullary respiratory areas; decreased latency to fall in the rotarod motor test; and attenuated respiratory frequency and minute ventilation parameters at rest and under hypercapnia conditions were observed. After 20â¯days of apocynin treatment, neurodegeneration of respiratory nuclei and breathing dysfunction in 6-OHDA animals were prevented. Thus, OS contributes to respiratory neuron death, consequently leading to breathing dysfunction in the 6-OHDA PD animal model. Furthermore, these results present a new perspective for preventing the onset and progression of PD-related respiratory impairments.
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Água Potável , Doença de Parkinson , Animais , Oxidopamina/toxicidade , Superóxidos , Neurônios Dopaminérgicos , Modelos Animais de Doenças , NADPH Oxidases , Estresse Oxidativo , Substância NegraRESUMO
Depression and anxiety commonly occur in chronic pain states and the coexistence of these diseases worsens outcomes for both disorders and may reduce treatment adherence and response. Despite the advances in the knowledge of chronic pain mechanisms, pharmacological treatment is still unsatisfactory. Research based on exposure to environmental enrichment is currently under investigation and seems to offer a promising low-cost strategy with no side effects. In this review, we discuss the role of inflammation as a major biological substrate and aetiological factor of chronic pain and depression/anxiety and report a collection of preclinical evidence of the effects and mechanisms of environmental enrichment. As microglia participates in the development of both conditions, we also discuss microglia as a potential target underlying the beneficial actions of environmental enrichment in chronic pain and comorbid depression/anxiety. We also discuss how alternative interventions under clinical guidelines, such as environmental enrichment, may improve treatment compliance and patient outcomes. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.
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Dor Crônica , Transtornos de Ansiedade/terapia , Dor Crônica/tratamento farmacológico , Depressão/tratamento farmacológico , Humanos , Doenças Neuroinflamatórias , NeurofarmacologiaRESUMO
The stress response is multifactorial and enrolls circuitries to build a coordinated reaction, leading to behavioral, endocrine, and autonomic changes. These changes are mainly related to the hypothalamus-pituitary-adrenal (HPA) axis activation and the organism's integrity. However, when self-regulation is ineffective, stress becomes harmful and predisposes the organism to pathologies. The chronic unpredictable stress (CUS) is a widely used experimental model since it induces physiological and behavioral changes and better mimics the stressors variability encountered in daily life. Corticotropin-releasing factor (CRF) and glucocorticoids (GCs) are deeply implicated in the CUS-induced physiological and behavioral changes. Nonetheless, the CUS modulation of CRF receptors and GR and the norepinephrine role in extra-hypothalamic brain areas were not well explored. Here, we show that 14 days of CUS induced a long-lasting HPA axis hyperactivity evidenced by plasmatic corticosterone increase and adrenal gland hypertrophy, which was dependent on both GCs and NE release induced by each stress session. CUS also increased CRF2 mRNA expression and GR protein levels in fundamental brain structures related to HPA regulation and behavior, such as the lateral septal nucleus intermedia part (LSI), ventromedial hypothalamic nucleus (VMH), and central nucleus of the amygdala (CeA). We also showed that NE participates in the CUS-induced increase in CRF2 and GR levels in the LSI, reinforcing the locus coeruleus (LC) involvement in the HPA axis modulation. Despite the CUS-induced molecular changes in essential areas related to anxiety-like behavior, this phenotype was not observed in CUS animals 24 h after the last stress session.
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Encéfalo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/metabolismo , Animais , Doença Crônica , Glucocorticoides/metabolismo , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Estresse Psicológico/psicologiaRESUMO
Depression and anxiety commonly occur in chronic pain states, and the co-existence of these diseases worsen outcomes for both disorders and may reduce treatment adherence and response. Despite the advances in the knowledge of chronic pain mechanisms, pharmacological treatment is still unsatisfactory. Research based on exposure to environmental enrichment (EE) is currently under investigation and seems to offer a promising low-cost strategy with no side effects. In this review, we discuss the role of inflammation as a major biological substrate and aetiological factor of chronic pain and depression/anxiety and report a collection of preclinical evidence of the effects and mechanisms of EE. As microglia participates in the development of both conditions, we also discuss microglia as a potential target underlying the beneficial actions of EE in chronic pain and comorbid depression/anxiety. We also discuss how alternative interventions in clinical guidelines, such as EE, may improve treatment compliance and patient outcomes.
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KEY POINTS: Parkinson's disease (PD) is associated with respiratory dysfunction. In the 6-OHDA rat model of PD this is seen as a reduction in respiratory frequency and minute ventilation during normoxia and hypercapnia stimulus. Respiratory dysfunction is caused by neuronal death of medullary respiratory nuclei in the 6-OHDA model of PD. Oxidative stress can be considered a strong candidate for neurodegeneration via miR-34c downregulation and pro-apoptotic signalling in respiratory neurons, preceding the functional impairment observed in the 6-OHDA model of PD. ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease caused by dopaminergic neuron death in the substantia nigra (SN). New evidence has revealed that this neurodegeneration is the result of complex interactions between genetic abnormalities, environmental toxins, mitochondrial dysfunction and disruption of the blood-brain barrier (BBB) in the SN. In addition to classic symptoms, PD patients also exhibit respiratory failure. Here, we investigated whether oxidative stress was associated with neurodegeneration in a respiratory group (RG) of 6-OHDA-treated rats, which act as a model of PD. We analysed how oxidative stress affected apoptotic signalling in the RG 30 days after 6-OHDA treatment, shortly before commencement of breathing impairment (40 days). After 30 days, a dihydroethidium assay showed increased oxidative stress in the RG, anti-apoptotic signalling, as shown by an increase in p-Akt and BcL-2 and a decrease in Bax in the caudal aspect of the nucleus of the solitary tract (cNTS), and a decrease in p-p38 and Bax levels in the retrotrapezoid nucleus (RTN); pro-apoptotic signalling was indicated by a decrease in p-Akt and BcL-2 and an increase in Bax in the rostral ventral respiratory group (rVRG) and pre-Botzinger complex (preBotC). miR-34c, a known oxidative stress protector, was downregulated in 6-OHDA animals in the RC. After 40 days of 6-OHDA, the NTS, rVRG, preBotC and RTN exhibited reduced NeuN immunoreactivity, no BBB disruption and an increase in thiobarbituric acid reactivity. We conclude that in the 6-OHDA model of PD, oxidative stress contributes to neurodegeneration in medullary respiratory neurons.
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Doenças Neurodegenerativas , Doença de Parkinson , Animais , Neurônios Dopaminérgicos , Humanos , Estresse Oxidativo , Oxidopamina/toxicidade , Ratos , Substância NegraRESUMO
Previous studies suggested the pharmacological potential of rat hemopressin (PVNFKFLSH) and its shorter synthetic peptide NFKF, to protect from pilocarpine-induced seizures in mice. Orally administered NFKF was shown to be hundred times more potent than cannabidiol in delaying the first seizure induced by pilocarpine in mice. Here, using an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis we have shown that C57BL/6 J mice orally administrated with NFKF (500 µg/kg) presented better EAE clinical scores and improved locomotor activity compared to saline administrated control mice. NFKF blocked the production of IL-1beta and IL-6, and has high scores binding cannabinoid type 2 receptors. Therefore, NFKF is an exciting new possibility to neurodegenerative diseases therapeutics.
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Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/prevenção & controle , Hemoglobinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Animais , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Hemoglobinas/química , Hemoglobinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular/métodos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , RatosRESUMO
Previous studies suggested the pharmacological potential of rat hemopressin (PVNFKFLSH) and its shorter synthetic peptide NFKF, to protect from pilocarpine-induced seizures in mice. Orally administered NFKF was shown to be hundred times more potent than cannabidiol in delaying the first seizure induced by pilocarpine in mice. Here, using an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis we have shown that C57BL/6J mice orally administrated with NFKF (500µg/kg) presented better EAE clinical scores and improved locomotor activity compared to saline administrated control mice. NFKF blocked the production of IL-1beta and IL-6, and has high scores binding cannabinoid type 2 receptors. Therefore, NFKF is an exciting new possibility to neurodegenerative diseases therapeutics.
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Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1-/-) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies per litter similar to C57BL/6 wild type mice (WT). In specific brain regions, THOP1-/- exhibit altered mRNA expression of proteasome beta5, serotonin 5HT2a receptor and dopamine D2 receptor, but not of neurolysin (NLN). Peptidomic analysis identifies differences in intracellular peptide ratios between THOP1-/- and WT mice, which may affect normal cellular functioning. In an experimental model of multiple sclerosis THOP1-/- mice present worse clinical behavior scores compared to WT mice, corroborating its possible involvement in neurodegenerative diseases. THOP1-/- mice also exhibit better survival and improved behavior in a sepsis model, but also a greater peripheral pain sensitivity measured in the hot plate test after bradykinin administration in the paw. THOP1-/- mice show depressive-like behavior, as well as attention and memory retention deficits. Altogether, these results reveal a role of THOP1 on specific behaviors, immune-stimulated neurodegeneration, and infection-induced inflammation.
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Metaloendopeptidases/metabolismo , Animais , Comportamento Animal , Feminino , Masculino , Metaloendopeptidases/deficiência , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , FenótipoRESUMO
BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the CNS, characterized by demyelination, focal inflammatory infiltrates and axonal damage. Oxidative stress has been linked to MS pathology. Previous studies have suggested the involvement of NADPH oxidase 2 (Nox2), an enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, in the MS pathogenesis. The mechanisms of Nox2 activation on MS are unknown. The purpose of this study was to investigate the effect of Nox2 deletion on experimental autoimmune encephalomyelitis (EAE) onset and severity, on astrocyte activation as well as on pro-inflammatory and anti-inflammatory cytokine induction in striatum and motor cortex. METHODOLOGY: Subcutaneous injection of MOG35-55 emulsified with complete Freund's adjuvant was used to evaluate the effect of Nox2 depletion on EAE-induced encephalopathy. Striatum and motor cortices were isolated and evaluated by immunoblotting and RT-PCR. RESULTS: Nox2 deletion resulted in clinical improvement of the disease and prevented astrocyte activation following EAE induction. Nox2 deletion prevented EAE-induced induction of pro-inflammatory cytokines and stimulated the expression of the anti-inflammatory cytokines IL-4 and IL-10. CONCLUSIONS: Our data suggest that Nox2 is involved on the EAE pathogenesis. IL-4 and IL-10 are likely to be involved on the protective mechanism observed following Nox2 deletion.
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Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1-/-) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies per litter similar to C57BL/6 wild type mice (WT). In specific brain regions, THOP1-/- exhibit altered mRNA expression of proteasome beta5, serotonin 5HT2a receptor and dopamine D2 receptor, but not of neurolysin (NLN). Peptidomic analysis identifies differences in intracellular peptide ratios between THOP1-/- and WT mice, which may affect normal cellular functioning. In an experimental model of multiple sclerosis THOP1-/- mice present worse clinical behavior scores compared to WT mice, corroborating its possible involvement in neurodegenerative diseases. THOP1-/- mice also exhibit better survival and improved behavior in a sepsis model, but also a greater peripheral pain sensitivity measured in the hot plate test after bradykinin administration in the paw. THOP1-/- mice show depressive-like behavior, as well as attention and memory retention deficits. Altogether, these results reveal a role of THOP1 on specific behaviors, immune-stimulated neurodegeneration, and infection-induced inflammation.
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We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN) of wild-type (wt) mice after PD induction. Gp91(phox-/-) 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA) neurons in the SN of wt mice. In gp91(phox-/-) 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91(phox-/-) 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91(phox-/-)-lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91(phox-/-) 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91(phox-/-) 6-OHDA lesioned mice, a likely mechanism whereby gp91(phox-/-) 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction.
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Microglia/patologia , NADPH Oxidases/genética , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Oxidopamina/farmacologia , Doença de Parkinson/patologia , Animais , Apomorfina/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Inflamação/genética , Inflamação/patologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Minociclina/farmacologia , NADH NADPH Oxirredutases/genética , NADPH Oxidase 1 , NADPH Oxidase 2 , NF-kappa B/genética , Degeneração Neural/genética , Doença de Parkinson/genética , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND/AIM: Nitric oxide (NO) modulates the expression of the chaperone Hsp72 in the heart, and exercise stimulates both NO production and myocardial Hsp72 expression. The main purpose of the study was to investigate whether NO interferes with an exercise-induced myocardial Hsp72 expression. METHODS: Male Wistar rats (70-100 days) were divided into control (C, n=12), L-NAME-treated (L, n=12), exercise (E, n=13) and exercise plus L-NAME-treated (EL, n=20) groups. L-NAME was given in drinking water (700 mg·L(-1)) and the exercise was performed on a treadmill (15-25 m·min(-1), 40-60 min.day(-1)) for seven days. Left ventricle (LV) protein Hsp content, NOS and phosphorylated-NOS (p-NOS) isoforms were measured using Western blotting. The activity of NOS was assayed in LV homogenates by the conversion of [(3)H]L-arginine to [(3)H]L-citrulline. RESULTS: Hsp72 content was increased significantly (223%; p < 0.05) in the E group compared to the C group, but exercise alone did not alter the NOS content, p-NOS isoforms or NOS activity. Contrary to our expectation, L-NAME enhanced (p < 0.05) the exercise-induced Hsp72 content (EL vs. C, L and E groups = 1019%, 548% and 457%, respectively). Although the EL group had increased stimulatory p-eNOS(Ser1177) (over 200%) and decreased inhibitory p-nNOS(Ser852) (ñ50%) compared to both the E and L groups (p < 0.05), NOS activity was similar in all groups. CONCLUSIONS: Our results suggest that exercise-induced cardiac Hsp72 expression does not depend on NO. Conversely, the in vivo L-NAME treatment enhances exercise-induced Hsp72 production. This effect may be due to an increase in cardiac stress.
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Proteínas de Choque Térmico HSP72/biossíntese , Ventrículos do Coração/enzimologia , Atividade Motora/fisiologia , Miocárdio/enzimologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/biossíntese , Óxido Nítrico Sintase Tipo I/biossíntese , Óxido Nítrico/metabolismo , Animais , Arginina/metabolismo , Western Blotting , Citrulina/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Fosforilação , Ratos , Ratos Wistar , Trítio/análise , Trítio/metabolismoRESUMO
Dental anxiety is still prevalent, despite advances in treatment, and affects the utilization of health care services. The purpose of this cross-sectional study was to determine if patients with different degrees of dental anxiety and pain undergoing emergency dental care have different stress reactions as measured by salivary cortisol. Seventy three patients completed the modified dental anxiety scale (MDAS), and described any previous dental traumatic experience. Their socio-demographic characteristics were also recorded. They also rated pain intensity on a 100 mm visual analogue scale (VAS). A saliva sample was collected before the procedure, and analyzed by enzyme immunoassay. Thirty patients were dentally anxious and forty one complained of pain. In this sample, dental anxiety was not related to gender, age, educational level and family income; however, a previous traumatic event was related to dental anxiety. There was no association between salivary cortisol concentrations and gender or dental anxiety. Patients with pain showed higher cortisol levels. When gathering patient information, the dentist should note patients' negative dental experiences in order to provide more effective, less traumatic treatment.
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Ansiedade ao Tratamento Odontológico/metabolismo , Ansiedade ao Tratamento Odontológico/psicologia , Assistência Odontológica/psicologia , Hidrocortisona/metabolismo , Aprendizagem da Esquiva , Estudos Transversais , Tratamento de Emergência , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Técnicas Imunoenzimáticas , Masculino , Escala de Ansiedade Manifesta , Memória , Pessoa de Meia-Idade , Medição da Dor , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/química , Estresse Psicológico/metabolismoRESUMO
Cocaine is a worldwide used drug and its abuse is associated with physical, psychiatric and social problems. The mechanism by which cocaine causes neurological damage is very complex and involves several neurotransmitter systems. For example, cocaine increases extracellular levels of dopamine and free radicals, and modulates several transcription factors. NF-kappaB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-kappaB activity by cocaine in PC 12 cells. Treatment with cocaine (1 mM) for 24 hours induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial activity. A decrease in Bcl-2 protein and mRNA levels, and an increase in caspase 3 activity and cleavage were also observed. In addition, cocaine (after 6 hours treatment) activated the p50/p65 subunit of NF-kappaB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-kappaB activation. Inhibition of NF-kappaB activity by using PDTC and Sodium Salicilate increased cell death caused by cocaine. These results suggest that cocaine induces cell death (apoptosis and necrosis) and activates NF-kappaB in PC12 cells. This activation occurs, at least partially, due to activation of D1 receptors and seems to have an anti-apoptotic effect on these cells.
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Cocaína/toxicidade , NF-kappa B/metabolismo , Animais , Benzazepinas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cocaína/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas I-kappa B/metabolismo , Modelos Biológicos , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , Células PC12 , Prolina/análogos & derivados , Prolina/farmacologia , Ligação Proteica/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Salicilato de Sódio/farmacologia , Espectrina/metabolismo , Tiocarbamatos/farmacologia , Fatores de TempoRESUMO
The presence of the epsilon4 allele of apolipoprotein E (APOE) is considered a risk factor for sporadic Alzheimer's disease (AD). Our recent data demonstrated that the systemic modulation of oxidative stress in platelets and erythrocytes is disrupted in aging and AD. In this study, the relationship between APOE genotype and oxidative stress markers, both in AD patients and controls, was evaluated. The AD group showed an increase in the content of thiobarbituric acid-reactive substances (TBARS) and in the activities of nitric oxide synthase (NOS) and Na, K-ATPase, when compared to controls. Both groups had a similar cGMP content and superoxide dismutase activity. APOE epsilon4 allele carriers showed higher NOS activity than non-carriers. These results suggest a possible influence of APOE genotype on nitric oxide (NO) production that might enhance the effects of age-related specific factor(s) associated with neurodegenerative disorders.
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Apolipoproteínas E/genética , Plaquetas/metabolismo , Óxido Nítrico/metabolismo , Alelos , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Eritrócitos/metabolismo , Genótipo , Humanos , Óxido Nítrico Sintase/genética , Estresse Oxidativo , Fatores de Risco , ATPase Trocadora de Sódio-Potássio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
The aim of the present study was to evaluate the effect of overstimulation of beta-adrenoceptors on vascular inflammatory mediators. Wistar rats were treated with the beta-adrenoceptor agonist isoproterenol (0.3 mg.kg(-1).day(-1) sc) or vehicle (control) for 7 days. At the end of treatment, the right carotid artery was catheterized for arterial and left ventricular (LV) hemodynamic evaluation. Isoproterenol treatment increased LV weight but did not change hemodynamic parameters. Aortic mRNA and protein expression were quantified by real-time RT-PCR and Western blot analysis, respectively. Isoproterenol enhanced aortic mRNA and protein expression of IL-1beta (124% and 125%) and IL-6 (231% and 40%) compared with controls but did not change TNF-alpha expression. The nuclear-to-cytoplasmatic protein expression ration of the NF-kappaB p65 subunit was increased by isoproterenol treatment (51%); in addition, it reduced the cytoplasmatic expression of IkappaB-alpha (52%) in aortas. An electrophoretic mobility shift assay was performed using the aorta, and increased NF-kappaB DNA binding (31%) was observed in isoproterenol-treated rats compared with controls (P < 0.05). Isoproterenol treatment increased phenylephrine-induced contraction in aortic rigs (P < 0.05), which was significantly reduced by superoxide dismutase (150 U/ml) and sodium salicylate (5 mM). Cotreatment with thalidomide (150 mg.kg(-1).day(-1) for 7 days) also reduced hyperreactivity to phenylephrine induced by isoproterenol. In conclusion, overstimulation of beta-adrenoceptors increased proinflammatory cytokines and upregulated NF-kappaB in the rat aorta. Moreover, local oxidative stress and the proinflammatory state seem to play key roles in the altered vascular reactivity of the rat aorta induced by chronic beta-adrenergic stimulation.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Aorta/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Isoproterenol/farmacologia , Acetilcolina/farmacologia , Agonistas Adrenérgicos beta/administração & dosagem , Animais , Aorta/metabolismo , Western Blotting , Relação Dose-Resposta a Droga , Ensaio de Desvio de Mobilidade Eletroforética , Hemodinâmica/efeitos dos fármacos , Proteínas I-kappa B/metabolismo , Injeções Subcutâneas , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Isoproterenol/administração & dosagem , Masculino , Inibidor de NF-kappaB alfa , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Salicilato de Sódio/farmacologia , Superóxido Dismutase/metabolismo , Talidomida/farmacologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologiaRESUMO
We investigated whether angiotensin II infusion modulates in vivo the kinin B1 receptor expression and the mechanisms involved in this process. We also evaluated the role of the B1 receptor activation in aorta. Wistar rats received 400 ng/kg per minute of angiotensin II or saline (control rats) infusion during 14 days through an osmotic minipump. To investigate the role of superoxide anion in B1 receptor expression, rats received a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor in the drinking water during 14 days (60 mg/L of apocynin) simultaneously with angiotensin II infusion. Angiotensin II induced B1 receptor expression in the aorta and increased significantly systolic blood pressure, superoxide anion, and the nuclear factor kappaB activity. Apocynin treatment did not alter the blood pressure levels of angiotensin II rats and reduced the B1 receptor expression, superoxide anion generation, and nuclear factor kappaB activity to similar levels of the control rats. Vascular reactivity studies in isolated aorta reveal that B1 receptor agonist promoted endothelium-dependent dilation and increased the NO generation in aorta of angiotensin II rats. NO synthase inhibitor and B1 receptor antagonist inhibited the vasodilation and NO generation, which were not affected by B2 receptor antagonist or indomethacin. These results provide evidence that angiotensin II induces B1 receptor expression in aorta by superoxide anion generation, via reduced nicotinamide-adenine dinucleotide phosphate oxidase, concomitant to nuclear factor kappaB activation. We have also shown that B1 receptor agonist causes endothelium-dependent vasodilation through NO production in aortic rings, suggesting that the B1 receptor expression could be related with the vascular tonus control of angiotensin II rats.