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1.
Int J Mol Sci ; 21(8)2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331300

RESUMO

A large percentage of primary sensory neurons in the trigeminal ganglia (TG) contain neuropeptides such as tachykinins or calcitonin gene-related peptide. Neuropeptides released from the central terminals of primary afferents sensitize the secondary nociceptive neurons in the trigeminal nucleus caudalis (TNC), but also activate glial cells contributing to neuroinflammation and consequent sensitization in chronic orofacial pain and migraine. In the present study, we investigated the newest member of the tachykinin family, hemokinin-1 (HK-1) encoded by the Tac4 gene in the trigeminal system. HK-1 had been shown to participate in inflammation and hyperalgesia in various models, but its role has not been investigated in orofacial pain or headache. In the complete Freund's adjuvant (CFA)-induced inflammatory orofacial pain model, we showed that Tac4 expression increased in the TG in response to inflammation. Duration-dependent Tac4 upregulation was associated with the extent of the facial allodynia. Tac4 was detected in both TG neurons and satellite glial cells (SGC) by the ultrasensitive RNAscope in situ hybridization. We also compared gene expression changes of selected neuronal and glial sensitization and neuroinflammation markers between wild-type and Tac4-deficient (Tac4-/-) mice. Expression of the SGC/astrocyte marker in the TG and TNC was significantly lower in intact and saline/CFA-treated Tac4-/- mice. The procedural stress-related increase of the SGC/astrocyte marker was also strongly attenuated in Tac4-/- mice. Analysis of TG samples with a mouse neuroinflammation panel of 770 genes revealed that regulation of microglia and cytotoxic cell-related genes were significantly different in saline-treated Tac4-/- mice compared to their wild-types. It is concluded that HK-1 may participate in neuron-glia interactions both under physiological and inflammatory conditions and mediate pain in the trigeminal system.

2.
Sci Rep ; 9(1): 14598, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601840

RESUMO

Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca2+-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.

3.
Front Aging Neurosci ; 11: 274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31649527

RESUMO

Corticotropin-releasing factor (CRF) immunoreactive (ir) neurons of the paraventricular nucleus of the hypothalamus (PVN) play pivotal role in the coordination of stress response. CRF-producing cells in the central nucleus of amygdala (CeA) and oval division of the bed nucleus of stria terminalis (BNSTov) are also involved in stress adaptation and mood control. Immediate early gene products, subunits of the transcription factor activator protein 1 (AP1) are commonly used as acute (FOS) and/or chronic (FOSB/deltaFOSB) markers for the neuronal activity in stress research. It is well known that the course of aging affects stress adaptation, but little is known about the aging-related stress sensitivity of CRF neurons. To the best of our knowledge, the stress-induced neuronal activity of CRF neurons in the course of aging in acute and chronic stress models was not studied systematically yet. Therefore, the aim of the present study was to quantify the acute restraint stress (ARS) and chronic variable mild stress (CVMS) evoked neuronal activity in CRF cells of the PVN, CeA, and BNSTov using triple-label immunofluorescence throughout the whole lifespan in the rat. We hypothesized that the FOS and FOSB content of CRF cells upon ARS or CVMS decreases with age. Our results showed that the FOS and FOSB response to ARS declined with age in the PVN-CRF cells. BNSTov and CeA CRF cells did not show remarkable stress-induced elevation of these markers neither in ARS, nor in CVMS. Exposure to CVMS resulted in an age-independent significant increase of FOSB/delta FOSB immunosignal in PVN-CRF neurons. Unexpectedly, we detected a remarkable stress-independent FOSB/deltaFOSB signal in CeA- and BNSTov-CRF cells that declined with the course of aging. In summary, PVN-CRF cells show decreasing acute stress sensitivity (i.e., FOS and FOSB immunoreactivity) with the course of aging, while their (FOSB/deltaFOSB) responsivity to chronic challenge is maintained till senescence. Stress exposure does not affect the occurrence of the examined Fos gene products in CeA- and BNSTov-CRF cells remarkably suggesting that their contribution to stress adaptation response does not require AP1-controlled transcriptional changes.

4.
Orv Hetil ; 160(35): 1366-1375, 2019 Sep.
Artigo em Húngaro | MEDLINE | ID: mdl-31448646

RESUMO

Cardiac autonomic neuropathy (CAN) is a common complication in type 1 and 2 diabetes and is defined as the impairment of autonomic control of the cardiovascular system. CAN is strongly associated with increased mortality, and in some studies with morbidity of vascular complications, such as stroke, coronary artery disease and myocardial infarction. At the early stages, CAN can be subclinical and it becomes clinically evident as the disease progresses. Subclinically, the disease is defined by cardiovascular reflex testing, which may have prognostic implications. Clinically, the impairment in autonomic function is associated with resting tachycardia, exercise intolerance, orthostatic hypotension, syncope, intraoperative cardiovascular instability, silent myocardial infarction and ischemia, and increased mortality. Although very common and serious, CAN is a frequently overlooked complication of diabetes. Because the progression of cardiovascular denervation is partly reversible or can be slowed down in the early stages of the disease, recent guidelines strongly recommend screening for CAN in patients with diabetes. In this review we summarize the diagnostic tools suggested in the screening for diabetic CAN. Orv Hetil. 2019; 160(35): 1366-1375.


Assuntos
Doenças do Sistema Nervoso Autônomo/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/diagnóstico , Neuropatias Diabéticas/diagnóstico , Cardiopatias/complicações , Doenças do Sistema Nervoso Autônomo/complicações , Neuropatias Diabéticas/complicações , Coração/inervação , Humanos
5.
Brain Res Bull ; 147: 165-173, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30664920

RESUMO

The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice. Chronic neuropathic mechanical and cold hyperalgesia after partial sciatic nerve ligation (PSL) were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate. Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any changes. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of wildtype, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion. We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research.

6.
J Mol Neurosci ; 68(3): 368-376, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29353438

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide having neurotrophic, neuroprotective, and general cytoprotective actions in a variety of tissues based on its anti-apoptotic, anti-inflammatory, and antioxidant effects. Several studies have demonstrated its cardioprotective effects in vitro and in various animal models. However, few data are available on the presence of PACAP in human cardiac tissues and its role in the pathomechanism and progression of different cardiac disorders, particularly heart failure. Earlier, our research group has shown PAC1 receptor immunoreactivity in human heart tissue samples and we have found significantly elevated PACAP27- and PACAP38-like immunoreactivity in ischemic cardiac samples compared to valvular abnormalities with radioimmunoassay. In the last few years, numerous studies examined the presence and the changes of PACAP levels in different human tissue samples and biological fluids to show alterations in different physiological and pathological conditions. Therefore, the aim of the present study was to measure the alterations of blood PACAP levels in chronic heart failure caused by primary dilated cardiomyopathy or ischemic cardiomyopathy and to examine the possible relationship between serum levels of PACAP, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systolic left ventricular function, the most reliable biomarkers of heart failure. In the group of mild heart failure patients, a significant strong negative correlation was detected. Furthermore, in moderate heart failure, we found a significant moderate negative correlation between PACAP and NT-proBNP levels only in ischemic subgroup. Positive correlation was found between serum PACAP level and ejection fraction only in patients with heart failure due to ischemic cardiomyopathy but not in patients with primary dilated cardiomyopathy. In summary, remarkable differences were observed between the ischemic and non-ischemic heart failure suggesting that PACAP might play an important role in the pathomechanism and progression of ischemic heart failure and it might be a potential biomarker of cardiac diseases in the future.


Assuntos
Cardiomiopatia Dilatada/sangue , Insuficiência Cardíaca/sangue , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/sangue , Idoso , Biomarcadores/sangue , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/fisiopatologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Precursores de Proteínas/sangue , Função Ventricular Esquerda
7.
Front Aging Neurosci ; 10: 248, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186150

RESUMO

The hypothalamus-pituitary-adrenal axis (HPA) is the main regulator of the stress response. The key of the HPA is the parvocellular paraventricular nucleus of the hypothalamus (pPVN) controlled by higher-order limbic stress centers. The reactivity of the HPA axis is considered to be a function of age, but to date, little is known about the background of this age-dependency. Sporadic literature data suggest that the stress sensitivity as assessed by semi-quantitation of the neuronal activity marker c-Fos may also be influenced by age. Here, we aimed at investigating the HPA activity and c-Fos immunoreactivity 2 h after the beginning of a single 60 min acute restraint stress in eight age groups of male Wistar rats. We hypothesized that the function of the HPA axis (i.e., pPVN c-Fos and blood corticosterone (CORT) level), the neuronal activity of nine stress-related limbic areas (i.e., magnocellular PVN (mPVN), medial (MeA), central (CeA), basolateral nuclei of the amygdala, the oval (ovBNST), dorsolateral (dlBNST), dorsomedial (dmBNST), ventral and fusiform (fuBNST) divisions of the bed nucleus of the stria terminalis (BNST)), and two brainstem stress centers such as the centrally projecting Edinger-Westphal nucleus (cpEW) and dorsal raphe nucleus (DR) show age dependency in their c-Fos response. The somatosensory barrel cortex area (S1) was evaluated to test whether the age dependency is specific for stress-centers. Our results indicate that the stress-induced rise in blood CORT titer was lower in young age reflecting relatively low HPA activity. All 12 stress-related brain areas showed c-Fos response that peaked at 2 months of age. The magnitude of c-Fos immunoreactivity correlated negatively with age in seven regions (MeA, CeA, ovBNST, dlBNST, dmBNST, fuBNST and pPVN). Unexpectedly, the CeA, ovBNST and cpEW showed a considerable basal c-Fos expression in 1-month-old rats which decreased with age. The S1 showed a U-shaped age-related dynamics in contrast to the decline observed in stress centers. We conclude that the age- and brain area dependent dynamics in stress-induced neuronal activity pattern may contribute to the age dependance of the stress reactivity. Further studies are in progress to determine the neurochemical identity of neurons showing age-dependent basal and/or stress-induced c-Fos expression.

8.
J Gerontol A Biol Sci Med Sci ; 73(4): 438-445, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29099963

RESUMO

Appearance of middle-aged obesity and aging anorexia both in humans and rodents suggests a role for regulatory alterations. Hypothalamic melanocortin agonist, α-melanocyte-stimulating hormone (α-MSH) produced in the arcuate nucleus (ARC), reduces body weight via inducing hypermetabolism and anorexia mainly through melanocortin 4 receptors (MC4Rs) in the paraventricular nucleus (PVN). Orexigenic ARC-derived agouti-related protein (AgRP) is an inverse agonist on MC4R in the PVN. Previously, we demonstrated that characteristic age-related shifts in the catabolic effects of α-MSH may contribute both to middle-aged obesity and aging anorexia. Responsiveness to α-MSH decreases in middle-aged rats compared with young adults, whereas in old age it rises again significantly. We hypothesized corresponding age-related dynamics of endogenous melanocortins. Therefore, we quantified mRNA gene expression and peptide or protein level of α-MSH, AgRP, and MC4R in the ARC and PVN of male Wistar rats of five age groups (from young to old). Immunofluorescence and quantitative reverse transcriptase polymerase chain reaction were applied. α-MSH and MC4R immunoreactivities in the ARC and PVN declined in middle-aged and increased together with their expressions in aging rats. AgRP gene expression but not its immunoreactivity increased in aging rats. Our results demonstrate that age-dependent changes of endogenous melanocortins contribute to middle-aged obesity and aging anorexia.


Assuntos
Anorexia/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Melanocortinas/metabolismo , Obesidade/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , alfa-MSH/farmacologia , Fatores Etários , Proteína Relacionada com Agouti/metabolismo , Animais , Peso Corporal , Calorimetria Indireta , Ingestão de Alimentos/efeitos dos fármacos , Imunofluorescência , Expressão Gênica , Imuno-Histoquímica , Masculino , Microscopia Confocal , Modelos Animais , Consumo de Oxigênio , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
9.
J Comp Eff Res ; 6(8): 649-657, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29148291

RESUMO

Aim & methods: This 6-month prospective, observational, noninterventional, open-label clinical study assessed the effectiveness/safety of trimetazidine in 737 patients with stable angina pectoris and Type 2 diabetes mellitus (OGYI/51534-1/2014). RESULTS: Trimetazidine-based therapy was effective in stable coronary artery disease, with significant improvements from baseline (p < 0.05) in: number of angina attacks/week (2.9 ± 2.4 vs 1.1 ± 1.6), angina severity (Canadian Cardiovascular Society Classification 1.9 ± 0.8 vs 1.2 ± 0.8), exercise capacity (metabolic equivalents 6.1 ± 1.7 vs 6.5 ± 1.7), and exercise-induced myocardial ischemia (min 5.5 ± 2.5 vs 6.5 ± 2.6). DISCUSSION: Trimetazidine treatment significantly (p < 0.05) improved glucose metabolism, lowered HbA1c (7.1 ± 1.1% vs 6.6 ± 1.0%), glucose levels (7.7 ± 2.1 mmol/l vs 6.9 ± 1.6 mmol/l) and decreased arterial stiffness (pulse wave velocity 11.2 ± 2.1 m/s vs 10.4 ± 2.2 m/s). In most patients, the tolerability of trimetazidine was rated as excellent to good, with a low incidence of adverse events.


Assuntos
Angina Estável/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Trimetazidina/administração & dosagem , Vasodilatadores/administração & dosagem , Idoso , Canadá , Doença da Artéria Coronariana/tratamento farmacológico , Esquema de Medicação , Feminino , Humanos , Masculino , Isquemia Miocárdica/tratamento farmacológico , Estudos Prospectivos , Análise de Onda de Pulso , Trimetazidina/efeitos adversos , Vasodilatadores/efeitos adversos
10.
Neuroscience ; 354: 11-29, 2017 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-28450265

RESUMO

Major depression is a common cause of chronic disability. Despite decades of efforts, no equivocally accepted animal model is available for studying depression. We tested the validity of a new model based on the three-hit concept of vulnerability and resilience. Genetic predisposition (hit 1, mutation of pituitary adenylate cyclase-activating polypeptide, PACAP gene), early-life adversity (hit 2, 180-min maternal deprivation, MD180) and chronic variable mild stress (hit 3, CVMS) were combined. Physical, endocrinological, behavioral and functional morphological tools were used to validate the model. Body- and adrenal weight changes as well as corticosterone titers proved that CVMS was effective. Forced swim test indicated increased depression in CVMS PACAP heterozygous (Hz) mice with MD180 history, accompanied by elevated anxiety level in marble burying test. Corticotropin-releasing factor neurons in the oval division of the bed nucleus of the stria terminalis showed increased FosB expression, which was refractive to CVMS exposure in wild-type and Hz mice. Urocortin1 neurons became over-active in CMVS-exposed PACAP knock out (KO) mice with MD180 history, suggesting the contribution of centrally projecting Edinger-Westphal nucleus to the reduced depression and anxiety level of stressed KO mice. Serotoninergic neurons of the dorsal raphe nucleus lost their adaptation ability to CVMS in MD180 mice. In conclusion, the construct and face validity criteria suggest that MD180 PACAP HZ mice on CD1 background upon CVMS may be used as a reliable model for the three-hit theory.


Assuntos
Depressão/etiologia , Depressão/genética , Modelos Animais de Doenças , Mutação/genética , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Adaptação Ocular/fisiologia , Glândulas Suprarrenais/patologia , Animais , Animais Recém-Nascidos , Peso Corporal/genética , Hormônio Liberador da Corticotropina/sangue , Hormônio Liberador da Corticotropina/metabolismo , Depressão/sangue , Depressão/patologia , Comportamento Exploratório/fisiologia , Feminino , Masculino , Privação Materna , Camundongos , Camundongos Knockout , Núcleos da Rafe/patologia , Núcleos Septais/patologia , Estresse Psicológico/complicações , Natação/psicologia
11.
Geroscience ; 39(1): 61-72, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28299639

RESUMO

Hypothalamic corticotropin-releasing factor (CRF) lays downstream to catabolic melanocortins and at least partly mediates their catabolic effects. Age-related changes in the melanocortin system (weak responsiveness in middle-aged and a strong one in old rats) have been shown to contribute to middle-aged obesity and later to aging anorexia and cachexia of old age groups. We hypothesized that catabolic (anorexigenic and hypermetabolic) CRF effects vary with aging similarly to those of melanocortins. Thus, we aimed to test whether age-related variations of CRF effects may also contribute to middle-aged obesity and aging anorexia leading to weight loss of old age groups. Food intake, body weight, core temperature, heart rate, and activity were recorded in male Wistar rats of young, middle-aged, aging, and old age groups (from 3 to 24 months) during a 7-day intracerebroventricular CRF infusion (0.2 µg/µl/h) in a biotelemetric system. In addition, CRF gene expression was also assessed by quantitative RT-PCR in the paraventricular nucleus (PVN) of intact animals of the same age groups. The infusion suppressed body weight in the young, aging, and old rats, but not in middle-aged animals. Weak anorexigenic and hypermetabolic effects were detected in the young, whereas strong anorexia (without hypermetabolism) developed in the oldest age groups in which post mortem analysis showed also a reduction of retroperitoneal fat mass. CRF gene expression in the PVN increased with aging. Our results support the potential contribution of age-related changes in CRF effects to aging anorexia and cachexia. The role of the peptide in middle-aged obesity cannot be confirmed.


Assuntos
Envelhecimento/genética , Anorexia/metabolismo , Caquexia/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Fatores Etários , Envelhecimento/efeitos dos fármacos , Animais , Anorexia/fisiopatologia , Peso Corporal , Caquexia/fisiopatologia , Hormônio Liberador da Corticotropina/genética , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Infusões Parenterais , Leptina/metabolismo , Masculino , Modelos Animais , RNA/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sensibilidade e Especificidade
12.
Neuropharmacology ; 118: 26-37, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28267582

RESUMO

The role of the urocortin 1 (Ucn1) expressing centrally projecting Edinger-Westphal (EWcp) nucleus in energy homeostasis and stress adaptation response has previously been investigated. Morphological and functional studies have proven that orexigenic and anorexigenic peptidergic afferents and receptors for endocrine messengers involved in the energy homeostasis are found in the EWcp. The central role of the hypothalamic melanocortin system in energy homeostasis is well known, however, no data have been published so far on possible crosstalk between melanocortins and EWcp-Ucn1. First, we hypothesized that members of the melanocortin system [i.e. alpha-melanocyte stimulating hormone (alpha-MSH), agouti-related peptide (AgRP), melanocortin 4 receptor (MC4R)] would be expressed in the EWcp. Second, we put forward, that alpha-MSH and AgRP contents as well as neuronal activity and Ucn1 peptide content of the EWcp would be affected by fasting. Third, we assumed that the intra-EWcp injections of exogenous MC4R agonists and antagonist would cause food intake-related and metabolic changes. Ucn1 neurons were found to carry MC4Rs, and they were contacted both by alpha-MSH and AgRP immunoreactive nerve fibers in the rat. The alpha-MSH immunosignal was reduced, while that of AgRP was increased upon starvation. These were associated with the elevation of FosB and Ucn1 expression. The intra-EWcp administration of MC4R blocker (i.e. HS024) had a similar, but enhanced effect on FosB and Ucn1. Furthermore, alpha-MSH injected into the EWcp had anorexigenic effect, increased oxygen consumption and caused peripheral vasodilation. We conclude that the melanocortin system influences the EWcp that contributes to energy-homeostasis.


Assuntos
Núcleo de Edinger-Westphal/citologia , Homeostase/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Receptor Tipo 4 de Melanocortina , Urocortinas/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Vias de Administração de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Jejum , Ligantes , Masculino , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/fisiologia , Proteínas Oncogênicas v-fos/metabolismo , Peptídeos Cíclicos/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , alfa-MSH/metabolismo , alfa-MSH/farmacologia
13.
Int J Mol Sci ; 18(2)2017 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-28216584

RESUMO

Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson's disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life.


Assuntos
Meio Ambiente , Doença de Parkinson/etiologia , Animais , Comportamento Animal , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Neuroproteção , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fenótipo , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
14.
Neuroscience ; 346: 320-336, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28161436

RESUMO

The somatostatin 4 receptor (sst4) is widely expressed in stress-related brain areas (e.g. hippocampus, amygdala) and regulates the emotional behavior in acute situations. Since its importance in chronic stress-induced complex pathophysiological alterations is unknown, we investigated the involvement of sst4 in the responsiveness to chronic variable stress (CVS). Sstr4 gene-deficient (Sstr4-/-) mice and their wildtype counterparts (Sstr4+/+) were used to examine the behavioral and neuroendocrine alterations as well as chronic neuronal activity (FosB expression) changes in response to CVS. In Sstr4+/+ mice, there was no behavioral response to the applied CVS paradigm. In contrast, immobility time in the tail suspension test increased after the CVS in the knockouts. In the forced swim test, Sstr4-/- animals showed increased baseline immobility and then it decreased after the CVS. Light-dark box and open field test behaviors and sucrose preference did not respond to the stress in the knockouts. Adrenal weights increased and thymus weights decreased in both Sstr4+/+ and Sstr4-/- mice demonstrating the effect of chronic stress. The relative adrenal weight of stressed knockouts increased to a greater extent, while relative thymus and body weights decreased only in the Sstr4-/- mice. Basal plasma corticosterone concentrations did not change after the CVS in either genotype. FosB immunopositivity in the central and basolateral amygdaloid nuclei was enhanced in stressed knockouts, but not in wild types. This is the first evidence that sst4 activation is involved in the behavioral and neuroendocrine alterations induced by chronic stress with a crucial role of plastic changes in the amygdala.


Assuntos
Encéfalo/fisiopatologia , Sistemas Neurossecretores/fisiopatologia , Receptores de Somatostatina/fisiologia , Estresse Psicológico/fisiopatologia , Glândulas Suprarrenais/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Ansiedade/fisiopatologia , Comportamento Animal , Corticosterona/sangue , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Neurônios/metabolismo , Tamanho do Órgão , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de Somatostatina/genética , Timo/patologia
15.
Brain Behav Immun ; 59: 219-232, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27621226

RESUMO

The tachykinin NK1 receptor was suggested to be involved in psychiatric disorders, but its antagonists have failed to be effective as antidepressants in clinical trials. Hemokinin-1 (HK-1), the newest tachykinin, is present in several brain regions and activates the NK1 receptor similarly to substance P (SP), but acts also through other mechanisms. Therefore, we investigated the roles of the Tac4 gene-derived HK-1 in comparison with SP and neurokinin A (NKA) encoded by the Tac1 gene, as well as the NK1 receptor in anxiety and depression-like behaviors in mice. Mice lacking SP/NKA, HK-1 or the NK1 receptor (Tac1-/-, Tac4-/-, Tacr1-/-, respectively) compared to C57Bl/6 wildtypes (WT), and treatment with the NK1 antagonist CP99994 were used in the experiments. Anxiety was evaluated in the light-dark box (LDB) and the elevated plus maze (EPM), locomotor activity in the open field (OFT) tests. Hedonic behavior was assessed in the sucrose preference test (SPT), depression-like behavior in the tail suspension (TST) and forced swim (FST) tests. FST-induced neuronal responsiveness was evaluated with Fos immunohistochemistry in several stress-related brain regions. In the LDB, Tac4-/- mice spent significantly less, while Tacr1-/- and CP99994-treated mice spent significantly more time in the lit compartment. In the EPM only Tac4-/- showed reduced time in the open arms, but no difference was observed in any other groups. In the OFT Tac4-/- mice showed significantly reduced, while Tac1-/- and Tacr1-/- animals increased motility than the WTs, but CP99994 had no effect. NK1-/- consumed markedly more, while Tac4-/- less sucrose solution compared to WTs. In the TST and FST, Tac4-/- mice showed significantly increased immobility. However, depression-like behavior was decreased both in cases of genetic deletion and pharmacological blockade of the NK1 receptor. FST-induced neuronal activation in different nuclei involved in behavioral and neuroendocrine stress responses was significantly reduced in the brain of Tac4 -/- mice. Our results provide the first evidence for an anxiolytic and anti-depressant-like actions of HK-1 through a presently unknown target-mediated mechanism. Identification of its receptor and/or signaling pathways might open new perspectives for anxiolytic and anti-depressant therapies.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/genética , Depressão/genética , Precursores de Proteínas/genética , Precursores de Proteínas/fisiologia , Taquicininas/genética , Taquicininas/fisiologia , Anedonia , Animais , Ansiedade/psicologia , Depressão/psicologia , Preferências Alimentares , Genes fos , Elevação dos Membros Posteriores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Receptores da Neurocinina-1/genética , Substância P/genética
16.
Peptides ; 85: 63-72, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27637621

RESUMO

Previously demonstrated age-related changes in the catabolic melanocortin system that may contribute to middle-aged obesity and aging anorexia, raise the question of the potential involvement of corticotropin-releasing factor (CRF) in these phenomena, as this catabolic hypothalamic mediator acts downstream to melanocortins. Catabolic effects of CRF were shown to be mediated by both CRF1 (hypermetabolism) and CRF2 (anorexia) receptors. To test the potential role of CRF in age-related obesity and aging anorexia, we investigated acute central effects of the peptide on energy balance in male and female rats during the course of aging. Effects of an intracerebroventricular CRF injection on food intake (FI), oxygen-consumption (VO2), core- and tail skin temperatures (Tc and Ts) were studied in male and female Wistar rats of five different age-groups (from 3- to 24-month). Anorexigenic responsiveness was tested during 180-min re-feeding (FeedScale) following 24-h fasting. Thermoregulatory analysis was performed by indirect calorimetry (Oxymax) complemented by thermocouples recording Tc and Ts (indicating heat loss). CRF suppressed FI in 3-month male and female animals. In males, CRF-induced anorexia declined with aging, whereas in females it was maintained in all groups. The peptide increased VO2 and Tc in all male age-groups, while the weaker hypermetabolic response characterizing 3-month females declined rapidly with aging. Thus, age-related alterations in acute central anorexigenic and hypermetabolic effects of CRF show different non-parallel patterns in males and females. Our findings underline the importance of gender differences. They also call the attention to the differential age-related changes in the CRF1 and CRF2 receptor systems.


Assuntos
Hormônio Liberador da Corticotropina/administração & dosagem , Peptídeos/administração & dosagem , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Fatores Etários , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Anorexia/tratamento farmacológico , Anorexia/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Masculino , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Peptídeos/metabolismo , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/genética , Caracteres Sexuais
17.
Rheumatology (Oxford) ; 55(12): 2119-2130, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27565177

RESUMO

OBJECTIVE: Cardiopulmonary manifestations have an important impact on the life expectancy of SSc patients. Functional and morphological macrovascular changes may appear early before the development of ischaemic symptoms. Several non-invasive methods are used in cardiovascular risk assessment. Heterogeneous data are available regarding these in SSc. We aimed to perform a systematic review and meta-analysis to characterize the importance of atherosclerosis in SSc. METHODS: A systematic literature search was performed to identify controlled studies on carotid intima-media thickness, flow- or nitrate-induced vasodilatation (flow-mediated dilatation, nitroglycerine-mediated dilatation), pulse wave velocity, augmentation index and ankle-brachial pressure index. Outcomes were pooled with the random-effects model. RESULTS: Thirty-five studies comprising a total of 1292 SSc patients qualified. Intima-media thickness, pulse wave velocity and ankle-augmentation index were higher and flow-mediated dilatation lower in SSc patients [standardized mean difference (SMD) 0.65 (95% CI: 0.29, 1.01), 0.62 (95% CI: 0.35, 0.88), 0.96 (95% CI: 0.45, 1.47) and -0.68 (95% CI: -1.39, -0.34), respectively, P < 0.01 for each]. Nitroglycerine-mediated dilatation and ankle-brachial pressure index were lower, but not significantly [SMD: -0.16 (95% CI: -0.50, 0.18) and -0.39 (95% CI: -0.91, 0.13), respectively]. Data showed high to moderate inconsistency and significant heterogeneity. Meta-regression analysis of the SMD and the disease duration found a regression coefficient of 0.086, P = 0.014, confirming that parameters of the included SSc population may have contributed to the heterogeneity. CONCLUSION: Meta-analysis of the published observational studies confirms that abnormalities attributable to macrovascular involvement are significantly more prevalent in SSc patients compared with controls. Considering the increasing importance of cardiovascular disease in SSc, a more widespread use of cardiovascular risk assessment is warranted.


Assuntos
Aterosclerose/etiologia , Escleroderma Sistêmico/complicações , Índice Tornozelo-Braço , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Velocidade do Fluxo Sanguíneo/fisiologia , Espessura Intima-Media Carotídea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Análise de Onda de Pulso , Medição de Risco , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia , Rigidez Vascular/fisiologia , Vasodilatação/fisiologia
18.
J Mol Neurosci ; 59(4): 521-30, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27339773

RESUMO

Spontaneously hypertensive rats (SHR) have high sympathetic tone and progressive hypertension. Chronic calorie-restriction prevents hypertension. Their food intake (FI) and body weight are lower than in normotensive (NT) controls, even on a high-fat diet, suggesting a dysregulation of energy homeostasis. We assumed enhanced activity of hypothalamic anorexigenic melanocortins and diminished tone of orexigenic neuropeptide Y (NPY) in the background. FI of male SHR and NT Wistar rats was recorded in a FeedScale system upon intracerebroventricular injection of NPY, melanocortin ligands alpha-melanocyte-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP) or during a 7-day intracerebroventricular infusion of melanocortin antagonist HS024. Alpha-MSH, NPY, and AgRP immunoreactivities were semi-quantified in the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus in NT vs. SHR. Proopiomelanocortin gene expression was also assessed by quantitative RT-PCR in the ARC. Melanocortin-induced anorexia was stronger, FI induced by NPY or HS024 was smaller and delayed in SHR. Cellular alpha-MSH-specific signal density was higher in the ARC of SHR as evaluated by immunofluerescence, which was supported by PCR data. In the PVN, no differences in alpha-MSH-, NPY-, or AgRP-immunosignal were observed. Our results suggest that a higher melanocortin production/responsiveness and lower NPY responsiveness may contribute to the body weight dysregulation of SHR.


Assuntos
Metabolismo Energético , Homeostase , Hipertensão/metabolismo , Proteína Relacionada com Agouti/farmacologia , Animais , Peso Corporal , Hormônios/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Neuropeptídeo Y/farmacologia , Fragmentos de Peptídeos/farmacologia , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , alfa-MSH/farmacologia
19.
J Comp Eff Res ; 5(4): 355-64, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27295112

RESUMO

AIM: Controlling cardiovascular (CV) risk factors is paramount in reducing atherosclerotic events. This 6-month prospective noninterventional trial assessed the safety and effectiveness of fixed-combination lisinopril-amlodipine plus rosuvastatin. PATIENTS & METHODS: Patients with mild/moderate hypertension and hypercholesterolemia, at high-/very high-CV risk, received lisinopril-amlodipine (10/5, 20/5 or 20/10 mg/day) plus rosuvastatin (10 or 20 mg/day). Primary end points: systolic/diastolic blood pressure, low-density lipoprotein cholesterol. RESULTS: At 6 months, 91% of 2241 evaluable patients achieved blood pressure target (<140/90 mmHg); low-density lipoprotein cholesterol targets, <3, <2.5 and 1.8 mmol/l, were achieved by 67, 49 and 40% of patients, respectively. Adverse events (4.4%) were mostly mild. CONCLUSION: Lisinopril-amlodipine plus rosuvastatin was well tolerated and effective in patients with mild/moderate hypertension and hypercholesterolemia at high/very high CV risk.


Assuntos
Anticolesterolemiantes/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Anlodipino , Colesterol , Humanos , Estudos Prospectivos
20.
Neuroscience ; 330: 335-58, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27282087

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in stress adaptation with potential relevance in mood disorder management. PACAP deficient (KO) mice on CD1 background were shown to have depression-like phenotype. Here we aimed at investigating effects of chronic variable mild stress (CVMS) in non-injected, vehicle and imipramine-treated KO mice vs. wildtype (WT) counterparts. We hypothesized reduced FosB neuronal activity in stress-related centers, altered activity and peptide/neurotransmitter content of corticotropin-releasing factor (CRF) cells of the oval (ovBST) bed nucleus of stria terminalis (BST), urocortin 1 (Ucn1) neurons of centrally projecting Edinger-Westphal nucleus (cpEW) and serotonin (5HT) cells of dorsal raphe (DR) in PACAP deficiency. CVMS caused decreased body weight and increased adrenal size, corticosterone (CORT) titers and depression-like behavior in WT mice, in contrast to KO animals. CVMS increased FosB in the central (CeA) and medial amygdala, dorsomedial (dmBST), ventral (vBST), ovBST, CA1 area, dentate gyrus (DG), ventral lateral septum, parvo- (pPVN) and magnocellular paraventricular nucleus, lateral periaqueductal gray, cpEW and DR. Lack of PACAP blunted the CVMS-induced FosB rise in the CeA, ovBST, dmBST, vBST, CA1 area, pPVN and DR. The CVMS-induced FosB expression in ovBST-CRF and cpEW-Ucn1 neurons was abolished in KO mice. Although CVMS did not induce FosB in 5HT-DR neurons, PACAP KO mice had increased 5HT cell counts and 5HT content. We conclude that PACAP deficiency affects neuronal reactivity in a brain area-specific manner in stress centers, as well as in ovBST-CRF, cpEW-Ucn1 and 5HT-DR neurons leading to reduced CVMS response and altered depression level.


Assuntos
Tronco Encefálico/metabolismo , Sistema Límbico/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/deficiência , Prosencéfalo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estresse Psicológico/metabolismo , Animais , Antidepressivos Tricíclicos/farmacologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/patologia , Doença Crônica , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Modelos Animais de Doenças , Imipramina/farmacologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/patologia , Masculino , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Serotonina/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia
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