RESUMO
Consumption of (-)-epicatechin (Epi), a cacao flavanol improves cognition. The aim was to compare the effects of (-)-Epi or its stereoisomer (+)-Epi on mouse frontal cortex-dependent short-term working memory and modulators of neurogenesis. Three-month-old male mice (n = 7 per group) were provided by gavage either water (vehicle; Veh), (-)-Epi, at 1 mg kg-1 or (+)-Epi at 0.1 mg per kg of body weight for 15 days. After treatment, spontaneous alternation was evaluated by Y-maze. Brain frontal cortex was isolated for nitrate/nitrite measurements, Western blotting for nerve growth factor (NGF), microtubule associated protein 2 (MAP2), endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and immunohistochemistry for neuronal specific protein (NeuN), doublecortin (DCX), capillary (CD31) and neurofilaments (NF200). Results demonstrate the stimulatory capacity of (-)-Epi and (+)-Epi on markers of neuronal proliferation as per increases in immunoreactive cells for NeuN (74 and 120% respectively), DCX (70 and 124%) as well as in NGF (34.4, 63.6%) and MAP2 (41.8, 63.8%). Capillary density yielded significant increases with (-)-Epi (â¼80%) vs. (+)-Epi (â¼160%). CD31 protein levels increased with (-)-Epi (â¼70%) and (+)-Epi (â¼140%). Effects correlated with nitrate/nitrite stimulation by (-)-Epi and (+)-Epi (110.2, 246.5%) and enhanced eNOS phosphorylation (Ser1177) with (-)-Epi and (+)-Epi (21.4, 41.2%) while nNOS phosphorylation only increased with (+)-Epi (18%). Neurofilament staining was increased in (-)-Epi by 135.6 and 84% with (+)-Epi. NF200 increased with (-)-Epi (116%) vs. (+)-Epi (84.5%). Frontal cortex-dependent short-term spatial working improved with (-)-Epi and (+)-Epi (15, 13%). In conclusion, results suggest that both enantiomers, but more effectively (+)-Epi, upregulate neurogenesis markers likely through stimulation of capillary formation and NO triggering, improvements in memory.
Assuntos
Catequina/farmacologia , Lobo Frontal/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Animais , Biomarcadores/análise , Química Encefálica , Cacau/química , Catequina/análise , Proliferação de Células/efeitos dos fármacos , Proteína Duplacortina , Lobo Frontal/irrigação sanguínea , Lobo Frontal/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Óxido Nítrico/metabolismo , EstereoisomerismoRESUMO
Evidence has implicated oxidative stress (OS) and inflammation as drivers of neurodegenerative pathologies. We previously reported on the beneficial effects of (-)-epicatechin (Epi) treatment on aging-induced OS and its capacity to restore modulators of mitochondrial biogenesis in the prefrontal cortex of 26-month-old male mice. In the present study using the same mouse model of aging, we examined the capacity of Epi to mitigate hippocampus OS, inflammation, hyperphosphorylation of tau protein, soluble ß-amyloid protein levels, cell survival, memory, anxiety-like behavior levels and systemic inflammation. Mice were subjected to 4 weeks of Epi treatment (1 mg kg-1 day-1) and samples of the hippocampus were obtained. Assessments of the OS markers, protein carbonyls, and malondialdehyde levels demonstrated their significant increase (â¼3 fold) with aging that were partially suppressed by Epi. The protein levels of the glial fibrillary acidic protein, inflammatory factor 1 (Iba1), pro-inflammatory cytokines, interleukins (IL-1ß, IL-3, 5, 6 and 15), cyclooxygenase 2, tumor necrosis factor α, nuclear factor-activated B cells and interferon γ increase with aging and were also significantly decreased with Epi treatment. However, anti-inflammatory cytokines, IL-1ra, IL-10 and 11 decrease with aging and were restored with Epi. Epi also reversed the aging effects on the hyperphosphorylation of tau, increased soluble ß-amyloid levels (â¼2 fold), cellular death (as per caspase 3 and 9 activity), and reduced nerve growth factor and triggering receptor expressed on myeloid cells 2 levels. Measures of anxiety like-behavior and memory demonstrated improvements with Epi treatment. Indicators of systemic inflammation increase with aging and Epi was capable of decreasing blood inflammatory markers. Altogether, the results show a significant capacity of Epi to mitigate hippocampus OS and inflammation leading to improved brain function.
Assuntos
Anti-Inflamatórios/farmacologia , Catequina/farmacologia , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteínas tau/metabolismo , Envelhecimento/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Citocinas/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , FosforilaçãoRESUMO
Endothelial dysfunction (EnD) occurs with aging and endothelial nitric oxide (NO) production by NO synthase (NOS) can be impaired. Low NO levels have been linked to increased arginase (Ar) activity as Ar competes with NOS for L-arginine. The inhibition of Ar activity can reverse EnD and (-)-epicatechin (Epi) inhibits myocardial Ar activity. In this study, through in silico modeling we demonstrate that Epi interacts with Ar similarly to its inhibitor Norvaline (Norv). Using in vitro and in vivo models of aging, we examined Epi and Norv-inhibition of Ar activity and its endothelium-protective effects. Bovine coronary artery endothelial cells (BCAEC) were treated with Norv (10 µM), Epi (1 µM) or the combination (Epi + Norv) for 48 h. Ar activity increased in aged BCAEC, with decreased NO generation. Treatment decreased Ar activity to levels seen in young cells. Epi and Epi + Norv decreased nitrosylated Ar levels by ~25% in aged cells with lower oxidative stress (~25%) (dihydroethidium) levels. In aged cells, Epi and Epi + Norv restored the eNOS monomer/dimer ratio, protein expression levels and NO production to those of young cells. Furthermore, using 18 month old rats 15 days of treatment with either Epi (1 mg/kg), Norv (10 mg/kg) or combo, decreased hypertension and improved aorta vasorelaxation to acetylcholine, blood NO levels and tetra/dihydribiopterin ratios in cultured rat aortic endothelial cells. In conclusion, results provide evidence that inhibiting Ar with Epi reverses aged-related loss of eNOS function and improves vascular function through the modulation of Ar and eNOS protein levels and activity.
Assuntos
Arginase/antagonistas & inibidores , Catequina/farmacologia , Senescência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Animais , Biopterinas/análogos & derivados , Biopterinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bovinos , Simulação por Computador , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Valina/análogos & derivados , Valina/farmacologiaRESUMO
The development of organ fibrosis has garnered rising attention as multiple diseases of increasing and/or high prevalence appear to progress to the chronic stage. Such is the case for heart, kidney, liver, and lung where diseases such as diabetes, idiopathic/autoimmune disorders, and nonalcoholic liver disease appear to notably drive the development of fibrosis. Noteworthy is that the severity of these pathologies is characteristically compounded by aging. For these reasons, research groups and drug companies have identified fibrosis as a therapeutic target for which currently, there are essentially no effective options. Although a limited body of published studies are available, most literature indicates that in multiple organs, premenopausal women are protected from developing severe forms of fibrosis suggesting an important role for sex hormones in mitigating this process. Investigators have implemented relevant animal models of organ disease linked to fibrosis supporting in general, these observations. In vitro studies and transgenic animals models have also been used in an attempt to understand the role that sex hormones and related receptors play in the development of fibrosis. However, in the setting of chronic disease in some organs such as the heart older (postmenopausal) women within a few years can quickly approach men in disease severity and develop significant degrees of fibrosis. This review summarizes the current body of relevant literature and highlights the imperative need for a major focus to be placed on understanding the manner in which sex and the presence or absence of related hormones modulates cell phenotypes so as to allow for fibrosis to develop.
Assuntos
Especificidade de Órgãos , Caracteres Sexuais , Animais , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , MasculinoRESUMO
IMPACT STATEMENT: The incidence of HFpEF continues to increase and â¼2/3 of the patient population are post-menopausal women. Unfortunately, most studies focus on the use of male animal models of remodeling. In this study, however, using female rats to set a model of pre-HFpEF, we provide insights to possible mechanisms that contribute to HFpEF development in humans that will lead us to a better understanding of the underlying pathophysiology of HFpEF.
Assuntos
Citocinas/metabolismo , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Remodelação Ventricular , Animais , Apoptose , Citocinas/genética , Feminino , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Carbonilação Proteica , Ratos , Ratos Endogâmicos F344 , Troponina I/genética , Troponina I/metabolismoRESUMO
INTRODUCTION: Scarce information exists on intracerebral hemorrhage (ICH) in Latin America, and the existent is derived from single-center registries with non-generalizable conclusions. The aim of this study is to describe the frequency, etiology, management and outcome of ICH in Mexico. PATIENTS AND METHODS: We studied consecutive patients with ICH pertaining to the National Multicenter Registry on Cerebro-vascular Disease (RENAMEVASC), conducted in 25 centers from 14 states of Mexico. The Intracerebral Hemorrhage Grading Scale (ICH-GS) at admission was used to assess prognosis at 30 days follow-up. RESULTS: Of 2,000 patients with acute cerebrovascular disease registered in RENAMEVASC, 564 (28%) had primary ICH (53% women; median age: 63 years; interquartile range: 50-75 years). Hypertension (70%), vascular malformations (7%) and amyloid angiopathy (4%) were the main etiologies. In 10% of cases etiology could not be determined. Main ICH locations were basal ganglia (50%), lobar (35%) and cerebellum (5%). Irruption into the ventricular system occurred in 43%. Median score of ICH-GS was 8 points: 49% had 5-7 points, 37% had 8-10 points and 15% had 11-13 points. The 30-day case fatality rate was 30%, and 31% presented severe disability. The 30-day survival was 92% for patients with ICH-GS 5-7 points, whereas it decreased to 27% in patients with ICH-GS 11-13 points. CONCLUSIONS: In Mexico, ICH represents about a third of the forms of acute cerebrovascular disease, and the majority of patients present severe disability or death at 30 days of follow-up. Hypertension is the main cause; hence, control of this important cardiovascular risk factor should reduce the health burden of ICH.