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Emerging evidence implicates an interplay among multiple organs such as brain, vasculature, gut and lung in the development of established pulmonary arterial hypertension (PAH). This has led us to propose that activated microglia mediated-enhanced sympathetic activation contributes to PAH pathophysiology. Since enhanced sympathetic activity is observed in human PAH and the gut is highly innervated by sympathetic nerves that regulate its physiological functions, we hypothesized that PAH would be associated with gut pathophysiology. A monocrotaline rat model of PAH was utilized to investigate the link between gut pathology and PAH. Haemodynamics, histology, immunocytochemistry and 16S RNA gene sequencing were used to assess cardiopulmonary functions, gut pathology and gut microbial communities respectively. Monocrotaline treatment caused increased right ventricular systolic pressure, haemodynamics and pathological changes associated with PAH. PAH animals also showed profound gut pathology that included increased intestinal permeability, increased muscularis layer, decreased villi length and goblet cells. These changes in gut pathology were associated with alterations in microbial communities, some unique to PAH animals. Furthermore, enhanced gut-neural communication involving the paraventricular nucleus of the hypothalamus and increased sympathetic drive were observed. In conclusion, our data show the presence of gut pathology and distinct changes in gut microbiota and increased sympathetic activity in PAH. They suggest that dysfunctional gut-brain crosstalk could be critical in PAH and considered a future therapeutic target for PAH.
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Fecal matter transfer from hypertensive patients and animals into normotensive animals increases blood pressure, strengthening the evidence for gut-microbiota interactions in the control of blood pressure. However, cellular and molecular events involved in gut dysbiosis-associated hypertension remain poorly understood. Therefore, our objective in this study was to use gene expression profiling to characterize the gut epithelium layer in the colon in hypertension. We observed significant suppression of components of T cell receptor (TCR) signaling in the colonic epithelium of spontaneously hypertensive rats (SHR) when compared with Wistar Kyoto (WKY) normotensive rats. Western blot analysis confirmed lower expression of key proteins including T cell surface glycoprotein CD3 gamma chain (Cd3g) and lymphocyte cytosolic protein 2 (Lcp2). Furthermore, lower expression of cytokines and receptors responsible for lymphocyte proliferation, differentiation, and activation (e.g., Il12r, Il15ra, Il7, Il16, Tgfb1) was observed in the colonic epithelium of the SHR. Finally, Alpi and its product, intestinal alkaline phosphatase, primarily localized in the epithelial cells, were profoundly lower in the SHR. These observations demonstrate that the colonic epithelium undergoes functional changes linked to altered immune, barrier function, and dysbiosis in hypertension.
Assuntos
Colo/metabolismo , Microbioma Gastrointestinal/genética , Hipertensão/metabolismo , Mucosa Intestinal/metabolismo , Transcriptoma , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Pressão Sanguínea , Complexo CD3/metabolismo , Citocinas/metabolismo , Disbiose , Isoenzimas/metabolismo , Masculino , Fosfoproteínas/metabolismo , RNA-Seq , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Background We have demonstrated that the antihypertensive effect of the angiotensin-converting enzyme inhibitor, captopril ( CAP ), is associated with beneficial effects on gut pathology. Coupled with the evidence that CAP exerts prolonged reduction in blood pressure ( BP ) after discontinuation of treatment, we investigate whether persistent beneficial actions of CAP are linked to alterations of gut microbiota and improvement of hypertension-induced gut pathology. Methods and Results Spontaneously hypertensive rats ( SHR ) and Wistar Kyoto rats were treated with CAP (250 mg/kg/day) for 4 weeks followed by withdrawal for 16 weeks. Gut microbiota, gut pathology, BP, and brain neuronal activity were assessed. CAP resulted in a ≈60 mm Hg decrease in systolic BP after 3 weeks of treatment in SHR , and the decrease remained significant at least 5 weeks after CAP withdrawal. In contrast, CAP caused modest decrease in systolic BP in Wistar Kyoto. 16S rRNA gene-sequencing-based gut microbial analyses in SHR showed sustained alteration of gut microbiota and increase in Allobaculum after CAP withdrawal. Phylogenetic investigation of communities by reconstruction of unobserved states analysis revealed significant increase in bacterial sporulation upon CAP treatment in SHR . These were associated with persistent improvement in gut pathology and permeability. Furthermore, manganese-enhanced magnetic resonance imaging showed significantly decreased neuronal activity in the posterior pituitary of SHR 4 weeks after withdrawal. Conclusions Decreased BP , altered gut microbiota, improved gut pathology and permeability, and dampened posterior pituitary neuronal activity were maintained after CAP withdrawal in the SHR . They suggest that CAP influences the brain-gut axis to maintain the sustained antihypertensive effect of CAP after withdrawal.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Captopril/farmacologia , Microbioma Gastrointestinal/fisiologia , Hipertensão/tratamento farmacológico , Mucosa Intestinal/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Permeabilidade , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
BACKGROUND: Black Americans have greater rates, severity and resistance to treatment of hypertension than White Americans. The gut microbiota and its metabolites may contribute to this. This concept was tested in a pilot study. METHODS: Subjects with high (HBP, >140/80â¯mmâ¯Hg) and normal (NBP, <120/80â¯mmâ¯Hg) blood pressure (BP) provided stool and blood samples for whole genome sequencing (WGS) of gut microbiota and global untargeted metabolomics of serum. Patients were either black (B) with NBP (nâ¯=â¯10 for WGS, 5 for metabolomics) and HBP (nâ¯=â¯10 and 9, BHBP) or white (W) with NBP (nâ¯=â¯20 and 13, WNBP) and HBP (nâ¯=â¯12 and 8, WHBP). RESULTS: All four subject groups had distinct gut microbiota taxonomy by partial least squares discriminant analysis (PLS-DA). More importantly, linear discriminant analysis effect size showed marked differences in function of the microbiota of BHBP and WHBP (PLS-DA) with LDA scores <1. This included pathways for synthesis and interconversion of amino acids and inflammatory antigens. Similarly, metabolites differed (PLS-DA) with BHBP having significantly higher sulfacetaldehyde, quinolinic acid, 5-aminolevulinic acid, leucine and phenylalanine and lower 4-oxoproline and l-anserine. DISCUSSION: Combination analyses of functional gut metabolic pathways and metabolomics data in this small pilot study suggest that BHBP may have greater oxidative stress markers in plasma, greater inflammatory potential of the gut microbiome and altered metabolites with gut microbial functions implying insulin resistance. A fuller understanding of these potential differences could lead to race-based treatments for hypertension.
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Negro ou Afro-Americano , Microbioma Gastrointestinal/fisiologia , Hipertensão/sangue , Hipertensão/etnologia , População Branca , Negro ou Afro-Americano/genética , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Metabolômica/métodos , Projetos Piloto , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut-epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R2 = 0.5301, P<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R2 = 0.4608, P<0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN.
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Bactérias/metabolismo , Pressão Sanguínea , Células Epiteliais/microbiologia , Microbioma Gastrointestinal , Hipertensão/microbiologia , Mucosa Intestinal/microbiologia , Animais , Bactérias/classificação , Bactérias/imunologia , Butiratos/sangue , Estudos de Casos e Controles , Toxina da Cólera/sangue , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Proteínas de Ligação a Ácido Graxo/sangue , Fezes/microbiologia , Haptoglobinas , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/sangue , Hipertensão/imunologia , Hipertensão/fisiopatologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiopatologia , Lipopolissacarídeos/sangue , Camundongos Endogâmicos C57BL , Permeabilidade , Precursores de Proteínas , Ratos Sprague-Dawley , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Hypertension is one of the major risk factors for central nervous system (CNS) disorders like stroke and Alzheimer's disease (AD). On the other hand, CNS diseases like AD have been associated with gliosis and impaired neurogenesis. Further, renin angiotensin system (RAS) is intricately associated with hypertension; however, the accumulating evidences suggest that over-activity of RAS may perpetuate the brain inflammation related with AD. Therefore, in the present study, we examined the effect of hypertension and RAS on glial (astrocytes and microglia) activation and hippocampal neurogenesis in a rat model of chronic hypertension. We used Candesartan [angiotensin type 1 receptor (AT1R) blocker (ARB)] both at a low dose (0.1 mg/kg) and anti-hypertensive dose (2 mg/kg) to explore whether their effect on astrocyte and microglial activation, neuroinflammation, and neurogenesis is blood pressure (BP) dependent or independent. Our data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, and cripples hippocampal neurogenesis. Importantly, AT1R blockade by Candesartan, even at low dose (0.1 mg/kg), prevented astrocyte and microglial activation and neuroinflammation in the brain of hypertensive rats. Mechanistically, AT1R blockade prevented the activation of NADPH oxidase, reactive oxygen species (ROS) generation, suppression of MAP kinase and NFкB signaling. Importantly, we, for the first time to our knowledge, provided the evidence that AT1R blockade by activating Wnt/ß-catenin signaling, promotes neurogenesis during hypertensive state. We conclude that AT1R blockade prevents astrocyte and microglial activation and improves hippocampal neurogenesis in hypertensive state, independent of BP lowering action.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Hipocampo/metabolismo , Hipertensão/metabolismo , Neurogênese , Neuroglia/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/farmacologia , Via de Sinalização Wnt , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Gliose/patologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/fisiopatologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , NADPH Oxidases/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Neurogênese/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Proteólise , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Clinical studies demonstrated a positive correlation between hypertension and cognitive decline. Beneficial effects of angiotensin II receptor blockers on cognitive functions have also been reported earlier; however, its role in chronic neuroinflammation-induced memory impairment in the hypertensive state is not well understood. Therefore, in the present study, we investigated the effect of angiotensin II receptor blockers on memory impairment induced by lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHRs). Our data provides the strong evidence that intracerebroventricular (ICV) administration of LPS (25 µg) on the 1st, 4th, 7th, and 10th days leads to sustained neuroinflammation (as indicated by increased TNF-α, GFAP, COX-2, and NF-κB) and oxidative stress (increased reactive oxygen species (ROS) and nitrite levels) resulting in amyloid beta (Aß1-42) deposition, apoptosis (increased Bax and decreased Bcl-2 expression as well as increased caspase-3 activity and TUNEL-positive cells), and memory impairment. Further, we found that exaggerated inflammatory response and oxidative stress were associated with RAS over-activation (as evident from the increased ACE expression, angiotensin II (Ang II) level, and angiotensin type 1 receptor (AT1R) expression) and decreased BDNF and p-CREB expression. Oral administration of candesartan (an AT1R blocker) at a non-anti-hypertensive dose (0.1 mg/kg) for 15 days attenuated LPS-induced (ICV) apoptosis, amyloidogenesis, and memory impairment. Candesartan shows neuroprotection by inhibiting TLR4/Ang II-induced NF-κB inflammatory signaling and by enhancing associated BDNF/CREB expression in SHRs. Our study also demonstrated that when both AT1R and angiotensin type 2 receptor (AT2R) were blocked by candesartan and PD123319 concomitantly, the protective effects of candesartan were blunted suggesting that functionally active AT2R is required for beneficial effects of AT1R blockade.
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Antagonistas de Receptores de Angiotensina/farmacologia , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Lipopolissacarídeos/farmacologia , Transtornos da Memória/metabolismo , Memória/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Masculino , Transtornos da Memória/induzido quimicamente , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 2 de Angiotensina/metabolismoRESUMO
INTRODUCTION: Increased gut permeability ("leaky gut") has been proposed as a potential contributor to age-related inflammation and gut dysbiosis. However, information on the relationship between a leaky gut and inflammation and physical frailty during aging are limited. OBJECTIVE: To investigate the hypothesis that an aging-associated leaky gut is linked to the age-related inflammation and frailty. METHODS: Two cohorts of healthy adults were studied: young (18-30 years old, n = 19) and older (≥70 years old, n = 18). Serum concentrations of the tumor necrosis factor (TNF)-α and interleukin (IL)-6, zonulin (a marker for leaky gut), and high-mobility group box protein (HMGB1, a nuclear protein triggering inflammation) were measured. Correlations of serum levels of zonulin and HMGB1 with strength of plantar flexor muscles and number of steps taken per day were analyzed. RESULTS: Serum concentration of zonulin and HMGB1 were 22% (P = .005) and 16% (P = .010) higher in the older versus young adults. Serum zonulin was positively associated with concentrations of TNF-α (r = 0.357, P = .032) and IL-6 (r = 0.345, P = .043). Importantly, both zonulin and HMGB1 were negatively correlated with skeletal muscle strength (zonulin: r = -0.332, P = .048; HMGB1: r = -0.383, P = .023), and habitual physical activity (zonulin: r = -0.410, P = .016; HMGB1: r = -0.483, P = .004). CONCLUSIONS: Serum zonulin was associated with both systemic inflammation and 2 key indices of physical frailty. These data suggest that a leaky gut may play a critical role in the development of age-related inflammation and frailty.
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Biomarcadores/sangue , Toxina da Cólera/sangue , Envelhecimento Saudável , Mucosa Intestinal/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Disbiose , Feminino , Haptoglobinas , Humanos , Masculino , Permeabilidade , Precursores de Proteínas , Adulto JovemRESUMO
Studies have demonstrated separately that hypertension is associated with platelet activation in the periphery (resulting in accumulation and localized inflammatory response) and glial activation in the brain. We investigated the contribution of platelets in brain inflammation, particularly glial activation in vitro and in a rat model of hypertension. We found that HTN increased the expression of adhesion molecules like JAM-1, ICAM-1, and VCAM-1 on brain endothelium and resulted in the deposition of platelets in the brain. Platelet deposition in hypertensive rats was associated with augmented CD40 and CD40L and activation of astrocytes (GFAP expression) and microglia (Iba-1 expression) in the brain. Platelets isolated from hypertensive rats had significantly higher sCD40L levels and induced more prominent glial activation than platelets from normotensive rats. Activation of platelets with ADP induced sCD40L release and activation of astrocytes and microglia. Moreover, CD40L induced glial (astrocytes and microglia) activation, NFкB and MAPK inflammatory signaling, culminating in neuroinflammation and neuronal injury (increased apoptotic cells). Importantly, injection of ADP-activated platelets into normotensive rats strongly induced activation of astrocytes and microglia and increased plasma sCD40L levels compared with control platelets. On the contrary, inhibition of platelet activation by Clopidogrel or disruption of CD40 signaling prevented astrocyte and microglial activation and provided neuroprotection in both in vivo and in vitro conditions. Thus, we have identified platelet CD40L as a key inflammatory molecule for the induction of astrocyte and microglia activation, the major contributors to inflammation-mediated injury in the brain.
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Astrócitos/imunologia , Plaquetas/química , Ligante de CD40/farmacologia , Hipertensão/imunologia , Microglia/imunologia , Animais , Ligante de CD40/sangue , Proteínas de Ligação ao Cálcio/biossíntese , Proteínas de Ligação ao Cálcio/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Citocinas/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Hipertensão/sangue , Inflamação/patologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Microcirculação , Proteínas dos Microfilamentos/biossíntese , Proteínas dos Microfilamentos/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/imunologia , Ratos , Ratos Sprague-DawleyRESUMO
Neuroinflammation, sustained by astroglial and microglial activation, is the preceding event in neurodegeneration. Various clinical reports showed better neuroprotection by AT1 receptor blockade (ARB) than angiotensin-converting enzyme inhibition (ACEi), but experimental evidences and associated mechanism for this observation are lacking. Therefore, we investigated the effect of ARB, using Candesartan, and ACEi, using Perindopril, in equimolar concentrations in astroglial (C6) and microglial (BV2) cells employing lipopolysaccharide (LPS) to induce neuroinflammation. Further, Candesartan (0.1 mg/kg) and Perindopril (0.1 mg/kg) were orally administered in male SD rats for five consecutive days, and on the fifth day, rats were challenged with LPS (i.p.; 250 µg/kg) and sacrificed after 24 h. LPS-induced neuroinflammation (increased astroglial and microglial activation, IκBα degradation, NFкB nuclear translocation, STAT3 activation, and TNF-α release) was more efficiently prevented by Candesartan (even at lower concentration of 1 nM) than by Perindopril (1 µM) in both the cell types and in rat model of neuroinflammation. In addition, increased AT1 receptor (AT1R) and decreased AT2 receptor (AT2R) expression was observed in LPS-induced neuroinflammation in both in vitro and in vivo studies. Candesartan, as compared to Perindopril, increased the expression of AT2R in both the experimental conditions. Interestingly, concomitant blockade of AT2R by PD123319 significantly reversed the beneficial effects of Candesartan in both the cell types and in rat model of neuroinflammation. Finally, our data emphasize that superiority of Candesartan as compared to Perindopril is due to better activation of AT2R which results in PP2A activation, IκBα stabilization, and suppression of NFкB and STAT3 inflammatory signaling.
Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inflamação/tratamento farmacológico , Microglia/patologia , NF-kappa B/metabolismo , Receptores de Angiotensina/metabolismo , Fator de Transcrição STAT3/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Gliose/tratamento farmacológico , Gliose/patologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Nitritos/metabolismo , Proteína Fosfatase 2/metabolismo , Transporte Proteico/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Clinical and preclinical studies account hypertension as a risk factor for dementia. We reported earlier that angiotensin-converting enzyme (ACE) inhibition attenuated the increased vulnerability to neurodegeneration in hypertension and prevented lipopolysaccharide (LPS)-induced memory impairment in normotensive wistar rats (NWRs) and spontaneously hypertensive rats (SHRs). Recently, a receptor for advanced glycation end products (RAGE) has been reported to induce amyloid beta (Aß1-42) deposition and memory impairment in hypertensive animals. However, the involvement of ACE in RAGE activation and amyloidogenesis in the hypertensive state is still unexplored. Therefore, in this study, we investigated the role of ACE on RAGE activation and amyloidogenesis in memory-impaired NWRs and SHRs. Memory impairment was induced by repeated (on days 1, 4, 7, and 10) intracerebroventricular (ICV) injections of LPS in SHRs (25 µg) and NWRs (50 µg). Our data showed that SHRs exhibited increased oxidative stress (increased gp91-phox/NOX-2 expression and ROS generation), RAGE, and ß-secretase (BACE) expression without Aß1-42 deposition. LPS (25 µg, ICV) further amplified oxidative stress, RAGE, and BACE activation, culminating in Aß1-42 deposition and memory impairment in SHRs. Similar changes were observed at the higher dose of LPS (50 µg, ICV) in NWRs. Further, LPS-induced oxidative stress was associated with endothelial dysfunction and reduction in cerebral blood flow (CBF), more prominently in SHRs than in NWRs. Finally, we showed that perindopril (0.1 mg/kg, 15 days) prevented memory impairment by reducing oxidative stress, RAGE activation, amyloidogenesis, and improved CBF in both SHRs and NWRs. These findings suggest that perindopril might be used as a therapeutic strategy for the early stage of dementia.
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Amiloidose/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Perindopril/uso terapêutico , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/induzido quimicamente , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Lipopolissacarídeos/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Melatonina/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Endogâmicos SHR , Fatores de TempoRESUMO
Hypertension is a risk factor for cognitive impairment. Furthermore, neuroinflammation and neurodegeneration are intricately associated with memory impairment. Therefore, the present study aimed to explore the involvement of hypertension and angiotensin system in neurodegeneration and memory dysfunction in the presence of neuroinflammatory stimulus. Memory impairment was induced by chronic neuroinflammation that was developed by repeated intracerebroventricular (ICV) injections of lipopolysaccharide (LPS) on the 1st, 4th, 7th, and 10th day. Memory functions were evaluated by the Morris water maze (MWM) test on days 13-15, followed by biochemical and molecular studies in the cortex and hippocampus regions of rat brain. LPS at the dose of 25µg ICV caused memory impairment in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar rats (NWRs). Memory deficit was obtained with 50µg of LPS (ICV) in NWRs. Control SHRs already exhibited increased angiotensin converting enzyme (ACE) activity and expression, neuroinflammation (increased TNF-α, GFAP, COX-2 and NF-kB), oxidative stress (increased iNOS, ROS and nitrite levels), TLR-4 expression and TUNEL positive cells as compared to control NWRs. Further, LPS (25µg ICV) exaggerated inflammatory response, oxidative stress and apoptosis in SHRs but similar effects were witnessed at 50µg of LPS (ICV) in NWRs. Oral administration of perindopril (ACE inhibitor), at non-antihypertensive dose (0.1mg/kg), for 15days attenuated LPS induced deleterious changes in both NWRs and SHRs. Our data suggest that susceptibility of the brain for neurodegeneration and memory impairment induced by neuroinflammation is enhanced in hypertension, and that can be protected by ACE inhibition.
Assuntos
Hipertensão/complicações , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Perindopril/farmacologia , Perindopril/uso terapêutico , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipertensão/induzido quimicamente , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , RatosRESUMO
RATIONAL: Studies have shown the involvement of angiotensin II (Ang II) in neurobehavioral aspects, but the exact role of Ang II in memory is still ambiguous. OBJECTIVE: This study explored the effect of central Ang II on spatial memory along with cholinergic neurotransmission, brain energy metabolism, cerebral blood flow (CBF), and brain-derived neurotrophic factor (BDNF) in rats. METHODS: Spatial memory was evaluated by Morris water maze (MWM) after Ang II (ICV) administration in male Sprague-Dawley rats. CBF was measured by laser Doppler flowmetry. Oxidative stress adenosine triphosphate (ATP), BDNF, acetylcholinesterase (AChE), and acetylcholine (ACh) were estimated in the cortex and hippocampus at 1, 24, and 48 h after Ang II administration. The effect of AT1 and AT2 receptor blocker (candesartan and PD123,319, respectively), AChE inhibitor (donepezil), and antioxidant melatonin was studied on memory, CBF, and biochemical parameters. RESULTS: Ang II caused spatial memory impairment by affecting acquisition, consolidation, and recall in the MWM test along with a significant reduction in CBF. Ang II significantly reduced ACh level and caused oxidative stress in the rat brain 1 h post-injection. No significant change was observed in BDNF, AChE, and ATP level. Candesartan and donepezil prevented Ang II-induced memory impairment, reduction in CBF and ACh level. However, PD123,319 and melatonin failed to prevent Ang II-induced memory impairment but improved CBF partially. CONCLUSION: This study suggests that Ang II, via the AT1 receptor, affects spatial memory formation, CBF, and ACh level while AT2 receptor has no significant role.