RESUMO
BACKGROUND: Brain perivascular macrophages (PVMs) are potential treatment targets for subarachnoid hemorrhage (SAH), and previous studies revealed that their depletion by clodronate (CLD) improved outcomes after experimental SAH. However, the underlying mechanisms are not well understood. Therefore, we investigated whether reducing PVMs by CLD pretreatment improves SAH prognosis by inhibiting posthemorrhagic impairment of cerebral blood flow (CBF). METHODS: In total, 80 male Sprague-Dawley rats received an intracerebroventricular injection of the vehicle (liposomes) or CLD. Subsequently, the rats were categorized into the prechiasmatic saline injection (sham) and blood injection (SAH) groups after 72 h. We assessed its effects on weak and severe SAH, which were induced by 200- and 300-µL arterial blood injections, respectively. In addition, neurological function at 72 h and CBF changes from before the intervention to 5 min after were assessed in rats after sham/SAH induction as the primary and secondary end points, respectively. RESULTS: CLD significantly reduced PVMs before SAH induction. Although pretreatment with CLD in the weak SAH group provided no additive effects on the primary end point, rats in the severe SAH group showed significant improvement in the rotarod test. In the severe SAH group, CLD inhibited acute reduction of CBF and tended to decrease hypoxia-inducible factor 1α expression. Furthermore, CLD reduced the number of PVMs in rats subjected to sham and SAH surgery, although no effects were observed in oxidative stress and inflammation. CONCLUSIONS: Our study proposes that pretreatment with CLD-targeting PVMs can improve the prognosis of severe SAH through a candidate mechanism of inhibition of posthemorrhagic CBF reduction.
Assuntos
Ácido Clodrônico , Hemorragia Subaracnóidea , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Ácido Clodrônico/farmacologia , Ácido Clodrônico/metabolismo , Hemorragia Subaracnóidea/complicações , Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Modelos Animais de DoençasRESUMO
The cause of age-related body weight loss in Alzheimer's disease (AD) is unclear. We compared the differences in food intake, malabsorption, locomotor activity, and gut microbiota composition between 5xFAD mice, a useful model of AD, and wild-type (WT) mice to investigate the mechanisms underlying lower body weight in 5xFAD mice. Fifteen-month-old male 5xFAD mice and age-matched WT mice were divided into four groups: a control diet (CD) or a high-fat diet (HFD). After feeding CD or HFD for eight to nine weeks, 5xFAD mice had a significantly lower body weight than WT mice regardless of diet (p < 0.05). Additionally, the 5xFAD mice did not show a reduction in food intake compared to the WT mice regardless of diet. To evaluate malabsorption, we performed a fecal fat test. There was no obvious fecal fat in both the 5xFAD mice and WT mice. However, 5xFAD mice showed greater locomotor activity than WT mice in the Y-maze test. The comprehensive analysis of gut microbiota composition showed that 15-month-old 5xFAD mice had more Proteobacteria population and fewer Actinobacteria and Bifidobacteriales populations than WT mice. To investigate the effects of fructooligosaccharides (FOS), we administrated FOS to 15-month-old 5xFAD mice. FOS administration decreased Proteobacteria and increased Actinobacteria population, although that did not change Bifidobacteriales population. Moreover, cognitive impairment and body weight of 5xFAD mice were not changed by FOS administration. In conclusion, loss of body weight in 15-month-old 5xFAD mice might be partially derived from excess energy output by hyperactivity. Moreover, 15-month-old 5xFAD mice might have unique alteration of gut microbiota composition and the potential resistance to FOS.
Assuntos
Doença de Alzheimer , Microbioma Gastrointestinal , Animais , Peso Corporal , Dieta Hiperlipídica , Fezes/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
[Figure: see text].
Assuntos
Células Epiteliais/metabolismo , Hipertensão/genética , Cloreto de Sódio na Dieta/efeitos adversos , Fatores de Transcrição/genética , Amilorida/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Perfilação da Expressão Gênica , Hipernatremia/genética , Hipernatremia/prevenção & controle , Hipertensão/etiologia , Hipertensão/metabolismo , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sódio/urina , Cloreto de Sódio na Dieta/administração & dosagem , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Sirt7 is a recently identified sirtuin and has important roles in various pathological conditions, including cancer progression and metabolic disorders. It has previously been reported that Sirt7 is a key molecule in acute myocardial wound healing and pressure overload-induced cardiac hypertrophy. In this study, the role of Sirt7 in neointimal formation after vascular injury is investigated.MethodsâandâResults:Systemic (Sirt7-/-) and smooth muscle cell-specific Sirt7-deficient mice were subjected to femoral artery wire injury. Primary vascular smooth muscle cells (VSMCs) were isolated from the aorta of wild type (WT) and Sirt7-/-mice and their capacity for cell proliferation and migration was compared. Sirt7 expression was increased in vascular tissue at the sites of injury. Sirt7-/-mice demonstrated significant reduction in neointimal formation compared to WT mice. In vitro, Sirt7 deficiency attenuated the proliferation of serum-induced VSMCs. Serum stimulation-induced upregulation of cyclins and cyclin-dependent-kinase 2 (CDK2) was significantly attenuated in VSMCs of Sirt7-/-compared with WT mice. These changes were accompanied by enhanced expression of the microRNA 290-295 cluster, the translational negative regulator of CDK2, in VSMCs of Sirt7-/-mice. It was confirmed that smooth muscle cell-specific Sirt7-deficient mice showed significant reduction in neointima compared with control mice. CONCLUSIONS: Sirt7 deficiency attenuates neointimal formation after vascular injury. Given the predominant role in vascular neointimal formation, Sirt7 is a potentially suitable target for treatment of vascular diseases.
Assuntos
Sirtuínas , Lesões do Sistema Vascular , Animais , Movimento Celular , Proliferação de Células/fisiologia , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/patologia , Sirtuínas/genética , Sirtuínas/metabolismo , Lesões do Sistema Vascular/genéticaRESUMO
Brain-derived neurotrophic factor (BDNF) is known to have neuroprotective effects on multiple neurovascular diseases especially poststroke recovery. On the other hand, BDNF reported to increase blood pressure (BP) which is one of the major risk factors for stroke onset. To clarify the conflicting effects on stroke onset, we examined the expression of endogenous BDNF in relation to stroke onset. In addition, we explored the effect of exogenous central BDNF against stroke onset and all-cause mortality as the primary endpoint and BP as the secondary object in hypertensive rats with high-salt diet. In experiment 1, male spontaneously hypertensive stroke-prone rats (SHRSP) were fed a 0.3% (n = 8) or an 8% (n = 22) sodium diet (Na) through 28 days. The SHRSP with 8% Na showed significant increase of stroke onset, all-cause mortality, upregulation of reactive astrocytes, and disruption of blood-brain barrier. BDNF in the rats with 8% Na was significantly upregulated and mainly expressed in reactive astrocytes, whereas phosphorylated tropomyosin-related kinase B did not change by the rich BDNF. In experiment 2, male SHRSP were treated with continuous intracerebroventricular injection of 2.1 µg/day BDNF (n = 10) or the vehicle (Phosphate buffer saline; n = 10) and fed an 8% Na through 24 days. Exogenous central BDNF induced significant increase of BP and heart rate, and exhibited higher stroke onset and all-cause mortality compared with vehicle group. The present study demonstrated that endogenous BDNF were significantly produced in reactive astrocytes in relation to stroke onset regardless of neuroprotection. In addition, exogenous central BDNF increased BP which might be associated with sympathetic nerve activity and provided unfavorable effects on the prognosis of hypertensive rats. As BDNF is still potentially a good candidate for the treatment of neurovascular diseases, we suggest that hypertensive patients need care for the elevation of BP in the clinical trials of BDNF.
Assuntos
Hipertensão , Acidente Vascular Cerebral , Animais , Pressão Sanguínea , Fator Neurotrófico Derivado do Encéfalo , Humanos , Hipertensão/tratamento farmacológico , Masculino , Ratos , Ratos Endogâmicos SHR , Cloreto de Sódio na DietaRESUMO
To test our hypothesis that the magnitude of reduction in hsCRP achieved by antihypertensive medications may predict the benefit for cardiovascular outcomes in hypertensive individuals, we performed subanalysis of the ATTEMPT-CVD study. The hypertensive participants enrolled in the ATTMEPT-CVD study were categorized into two groups according to whether achieved reduction in hsCRP levels at 6 months after initiation of antihypertensive medications from baseline was equal to or greater than 40% (responder group) or less than 40% (non-responder group). Baseline characteristics and blood pressure during follow-up period were similar between the groups. For women, the incidence of cardiovascular events was significantly less in responder group than non-responder group (P < 0.0221). However, for men, there was no significant difference between the groups regarding incident cardiovascular events (P = 0.2434). There was a significant interaction (P = 0.0187) between sexes for incident cardiovascular events. Our results provide the evidence suggesting that substantial reduction (40% or greater reduction) in hsCRP on antihypertensive medication predicts the benefit for cardiovascular outcomes in hypertensive women but it does not in hypertensive men. The magnitude of achieved reduction in hsCRP by antihypertensive medications seems to be a useful indicator of successful treatment in Japanese hypertensive women.This trial was registered with ClinicalTrials.gov, number NCT01075698.
Assuntos
Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Hipertensão/tratamento farmacológico , Idoso , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/sangue , Feminino , Humanos , Hipertensão/sangue , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores SexuaisRESUMO
Although Alzheimer's disease (AD) is associated with an increased risk of intracerebral hemorrhage (ICH) caused by hypertension and cerebral amyloid angiopathy, the precise clinical course after hypertensive ICH in AD patients is still unknown. In this study, we investigated how striatal ICH, a frequent site for hypertensive ICH, affected the prognosis of AD. We employed 17- and 18-month-old male 5XFAD (5X) mice and littermate (LT) controls, and striatal ICH was induced by collagenase injection. First, to address the acute effects of ICH on 5X mice, hemorrhagic volume and brain edema were evaluated 3 days after ICH. Next, to address the long-term effects of ICH on 5X mice, morbidity, mortality, neurological function (beam-walking and rotarod tests), and cognitive function (Y-maze and nest-building tests) were monitored. Twenty-eight days later, the animals were euthanized, their brains were isolated, and the cytotoxic alterations were investigated. The results revealed that the acute effects of ICH were not significantly different between 5X and LT mice. In contrast, 5X mice showed significantly higher morbidity and mortality in response to ICH, as well as delayed neurological function recovery, compared to LT mice through 28 days. ICH did not affect cognitive function in either group. Infiltrated macrophages in the perihemorrhagic cortex, gp91phox , p67phox , and COX-2 were significantly increased in 5X mice in response to ICH. We demonstrated that striatal ICH deteriorated prognosis and delayed neurofunctional recovery in 5X mice, which might be associated with enhanced oxidative stress in the presence of AD-like pathology.
Assuntos
Doença de Alzheimer , Hemorragia Cerebral , Animais , Encéfalo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Estresse Oxidativo , PrognósticoRESUMO
The poor prognosis of subarachnoid hemorrhage (SAH) might be associated with sympathetic nerve activation (catecholamine surge) initiated by hypothalamic injury. As renal denervation (RD) has been shown to exert protective effects on cardiovascular dysfunction by suppressing increased central sympathetic nerve activation, we examined whether RD improved the experimental SAH prognosis in this study. Two hundred thirty-eight male Sprague-Dawley rats were divided into sham-operated and SAH-operated groups, and then each rat was further separated into Sham-operated and RD-operated groups. Bilateral RD was performed approximately 45 min after SAH induction. We examined the effect of RD on early brain injury (EBI) and delayed cerebral ischemia (DCI) as a primary endpoint, and also explored the effect on cerebral vasospasm (CVS) as a secondary endpoint. Although RD did not exert significant effects on primary endpoint, RD significantly prevented CVS and reduced SAH-induced increases in the number of phosphorylated extracellular signal-regulated kinase (ERK)-positive endothelial cells, cyclooxygenase-2 expression, and macrophage infiltration in major cerebral arteries. Moreover, RD significantly decreased the areas displaying dopamine ß-hydroxylase and glial fibrillary acidic protein immunopositivity in the paraventricular nucleus of the hypothalamus and serum angiotensin II levels, all of which were increased by SAH. Although RD decreased systolic blood pressure, significant changes in cerebral blood flow were not observed compared with SAH + Sham group. Based on the findings, RD improved CVS by reducing endothelial cell damage and the effects were associated with the stabilization of central sympathetic nerve activation in a SAH model.
Assuntos
Rim/inervação , Hemorragia Subaracnóidea/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Vasoespasmo Intracraniano/fisiopatologia , Animais , Astrócitos/fisiologia , Denervação , Hipotálamo/fisiopatologia , Rim/irrigação sanguínea , Masculino , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/etiologiaRESUMO
The predictive value of serum adiponectin for hypertensive cardiovascular outcomes is unknown. This study was performed to investigate the association of adiponectin with incident cardiovascular and renal events (CV events) in hypertensive patients. We performed post-hoc analysis on 1,228 hypertensive patients enrolled in the ATTEMPT-CVD study, a prospective randomized study comparing the effects of two antihypertensive therapies. The participants were divided into quartiles of baseline serum total adiponectin or high molecular weight (HMW) adiponectin. Multivariable Cox proportional hazards analysis was performed to determine the prognostic factors associated with CV events. Kaplan-Meier analysis for CV events by quartiles of baseline total adiponectin showed that patients in the highest total adiponectin quartile (Q4) had more CV events (P = 0.0135). On the other hand, no significant difference was noted regarding the incidence of CV events among patients stratified by HMW adiponectin quartile (P = 0.2551). Even after adjustment for potential confounders, the highest total adiponectin quartile (Q4) remained independently associated with incident CV events in hypertensive patients (HR = 1.949: 95%CI 1.051-3.612; P = 0.0341). These results showed that total adiponectin, but not HMW adiponectin, was independently associated with the incidence of CV events in treated hypertensive patients, thereby highlighting total adiponectin as a valuable predictor for hypertensive cardiovascular outcomes.
Assuntos
Adiponectina/sangue , Anti-Hipertensivos/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Hipertensão/tratamento farmacológico , Nefropatias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Feminino , Seguimentos , Humanos , Hipertensão/patologia , Incidência , Nefropatias/sangue , Nefropatias/induzido quimicamente , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
Alzheimer's disease (AD) is increasingly viewed as a neurological disease accompanied by a systemic disorder. Accumulating evidence supports that angiotensin II and angiotensin 1-7 exert opposite effects on various organs including the brain. However, the interaction between angiotensin II and angiotensin 1-7 in AD remains to be defined. The present study was undertaken to examine the interaction between these peptides in AD. 5XFAD mice, a useful model of AD, were separated into three groups: 1) saline-infused, 2) angiotensin II-infused, and 3) angiotensin II-infused and angiotensin 1-7-co-infused. These peptides were systemically given to 5XFAD mice via osmotic minipump for 4 weeks. Systemic angiotensin II infusion for 4 weeks induced significant hypertension in both wild-type and 5XFAD mice. Angiotensin II induced cognitive abnormality in 5XFAD mice as estimated by the Morris water maze test and the nest building test, and this effect was associated with cerebral blood flow reduction, cortical arterial amyloid-ß deposition, hippocampal inflammation, and neuron loss in 5XFAD mice. In addition, angiotensin II infusion led to gastrocnemius muscle atrophy in 5XFAD mice. Co-infusion of angiotensin 1-7 prevented the above mentioned detrimental effects of angiotensin II in the brain and gastrocnemius muscle in 5XFAD mice, without significant influence on blood pressure. The left ventricular hypertrophic response to angiotensin II was attenuated in 5XFAD mice compared with wild-type mice, which was not significantly altered by co-administration of angiotensin 1-7. Our results show that angiotensin 1-7 counteracts angiotensin II-induced cognitive impairment, brain injury, and skeletal muscle injury in AD mice.
Assuntos
Doença de Alzheimer/prevenção & controle , Angiotensina II , Angiotensina I/administração & dosagem , Angiotensina I/uso terapêutico , Disfunção Cognitiva/prevenção & controle , Hipocampo/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Músculo Esquelético/patologia , Teste de Desempenho do Rota-RodRESUMO
Systemic organ dysfunction is one of the important issues for the patients with Alzheimer's disease (AD) and their caregivers. Recent evidences suggest that periodontitis is a possible risk factor for progression of AD and lipopolysaccharide derived from Porphyromonas gingivalis (Pg-LPS) which is a major periodontopathic bacteria induces cognitive impairment in mice. However, the precise relationships between the brain exposure of Pg-LPS and systemic organ dysfunction in AD patients are still undetermined. In this study, we investigated whether brain exposure of Pg-LPS induced systemic organ dysfunction in a model of AD mouse. We employed 6 (young) and 13 (middle-aged) months-old 5XFAD mice and 6â¯months-old littermate (LT) mice, and treated with intracerebroventricular (ICV) injection of 2⯵g Pg-LPS or saline (vehicle). The animals were monitored cognitive functions (Y maze, nest building, and Morris water maze tests), motor functions (wire hang and rotarod tests), physical condition (symptom score), and blood pressure (BP). Twenty-eight days later, their organs were weighted and the organ damages were examined. Continuous ICV injection of 2⯵g/day Pg-LPS increased ionized calcium binding adapter molecule-1 (Iba-1) and cluster of differentiation 3 (CD3) positive cells in periventricular area of 5XFAD mice without enhancement of cognitive impairment, amyloid ß protein deposition, expressions of phosphorylated nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (COX-2). In addition, the Pg-LPS lowered the latency of rotarod test in young 5XAD mice and also reduced symptom score and weight of gastrocnemius muscle in the middle-aged animals. Moreover, the Pg-LPS induced cardiac atrophy in both young and middle-aged 5XFAD mice, and increased Iba-1 positive cells in left ventricle of the young animals. On the other hand, single ICV injection of 2⯵g Pg-LPS in 5XFAD and continuous injection of 2⯵g/day Pg-LPS in LT mice did not show any positive findings. Our present results demonstrated that continuous brain exposure of Pg-LPS started sarcopenia and cardiac injury without enhancing cognitive impairment in AD model mice.
Assuntos
Doença de Alzheimer/etiologia , Modelos Animais de Doenças , Lipopolissacarídeos/toxicidade , Insuficiência de Múltiplos Órgãos/etiologia , Porphyromonas gingivalis/patogenicidade , Animais , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Periodontite/complicações , Condicionamento Físico AnimalRESUMO
To investigate whether anemia is an independent risk factor for cardiovascular and renal events in hypertensive outpatients, we performed a subgroup analysis of the ATTEMPT-CVD study based on baseline hemoglobin. The ATTEMPT-CVD study was a multicenter, prospective, randomized study of hypertensive outpatients that compared the efficacy of angiotensin receptor blocker (ARB)-based antihypertensive treatment with non-ARB antihypertensive treatment over 3 years. In the present subanalysis, ATTEMPT-CVD study participants (n = 1213) were categorized into the anemic group and nonanemic group according to their baseline hemoglobin. We compared the anemic and nonanemic groups mainly in regard to the incidence of cardiovascular and renal events and blood pressure. We also performed a multivariable Cox proportional hazards analysis to determine the prognostic factors that were independently associated with cardiovascular and renal events. Of the 1213 patients enrolled in the ATTEMPT-CVD, 194 patients had anemia (mostly mild anemia) and 1019 patients did not. Blood pressure was well-controlled during the 3 years of antihypertensive therapy in both the anemic and nonanemic groups. However, the incidence of cardiovascular and renal events was significantly greater in the anemic group than in the nonanemic group (HR = 1.945: 95%CI 1.208-3.130; P = 0.0062). Even after adjustment, anemia was independently associated with cardiovascular and renal events (HR = 1.816: 95%CI 1.116-2.955; P = 0.0163) in overall hypertensive patients with well-controlled blood pressure. Anemia, even mild anemia, is an independent risk factor for cardiovascular and renal events in hypertensive outpatients whose blood pressure is well-controlled. Thus, anemia may be a novel therapeutic target for cardiovascular and renal diseases in hypertensive outpatients with anemia.
Assuntos
Anemia/complicações , Anemia/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Hipertensão/complicações , Hipertensão/epidemiologia , Nefropatias/epidemiologia , Nefropatias/etiologia , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Feminino , Hemoglobinas/análise , Humanos , Hipertensão/tratamento farmacológico , Incidência , Estimativa de Kaplan-Meier , Masculino , Pacientes Ambulatoriais , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
The ATTEMPT-CVD study was prospective randomized active-controlled trial and the main findings had been reported. According to baseline GFR and albuminuria categories, we divided the patients of the ATTEMPT-CVD study into 2 subgroups: (Group 1) the patients with at least one of eGFR of <45 ml/min per 1.73 m2 and UACR of ≥300 mg/g creatinine, defined as G3b and/or A3; (Group 2) the patients except for Group 1, defined as the other patients. In patients with G3b and/or A3, the incidence of cardiovascular events was significantly less in ARB group than in non-ARB group (11 vs 22, respectively) (HR = 0.465: 95%CI = 0.224-0.965; P = 0.040). UACR was significantly less in ARB group than in non-ARB group during follow-up period in patients with G3b and/or A3 (P = 0.0003), while eGFR, plasma BNP levels, and blood pressure were comparable between ARB and non-ARB groups. Allocation to ARB therapy was a significant independent prognostic factor for cardiovascular events in patients with G3b and/or A3 (P = 0.0268). On the other hand, in the other patients, the occurrence of cardiovascular events was comparable between ARB and non-ARB groups. In patients with advanced CKD, ARB-based therapy may confer greater benefit in prevention of cardiovascular events than non-ARB therapy.
Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Receptores de Angiotensina/metabolismo , Insuficiência Renal Crônica/complicações , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertensão/patologia , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , PrognósticoRESUMO
To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aß, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.
Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Regulação da Expressão Gênica/genética , MAP Quinase Quinase Quinase 5/deficiência , Sistema de Sinalização das MAP Quinases/genética , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Aprendizagem da Esquiva/fisiologia , Modelos Animais de Doenças , MAP Quinase Quinase Quinase 5/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , Tempo de Reação/genéticaRESUMO
BACKGROUND: The potential of anti-aging effect of DPP-4 inhibitors is unknown. This study was performed to determine whether linagliptin, a DPP-4 inhibitor, could protect against premature aging in klotho-/- mice. METHODS: Klotho-/- mice exhibit multiple phenotypes resembling human premature aging, including extremely shortened life span, cognitive impairment, hippocampal neurodegeneration, hair loss, muscle atrophy, hypoglycemia, etc. To investigate the effect of linagliptin on these aging-related phenotypes, male klotho-/- mice were divided into two groups: (1) control group fed the standard diet, and (2) linagliptin group fed the standard diet containing linagliptin. Treatment with linagliptin was performed for 4 weeks. The effect of linagliptin on the above mentioned aging-related phenotypes was examined. RESULTS: Body weight of klotho-/- mice was greater in linagliptin group than in control group (11.1 ± 0.3 vs 9.9 ± 0.3 g; P < 0.01), which was associated with greater gastrocnemius muscle weight (P < 0.01) and greater kidney weight (P < 0.05) in linagliptin group. Thus, linagliptin significantly prevented body weight loss in klotho-/- mice. Survival rate of klotho-/- mice was greater in linagliptin group (93%) compared to control group (67%), although the difference did not reach statistical significance (P = 0.08). None of linagliptin-treated klotho-/- mice had alopecia during the treatment (P < 0.05 vs control klotho-/- mice). Latency of klotho-/- mice in passive avoidance test was larger in linagliptin group than in control group (P < 0.05), indicating the amelioration of cognitive impairment by linagliptin. Cerebral blood flow of klotho-/- mice was larger in linagliptin group than in control group (P < 0.01), being associated with greater cerebral phospho-eNOS levels (P < 0.05) in linagliptin group. Neuronal cell number in hippocampal CA1 region was greater in linagliptin group than in control group (P < 0.05). Linagliptin group had greater cerebral phospho-Akt (P < 0.05) and phospho-CREB (P < 0.05) than control group. Thus, linagliptin ameliorated brain aging in klotho-/- mice. The degree of hypoglycemia in klotho-/- mice was less in linagliptin group than in control group, as estimated by the findings of OGTT. CONCLUSIONS: Out work provided the evidence that DPP-4 inhibition with linagliptin slowed the progression of premature aging in klotho-/- mice, and provided a novel insight into the potential role of DPP-4 in the mechanism of premature aging.
Assuntos
Senilidade Prematura , Envelhecimento/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glucuronidase/deficiência , Linagliptina/farmacologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/psicologia , Alopecia/enzimologia , Alopecia/genética , Alopecia/fisiopatologia , Alopecia/prevenção & controle , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Genótipo , Glucuronidase/genética , Hipoglicemia/sangue , Hipoglicemia/enzimologia , Hipoglicemia/genética , Hipoglicemia/prevenção & controle , Proteínas Klotho , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Óxido Nítrico Sintase Tipo III/metabolismo , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: The significance of brain angiotensin II in Alzheimer disease (AD) is unclear. METHODS AND RESULTS: To examine the role of brain angiotensin II in AD, intracerebroventricular angiotensin II infusion was performed on 5XFAD mice, a mouse model of AD, and wild-type mice, and the detrimental effects of brain angiotensin II was compared between the 2 strains of mice. Intracerebroventricular angiotensin II infusion significantly impaired cognitive function in 5XFAD mice but not in wild-type mice. This vulnerability of 5XFAD mice to brain angiotensin II was associated with enhancement of hippocampal inflammation and oxidative stress and with increased cerebrovascular amyloid ß deposition. We also compared the effect of brain angiotensin II on the heart and skeletal muscle between the 2 strains because AD is associated with heart failure and sarcopenia. We found that cardiac compensatory response of 5XFAD mice to brain angiotensin II-induced hypertension was less than that of wild-type mice. Brain angiotensin II caused skeletal muscle atrophy and injury in 5XFAD mice more than in wild-type mice. CONCLUSIONS: Brain angiotensin II seems to be involved in cognitive impairment and brain injury in AD, which is associated with oxidative stress, inflammation, and cerebral amyloid angiopathy. Further, brain angiotensin II may participate in cardiac disease and sarcopenia observed in AD.
Assuntos
Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Vasoconstritores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Hipocampo/imunologia , Inflamação , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular , Estresse Oxidativo/efeitos dos fármacos , SarcopeniaRESUMO
BACKGROUND AND PURPOSE: Renal denervation (RD) may protect against cardiovascular diseases regardless of blood pressure (BP)-lowering effect. We hypothesized that RD can improve the outcome of acute ischemic stroke (AIS) in hypertensive rats. METHODS: An AIS model of spontaneously hypertensive stroke-prone rats (SHRSPs) was prepared by 90-minute middle cerebral artery occlusion followed by reperfusion. At 30 minutes poststroke, the SHRSPs were subjected to (1) sham operation or (2) RD to determine the beneficial effects of RD posttreatment. In addition, we evaluated the neuroprotective effects of RD posttreatment in Wistar Kyoto rats and RD pretreatment in SHRSPs with AIS. RESULTS: RD significantly ameliorated neurological deficit and infarct volume at 1 and 7 days after middle cerebral artery occlusion. RD immediately and continuously normalized elevated BP during 24 hours. This normalization of BP by RD was associated with the reduction of cerebral blood flow during both middle cerebral artery occlusion and reperfusion periods. Thus, RD-induced BP normalization seems to ameliorate cerebrovascular overperfusion in SHRSPs with AIS. On the contrary, RD did not affect cerebral vascular resistance or cerebral vasoreactivity and did not increase Akt and endothelial NO synthase phosphorylation, thereby indicating no apparent change of cerebrovascular function. RD significantly attenuated cerebral oxidative stress as estimated by dihydroethidium staining and gp91phox expression. The beneficial effects were not seen in Wistar Kyoto rats, whereas RD pretreatment improved neurological function in SHRSPs. CONCLUSIONS: RD posttreatment improved outcome in the hypertensive AIS rat model. Therefore, we suggest that BP normalization by RD may be a promising therapeutic strategy for AIS.
Assuntos
Pressão Sanguínea , Isquemia Encefálica/terapia , Circulação Cerebrovascular , Artéria Renal/inervação , Acidente Vascular Cerebral/terapia , Simpatectomia/métodos , Animais , Modelos Animais de Doenças , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Epidemiological studies suggest that chronic kidney disease (CKD) is a significant risk factor in the development of cognitive decline. However, the exact role of CKD in cognitive impairment or dementia is unclear. This work was performed to examine the potential impact of CKD on cognitive impairment in Alzheimer's disease (AD), focusing on angiotensin II. (1) CKD was induced in 5XFAD mice, an AD model mouse, and wild-type mice by feeding an adenine-containing diet and the effect on cognitive function was compared between both strains. There was no significant difference regarding the severity of CKD induced by adenine between the strains. In 5XFAD mice, the CKD group exhibited significant cognitive impairment while the control group (control diet-fed group) did not, as evidenced by a passive avoidance test. On the other hand, in wild-type mice, neither the CKD group nor the control group showed cognitive impairment. Thus, CKD itself appears to accelerate cognitive impairment in AD mice. (2) We also examined the effect of olmesartan, an angiotensin II receptor blocker, on 5XFAD mice with CKD to elucidate the potential involvement of angiotensin II. As evidenced by the findings of the water maze test, olmesartan treatment significantly ameliorated the impairment of spatial learning and memory function induced by CKD in 5XFAD mice. Olmesartan treatment significantly ameliorated blood-brain barrier (BBB) disruption induced by CKD in 5XFAD mice. Furthermore, olmesartan reduced hippocampal oxidative stress in 5XFAD with CKD to similar levels to the control group of 5XFAD fed standard diet. Hence, the amelioration of CKD-induced cognitive impairment in 5XFAD mice by olmesartan appears to be mediated by the suppression of BBB disruption or oxidative stress. In conclusion, we obtained the evidence suggesting that CKD itself accelerates cognitive impairment in AD mice, through angiotensin II. Thus, our work provides a novel insight into the underlying mechanism of the link between CKD and AD.
Assuntos
Envelhecimento/efeitos dos fármacos , Doença de Alzheimer/complicações , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Imidazóis/administração & dosagem , Insuficiência Renal Crônica/complicações , Tetrazóis/administração & dosagem , Animais , Barreira Hematoencefálica/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND: Although sphingosine 1-phosphate (S1P) receptor activation by FTY720 (fingolimod) has been suggested to improve the prognosis of experimental stroke, the effect of the drug in early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the precise mechanism of the effect are undetermined. In this study, we investigated the protective effect of systemic administration of FTY720 in EBI after SAH and assessed the mechanism using intracerebroventricular infusion of VPC23019 which is the S1P receptor antagonist. METHOD: SAH rats were produced by the endovascular perforation model and injected saline or 1mg/kg FTY720 intraperitoneally at 30 minutes after SAH induction. Neurological function, cerebral blood flow, amount of subarachnoid blood, and brain edema were evaluated to confirm the protective effect of systemic administration of FTY720. SAH rats also received VPC23019 intraventricularly before SAH induction to abolish the central S1P receptor activation. RESULTS: Systemic administration of FTY720 significantly ameliorated SAH-induced neurological deficits and brain edema without modulation of CBF and the amount of subarachnoid blood. Blockage of central S1P receptor with VPC23019 did not abolish the protective effects of FTY720. CONCLUSION: The present study suggests that systemic administration of FTY720 reduces EBI after SAH and that the effect might not come from central S1P activation but be associated with pleiotropic actions of the drug.