RESUMO
Metrnl is a secreted protein involved in neurite outgrowth, insulin sensitivity, immunoinflammatory responses, blood lipids and endothelial protection. In this study, we investigated the role of Metrnl in ischemic stroke. Fifty-eight ischemic stroke patients (28 inpatient patients within 2 weeks of onset and 30 emergency patients within 24 h of onset) and 20 healthy controls were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. We showed that serum Metrnl levels were significantly reduced in both inpatient and emergency patient groups compared with the controls. Different pathological causes for ischemic stroke such as large artery atherosclerosis and small artery occlusion exhibited similar reduced serum Metrnl levels. Transient ischemic attack caused by large artery atherosclerosis without brain infarction also had lower serum Metrnl levels. Metrnl was correlated with some metabolic, inflammatory and clotting parameters. Reduced serum Metrnl was associated with the severity of intracranial arterial stenosis and the presence of ischemic stroke. In order to elucidate the mechanisms underlying the reduced serum Metrnl levels, we established animal models of ischemic stroke in normal mice, atherosclerotic apolipoprotein E-knockout mice and Metrnl-knockout mice by middle cerebral artery occlusion (MCAO) using intraluminal filament or electrocoagulation. We demonstrated that serum Metrnl levels were significantly lower in atherosclerosis mice than normal mice, whereas acute ischemic stroke injury in normal mice and atherosclerosis mice did not alter serum Metrnl levels. Metrnl knockout did not affect acute ischemic stroke injury and death. We conclude that reduced serum Metrnl levels are attributed to the chronic vascular pathogenesis before the onset of ischemic stroke. Metrnl is a potential target for prevention of ischemic stroke.
Assuntos
Adipocinas , AVC Isquêmico , Humanos , Animais , Masculino , AVC Isquêmico/sangue , AVC Isquêmico/genética , Feminino , Pessoa de Meia-Idade , Idoso , Camundongos Endogâmicos C57BL , Camundongos , Infarto da Artéria Cerebral Média/sangue , Camundongos Knockout para ApoERESUMO
Stroke is a common cause of death and disability. Allisartan isoproxil (ALL) is a new angiotensin II receptor blocker and a new antihypertensive drug discovered and developed in China. In the present study we investigated the therapeutic effects of ALL in stroke-prone renovascular hypertensive rats (RHR-SP) and the underlying mechanisms. The model rats were generated via two-kidney two-clip (2K2C) surgery, which led to 100% of hypertension, 100% of cerebrovascular damage as well as 100% of mortality 1 year after the surgery. Administration of ALL (30 mg · kg-1 · d-1 in diet, for 55 weeks) significantly decreased stroke-related death and prolonged lifespan in RHR-SP, but the survival ALL-treated RHR-SP remained of hypertension and cardiovascular hypertrophy compared with sham-operated normal controls. In addition to cardiac, and aortic protection, ALL treatment for 10 or 12 weeks significantly reduced cerebrovascular damage incidence and scoring, along with a steady reduction of blood pressure (BP) in RHR-SP. Meanwhile, it significantly decreased serum aldosterone and malondialdehyde levels and cerebral NAD(P)H oxidase expressions in RHR-SP. We conducted 24 h continuous BP recording in conscious freely moving RHR-SP, and found that a single intragastric administration of ALL produced a long hypotensive effect lasting for at least 12 h on systolic BP. Taken together, our results in RHR-SP demonstrate that ALL can be used for stroke prevention via BP reduction and organ protection, with the molecular mechanisms related to inhibition of angiotensin-aldosterone system and oxidative stress. This study also provides a valuable scoring for evaluation of cerebrovascular damage and drug efficacy.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Doenças da Aorta/prevenção & controle , Compostos de Bifenilo/uso terapêutico , Transtornos Cerebrovasculares/prevenção & controle , Imidazóis/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Aldosterona/metabolismo , Animais , Aorta/efeitos dos fármacos , Doenças da Aorta/complicações , Doenças da Aorta/mortalidade , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/mortalidade , Transtornos Cerebrovasculares/patologia , Coração/efeitos dos fármacos , Hipertensão/complicações , Hipertensão/mortalidade , Estimativa de Kaplan-Meier , Rim/efeitos dos fármacos , Rim/patologia , Rim/cirurgia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidadeRESUMO
Hypertension is a serious public health problem worldwide. MT-1207, chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl) benzisothiazole hydrochloride, is a new chemical entity that has entered into clinical trial as antihypertensive agent in China. In this paper we report the pharmacological profile of MT-1207 regarding its acute, subacute, and long-term effects on hypertensive animal models, and its actions on isolated organs in vitro as well as its molecular targets. Blood pressure (BP) was measured in conscious animals; amlodipine was taken as a positive control drug. We showed that both single dose of MT-1207 (1.25-20 mg/kg, ig) in spontaneously hypertensive rats (SHR) and MT-1207 (0.25-6 mg/kg, ig) in two-kidney one-clip (2K1C) dogs dose-dependently decreased BP. MT-1207 quickly decreased BP within 5 min after administration; the hypotensive effect lasted for 8 and 12 h, respectively, in SHR and 2K1C dogs without reflex increase in heart rate. Multiple doses of MT-1207 (5 mg · kg-1 · d-1 in SHR; 2 mg · kg-1 · d-1 in 2K1C dogs, for 7 days) significantly decreased BP, slightly reduced heart rate, and both of them recovered after withdrawal. Long-term administration of MT-1207 (10 mg · kg-1 · d-1 for 4 months or more time) produced a stable BP reduction, improved baroreflex sensitivity, reduced renal and cardiovascular damage in SHR, and delayed stroke occurrence and death in stroke-prone SHR. In isolated rat aortic rings precontracted by adrenaline, KCl, noradrenaline or 5-hydroxytryptamine (5-HT), MT-1207 (10-9-10-4 M) caused concentration-dependent relaxation. In a panel of enzyme activity or radioligand binding assays of 87 molecular targets, MT-1207 potently inhibited adrenergic α1A, α1B, α1D, and 5-HT2A receptors with Ki < 1 nM. The antagonism of MT-1207 against these receptors was confirmed in isolated rabbit arteries. We conclude that MT-1207 is a novel and promising single-molecule multitarget agent for hypertension treatment to reduce hypertensive organ damage and stroke mortality.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Triazóis/uso terapêutico , Animais , Anti-Hipertensivos/metabolismo , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cães , Eletrocardiografia/efeitos dos fármacos , Feminino , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/mortalidade , Masculino , Simulação de Acoplamento Molecular , Coelhos , Ratos Endogâmicos SHR , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Acidente Vascular Cerebral/mortalidade , Tiazóis/metabolismo , Triazóis/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/metabolismo , Vasodilatadores/uso terapêuticoRESUMO
MT-1207 (MT) as a new antihypertensive drug is under clinical trial. However, its hypotensive mechanism has not been experimentally explored, and it is unknown whether MT can be used for bilateral renal artery stenosis hypertension. Using two-kidney two-clip (2K2C) to mimic bilateral renal artery stenosis in rats, a stroke-prone renovascular hypertension model, the present study further verified its antihypertensive effect, cardiovascular and renal protection, mortality reduction and lifespan prolongation, as well as demonstrated its two novel pharmacological effects for uric acid-lowering and cognition-improving. Notably, MT did not aggravate renal dysfunction; instead, it had beneficial effects on reducing serum uric acid level and maintaining serum K+ at a relatively stable level in 2K2C rats. In contrast, angiotensin receptor blocker losartan aggravated renal dysfunction in 2K2C rats. Mechanistically, MT hypotensive effect was dependent on its blockade of α1 and 5-HT2 receptors, since MT pretreatment abolished these receptor agonists-induced blood pressure elevations in vivo. Further evidence showed MT bound to and interacted with these receptor subtypes including α1A, α1B, α1D, 5-HT2A, 5-HT2B, and 5-HT2C receptors known for control of blood pressure. In conclusion, MT may be used for treatment of bilateral renal artery stenosis hypertension, different from losartan that is prohibited for treatment of bilateral renal artery stenosis hypertension. Targets validation of MT hypotensive mechanism and beneficial effects of MT on uric acid and cognitive function provide new insights for this novel multitarget drug, deserving clinical trial attention.
Assuntos
Anti-Hipertensivos , Hipertensão Renovascular , Ratos Sprague-Dawley , Obstrução da Artéria Renal , Animais , Masculino , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Ratos , Obstrução da Artéria Renal/tratamento farmacológico , Obstrução da Artéria Renal/complicações , Hipertensão Renovascular/tratamento farmacológico , Pressão Sanguínea/efeitos dos fármacos , Ácido Úrico/sangue , Modelos Animais de Doenças , Losartan/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismoRESUMO
Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through in vitro and in vivo studies. The most promising compound, II-13 (later named as MT-1207), is a potent α1 and 5-HT2A receptor antagonist with remarkable IC50 in the picomolar level. Importantly, in the in vivo assay, II-13 achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function. Compound II-13, with its significant advantages in terms of pharmacological effects, pharmacokinetic parameters, and a large safety window, was extensively investigated. Moreover, data also showed that compound II-13 had fewer side effects in a postural BP assay and could prevent the onset of postural hypotension. Together, these results suggested that compound II-13 is a highly potent antihypertensive drug candidate with multitarget mechanisms of action in preclinical models. Currently, MT-1207 is in phase II hypertensive clinical trials in China.
RESUMO
Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Thus far, hepatic Nampt has not been extensively explored in terms of its effects on serum lipid stability and liver lipids metabolism. In this study, hepatocyte-specific Nampt knockout (HC-Nampt-/-) mice were generated by Cre/loxP system. Nampt mRNA expression was reduced in the liver, but not in other tissues, in HC-Nampt-/- mice compared with wild-type (WT) mice. Hepatic Nampt deficiency had no effect on body weight and fasting blood glucose, and it did not induce atherosclerosis in mice under both normal chow diet (NCD) and high fat diet (HFD). At baseline state under NCD, hepatic Nampt deficiency also did not affect liver weight, liver function index, including alanine aminotransferase, aspartate aminotransferase, albumin and alkaline phosphatase, and serum levels of lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFA). However, under HFD, deficiency of hepatic Nampt resulted in increased liver weight, liver function index, and serum levels of TG, TC, HDL-C, and NEFA. Meanwhile, histopathological examination showed increased fat accumulation and fibrosis in the liver of HC-Nampt-/- mice compared with WT mice. Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver.
Assuntos
Dislipidemias , Fígado Gorduroso , Doenças não Transmissíveis , Camundongos , Animais , Dieta Hiperlipídica , Nicotinamida Fosforribosiltransferase/metabolismo , Ácidos Graxos não Esterificados , Fígado Gorduroso/metabolismo , Triglicerídeos/metabolismo , HDL-ColesterolRESUMO
AIMS: Acute cerebral ischemia may lead to ischemic stroke, which is a major cause of death and disability worldwide. Hydrogen sulfide (H2 S) functions importantly in mammalian systems. The present work was designed to study the effect of sodium sulfide, a donor of H2 S, on acute cerebral ischemia. METHODS: Acute cerebral focal ischemia was produced by middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats. Bilateral vertebral arteries and common carotid arteries were blocked to establish cerebral global ischemia in SD rats. Acute cerebral anoxia was produced by hypobaric anoxia in C57BL/6 mice and hypoxic anoxia in SD rats. Nimodipine and aspirin were set as positive control separately. RESULTS: Infarct size after MCAO was decreased by sodium sulfide. Sodium sulfide improved cerebral energy metabolism after cerebral global ischemia and prolonged survival time of animals with acute cerebral anoxia. In addition, increased cerebral blood flow and decreased cerebrovascular resistance, blood viscosity, and thrombogenesis were observed in animals treated with sodium sulfide. In cultured neurons, sodium sulfide increased cell viability and decreased cell apoptosis induced by oxygen-glucose deprivation. CONCLUSION: Sodium sulfide, a H2 S donor, presents protective effect on acute cerebral ischemia, and might be a promising therapeutic drug.
Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Sulfetos/uso terapêutico , Doença Aguda , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Aspirina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Eletroencefalografia , Fibrinolíticos/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Nimodipina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
BACKGROUND AND AIMS: Severe motion sickness is a huge obstacle for people conducting precise aviation, marine or emergency service tasks. The combination of scopolamine and d-amphetamine is most effective in preventing severe motion sickness. However, this combination is not included in any present pharmacopoeia due to the abuse liability of d-amphetamine. We wanted to find a combination to replace it for the treatment of severe motion sickness. METHODS AND RESULTS: We compared the efficacy of scopolamine, diphenhydramine, and granisetron (representing three classes of drugs) with different doses, and found that scopolamine was the most effective one. We also found scopolamine inhibited central nervous system at therapeutic doses and caused anxiety. Then, we combined it with different doses of psychostimulants (d-amphetamine, modafinil, caffeine) to find the best combination for motion sickness. The efficacy of scopolamine with modafinil (1 + 10 mg/kg) was equivalent to that of scopolamine with d-amphetamine (1 + 1 mg/kg); This combination also excited central nervous system and abolished the anxiety caused by scopolamine. CONCLUSIONS: The optimal dose ratio of scopolamine and modafinil is 1:10. This combination is beneficial for motion sickness and can abolish the side effects of scopolamine. So, it might be a good replacement of scopolamine and d-amphetamine for severe motion sickness.