RESUMO
BACKGROUND: We describe a case of a very unusual complication following a coiling procedure in which the patient developed transient unique cerebral and cerebellar lesions. Lesions were examined not only by magnetic resonance imaging (MRI) but also by positron emission tomography-computed tomography (PET-CT) and proton magnetic resonance spectroscopy ((1)H-MRS). CASE PRESENTATION: A 33-year-old woman presented an incidental 3.7 × 3.3-mm unruptured cerebral aneurysm (CAn) in her basilar artery, which was successfully coiled with balloon assistance. A follow-up brain MRI at 1 and 2 months showed a gradual increase in several white matter hyperintense lesions in the left cerebellar, bilateral occipitotemporal and left parietoccipital lobe during fluid-attenuated inversion recovery (FLAIR). These were the only lesions associated with perfused CAn. However, the patient did not show any additional symptoms such as visual disturbance throughout the entire course. (11)C-methionine-PET (MET-PET) showed an obvious increase in methionine uptake in the lesion corresponding to enhanced areas with gadolinium-enhanced MRI. MRS showed a decrease in the N-acetylaspartate/creatine (NAA/cr) ratio and a slight elevation of the choline/creatine (cho/cr) ratio and a lactate peak in the lesion. A follow-up MRI at 6 and 12 months showed a gradual decrease in the initial hyperintense lesions in FLAIR without any treatment. CONCLUSION: We present a case of an unusual complication after a coiling procedure. Although it is difficult to identify this etiology without a pathological examination, it is importance to increase awareness of such a potential complication arising from coiling procedures, because interventional procedures have become the first choice of treatment for cerebrovascular diseases in many countries.
Assuntos
Cerebelo , Córtex Cerebral , Embolização Terapêutica , Aneurisma Intracraniano/terapia , Adulto , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Espectroscopia de Prótons por Ressonância Magnética , Tomografia Computadorizada por Raios XRESUMO
Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/farmacologia , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Encefalite/prevenção & controle , Hipertensão/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acetilglucosamina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Encefalite/etiologia , Encefalite/metabolismo , Encefalite/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Inflamassomos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Endogâmicos SHR , Telmisartan , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo. METHODS: Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography. RESULTS: The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarin-pretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban- and apixaban-pretreated rats. CONCLUSIONS: This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.
Assuntos
Anticoagulantes/uso terapêutico , Fibrinolíticos/efeitos adversos , Hemorragias Intracranianas/prevenção & controle , Morfolinas/uso terapêutico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Tiofenos/uso terapêutico , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Animais , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/etiologia , Masculino , Morfolinas/farmacologia , Pirazóis/farmacologia , Piridonas/farmacologia , Ratos , Ratos Wistar , Rivaroxabana , Acidente Vascular Cerebral/tratamento farmacológico , Tiofenos/farmacologia , Ativador de Plasminogênio Tecidual/uso terapêuticoRESUMO
This study assesses the risks and benefits of tissue plasminogen activator (tPA) treatment under oral anticoagulation with dabigatran compared with warfarin or vehicle control in transient middle cerebral artery occlusion (tMCAO). After pretreatment with warfarin (0.2 mg/kg/day), dabigatran (20 mg/kg/day), or vehicle (0.5% carboxymethyl cellulose sodium salt) for 7 days, tMCAO was induced for 120 min, followed by reperfusion and tPA (10 mg/kg/10 ml). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. At 24 hr after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and MMP-9 activity was measured by zymography. Paraparesis and intracerebral hemorrhage volume were significantly improved in the dabigatran-pretreated group compared with the warfarin-pretreated group. A marked dissociation between astrocyte foot processes and the basal lamina or pericyte was observed in the warfarin-pretreated group, which was greatly improved in the dabigatran-pretreated group. Furthermore, a remarkable activation of MMP-9 in the ipsilateral warfarin-pretreated rat brain was greatly reduced in dabigatran-pretreated rats. The present study reveals that the mechanism of intracerebral hemorrhage with warfarin-pretreatment plus tPA in ischemic stroke rats is the dissociation of the neurovascular unit, including the pericyte. Neurovascular protection by dabigatran, which was first shown in this study, could partially explain the reduction in hemorrhagic complication by dabigatran reported from clinical study.
Assuntos
Antitrombinas/uso terapêutico , Benzimidazóis/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Hemorragias Intracranianas/prevenção & controle , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos adversos , beta-Alanina/análogos & derivados , Animais , Dabigatrana , Modelos Animais de Doenças , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , Masculino , Ratos , Ratos Wistar , Ativador de Plasminogênio Tecidual/uso terapêutico , Varfarina/uso terapêutico , beta-Alanina/uso terapêuticoRESUMO
An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.
Assuntos
Ácido Azetidinocarboxílico/análogos & derivados , Lesões Encefálicas/prevenção & controle , Di-Hidropiridinas/uso terapêutico , Imidazóis/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Tetrazóis/uso terapêutico , Fatores Etários , Animais , Ácido Azetidinocarboxílico/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Quimiocina CCL2/metabolismo , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Frequência Cardíaca/efeitos dos fármacos , Fluxometria por Laser-Doppler , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Acidente Vascular Cerebral/genéticaRESUMO
Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke-prone spontaneously hypertensive rats (SHR-SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP-9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP-9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR-SP.
Assuntos
Fibrinolíticos/uso terapêutico , Neovascularização Patológica/prevenção & controle , Pericitos/efeitos dos fármacos , Acidente Vascular Cerebral/prevenção & controle , Tetrazóis/uso terapêutico , Animais , Antígenos/metabolismo , Aspirina/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Cilostazol , Clopidogrel , Modelos Animais de Doenças , Endotélio/patologia , Fibrinolíticos/farmacologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Patológica/etiologia , Proteínas do Tecido Nervoso/metabolismo , Proteoglicanas/metabolismo , Ratos , Ratos Endogâmicos SHR , Acidente Vascular Cerebral/etiologia , Tetrazóis/farmacologia , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Telmisartan is an angiotensin receptor blocker with high lipid solubility, also called metabosartan, which exerts a special protective effect on both acute brain damage and chronic neurodegeneration. We examined the effects of telmisartan on oxidative stress by advanced glycation end product (AGE) and 4-hydroxynonenal (4-HNE) assays and the accumulation of phosphorylated α-synuclein (pSyn) in the brain of stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 12 weeks, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups: the vehicle group, the low-dose telmisartan group (.3 mg/kg/day), and the high-dose telmisartan group (3 mg/kg/day, postoperatively). Immunohistologic analysis was performed when rats were 6, 12, and 18 months old. AGE, 4-HNE, and pSyn-positive cells (per square millimeter) increased with age in the cerebral cortex and hippocampus of the vehicle group, in the low-dose telmisartan group, these parameters decreased without lowering blood pressure (BP), and in the high-dose telmisartan group, these parameters increased with lowering BP. The present study suggests that a persistent hypertension after tMCAO caused a progressive oxidative stress with the abnormal accumulation of pSyn, and that telmisartan reduced oxidative stress and the accumulation of pSyn without lowering BP (low dose) or improved these conditions with a reduction in BP (high dose) via its pleiotropic effects through a potential peroxisome proliferator-activated receptor gamma stimulation in the brain of SHR-SR.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sinucleínas/metabolismo , Aldeídos/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Hipertensão/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , TelmisartanRESUMO
Telmisartan, an angiotensin receptor blocker with high lipid solubility, also called metabo-sartan, not only reduces blood pressure (BP), but also ameliorates inflammation in the cerebral cortex and in adipose tissue. We examined the effects of telmisartan on inflammatory responses of monocyte chemotactic protein-1, tumor necrosis factor-α, and ionized calcium-binding adapter molecule 1 in the brain of spontaneously hypertensive rat stroke-resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO). At 12 weeks of age, SHR-SR received tMCAO for 90 minutes and were divided into 3 groups, that is, the vehicle group, a low-dose telmisartan group (.3 mg/kg/day), and a high-dose telmisartan group (3 mg/kg/day). Immunohistological analysis was performed when rats became 6, 12 and 18 months old. Monocyte chemotactic protein-1, tumor necrosis factor-α, and ionized calcium-binding adapter molecule 1 cells (/mm(2)) immunoreactivities increased with age in the cerebral cortex and hippocampus of the vehicle group, suggesting strong and persistent inflammatory changes in SHR-SR after tMCAO up to 18 months of age. On the other hand, a low dose of telmisartan significantly reduced such inflammatory changes without lowering BP, whereas a high dose of telmisartan showed a few additional improvements, including the lowering of BP throughout 6-18 months of age. The present study suggests that persistent hypertension after tMCAO caused a long-lasting inflammatory response in the SHR-SR brain, and that even a low dose of telmisartan reduced continuous inflammation without lowering BP via its pleiotropic effects in the SHR-SR brain. A high dose of telmisartan had a few additional benefits, including lowering BP.
Assuntos
Benzimidazóis/farmacologia , Benzoatos/farmacologia , Hipertensão/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/imunologia , Fatores Etários , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/complicações , Masculino , Proteínas dos Microfilamentos/metabolismo , Ratos , Ratos Endogâmicos SHR , Acidente Vascular Cerebral/etiologia , Telmisartan , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Telmisartan, an angiotensin receptor blocker also called metabosartan, is a promising solution for preventing cognitive decline or the incidence of dementia. METHODS: We examined the effects of telmisartan on cholesterol transport-related proteins (apolipoprotein E [ApoE]/low-density lipoprotein receptor [LDL-R]) and microtubule-associated protein 2 (MAP2) in the brain of spontaneously hypertensive stroke resistant (SHR-SR). SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes at 12 weeks of age and then was divided into 3 experiment groups including a vehicle, low-dose telmisartan (.3 mg/kg/day), and high-dose telmisartan (3 mg/kg/day). RESULTS: The low dose served to improve the metabolic syndrome of SHR-SR without lowering the blood pressure (BP) whereas the high dose was used to improve metabolic syndrome while lowering BP. Immunohistologic analysis showed that ApoE expression of cortical neurons was strong in the vehicle group at 6, 12, and 18 months of age, and that this ApoE expression pattern was very similar between the ipsilateral and contralateral sides of cerebral ischemia. On the other hand, LDL-R expression of cortical neurons was transiently increased at 6 months of age only on the ipsilateral side. Telmisartan dramatically suppressed the expression of ApoE/LDL-R at both doses. There was no remarkable difference in neuronal MAP2 staining between the 3 groups. CONCLUSIONS: These findings suggest that both low and high doses of telmisartan prevented the activation of ApoE/LDL-R in SHR-SR after tMCAO, and that the antimetabolic effect was regarded as the most important mechanism with few additional benefits by lowering BP in this transient stroke model.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Apolipoproteínas E/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Receptores de LDL/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/patologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Ratos , Ratos Endogâmicos SHR , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/fisiopatologia , TelmisartanRESUMO
Previously, we reported that reactive oxygen species and signaling molecules of angiotensin II produced lipid peroxides, degenerated proteins, and injured DNA after cerebral ischemia in normotensive Wistar rats. Here, we investigated the long-term effect of the angiotensin II type I receptor blocker telmisartan on oxidative stress and hyperphosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 3 months, SHR-SR were divided into 3 treatment groups: SHR-SR vehicle (SHR/Ve), SHR-SR low-dose telmisartan (.3 mg/kg/day) (SHR/low), and SHR-SR high-dose telmisartan (3 mg/kg/day) (SHR/high). Immunohistologic analyses were conducted in these groups and Wistar rats at the age of 6, 12, and 18 months. The SHR/Ve group demonstrated more progressive increase in advanced glycation end product (AGE)-, 4-hydroxy-2-nonenal (4-HNE)-, and phosphorylated α-synuclein (pSyn)-positive cells in the cerebral cortex and hippocampus compared with the Wistar group at 18 months. These expressions were reduced in the SHR/low group even without lowering blood pressure (BP), and expressions were dramatically suppressed in the SHR/high group with lowering of BP. These data suggest that persistent hypertension in SHR-SR strongly potentiate the markers of oxidative damage (AGEs and 4-HNE) and abnormal accumulation of pSyn, which were greatly suppressed by telmisartan in a dose-dependent manner without and with lowering of BP.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sinucleínas/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Hipertensão/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , TelmisartanRESUMO
BACKGROUND: In addition to reducing the level of blood pressure (BP), telmisartan was expected to show the long-term neuroprotective effects preventing accumulation of cellular amyloid beta peptide (Aß) and phosphorylated tau (pτ) by ameliorating neuroinflammation. METHODS: We examined effects of telmisartan on cellular Aß and pτ with inflammatory responses in the brain of a spontaneously hypertensive stroke resistant (SHR-SR) rat by giving either telmisartan at 0 (vehicle), .3 mg/kg/day or 3 mg/kg/day, orally, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months. Compared with normotensive Wistar rats, numbers of Aß- and pτ-positive neurons in the cerebral cortex progressively increased with age until 18 months in the SHR-SR rats, as did the numbers of ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, tumor necrosis factor alpha (TNF-α)-positive neurons, and monocyte chemotactic protein 1 (MCP-1)-positive neurons. RESULTS: Low-dose telmisartan significantly decreased the numbers of Aß- and pτ-positive neuron as well as the numbers of TNF-α-positive neurons, Iba-1-positive microglia, and MCP-1-positive neurons at 6, 12, and 18 months. High-dose telmisartan reduced BP and showed a further reduction of cellular Aß and pτ. CONCLUSIONS: The present study suggests that accumulation of cellular Aß and pτ and the inflammatory responses were decreased via improving metabolic syndrome with low-dose telmisartan and improving both metabolic syndrome and hypertension with high-dose telmisartan.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Microglia/metabolismo , Neurônios/metabolismo , Proteínas tau/metabolismo , Fatores Etários , Animais , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Proteínas de Ligação ao Cálcio/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Inflamação/tratamento farmacológico , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Telmisartan , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Telmisartan is expected to ameliorate not only hypertension, but also metabolic syndrome as a metabosartan. We examined the effects of telmisartan on metabolic syndrome-related molecules such as insulin receptor (IR), peroxisome proliferator-activated receptor gamma (PPAR-γ), and angiotensin 2 type 1 receptor (AT1R) in stroke-resistant spontaneously hypertensive rat (SHR-SR) after transient middle cerebral artery occlusion (tMCAO), by administering telmisartan at either 0 (vehicle), .3 mg/kg/day (low dose), or 3 mg/kg/day (high dose), postoperatively, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months of age. Compared with the vehicle group, the 2 telmisartan groups dose dependently decreased the number of IR- and AT1R-positive neurons in the cerebral cortex in the ipsilateral cerebral cortex from 6 to 18 months after tMCAO. On the other hand, the number of PPAR-γ-positive neurons increased in a dose-dependent manner in the 2 telmisartan groups from 6 to 18 months. The present study suggests that telmisartan dose-dependently ameliorated metabolic syndrome-related changes in the poststroke brain of SHR-SR with a direct protective effect (low dose) and an additive benefit, an antihypertensive effect at a high dose, for long-term protection after tMCAO.
Assuntos
Benzimidazóis/farmacologia , Benzoatos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Síndrome Metabólica/metabolismo , Neurônios/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/complicações , Masculino , Síndrome Metabólica/tratamento farmacológico , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , PPAR gama/metabolismo , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor de Insulina/metabolismo , Telmisartan , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Telmisartan is a unique angiotensin II type 1 receptor blocker with a partial peroxisome proliferator-activated receptor-γ (PPARγ) agonistic property to exert not only antihypertensive effect but also antimetabolic syndrome effect. METHODS: We examined the long-term effect of telmisartan on cholesterol transport-related proteins (low-density lipoprotein receptor [LDL-R]/apolipoprotein E [ApoE]) and microtubule-associated proteins 2 (MAP2) in the brains of stroke resistant spontaneously hypertensive rats (SHR-SRs), which were divided into 3 experiment groups including vehicle group (SHR/Ve), low-dose telmisartan group (SHR/Low, .3 mg/kg/day), and high-dose telmisartan group (SHR/High, 3 mg/kg/day). RESULTS: The numbers of LDL-R- and immuno-ApoE-positive neurons increased in both cerebral cortex and hippocampus of SHR/Ve throughout 6, 12, and 18 months of age, compared with age-matched normotensive Wistar rats. On the other hand, telmisartan significantly reduced the numbers of LDL-R- and ApoE immuno-positive neurons in both cerebral cortex and hippocampus, with similar effectiveness in the SHR/Low group without blood pressure (BP) lowering to BP lowering (SHR/High). The decrease of MAP2-positive neuron in SHR/Ve was recovered by telmisartan in both cerebral cortex and hippocampus. CONCLUSIONS: These findings suggest that a long-term treatment with telmisartan directly improved neuronal lipid metabolism in the cerebral cortex and hippocampus of SHR-SR, mainly improving LDL-R and ApoE metabolism (SHR/Low) with a small additive benefit by BP lowering (SHR/High), which could provide a preventative approach in patients with hypertension at risk of Alzheimer disease.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Apolipoproteínas E/biossíntese , Apolipoproteínas E/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Receptores de LDL/biossíntese , Receptores de LDL/efeitos dos fármacos , Acidente Vascular Cerebral/genética , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Demência Vascular/patologia , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/biossíntese , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , TelmisartanRESUMO
We recently reported spinal blood flow-metabolism uncoupling in the Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mouse model of amyotrophic lateral sclerosis (ALS), suggesting relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway in ALS has not been well studied. In the present work, we examined the temporal and spatial changes of hypoxic stress sensor proteins (Siah-1, PHD3, and FIH) following motor neuron (MN) degeneration in the spinal cord of normoxic ALS mice. The expression of Siah-1 and PHD3 proteins progressively increased in the surrounding glial cells of presymptomatic Tg mice (10 weeks, 10 weeks) compared with the large MN of the anterior horn. In contrast, a significant reduction in Siah-1 and PHD3 protein expression was evident in end-stage ALS mice (18 weeks, 18 weeks). Double-immunofluorescence analysis revealed PHD3 plus Siah-1 double-positive cells in the surrounding glia of symptomatic Tg mice (14-18 weeks), with no change in the large MNs. In contrast, FIH protein expression decreased in the surrounding glial cells of Tg mice at end-stage ALS (18 weeks). The present study suggests a partial loss in the neuroprotective response of spinal MNs in ALS results from a relative hypoxia through the Siah-1, PHD3, and FIH system under normoxic conditions. This response could be an important mechanism of neurodegeneration in ALS.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Oxigenases de Função Mista/metabolismo , Neurônios Motores/metabolismo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Medula Espinal/patologia , Esclerose Lateral Amiotrófica/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Processamento de RNA , Superóxido Dismutase/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
FADD is an adaptor protein that transmits apoptotic signals from death receptors. Additionally, FADD has been shown to play a role in various functions including cell proliferation. However, the physiological role of FADD during embryonic development remains to be delineated. Here, we show the novel roles FADD plays in development and the molecular mechanisms of these roles in Xenopus embryos. By whole-mount in situ hybridization and RT-PCR analysis, we observed that fadd is constantly expressed in early embryos. The upregulation or downregulation of FADD proteins by embryonic manipulation resulted in induction of apoptosis or size changes in the heart during development. Expression of a truncated form of FADD, FADDdd, which lacks pro-apoptotic activity, caused growth retardation of embryos associated with dramatic expressional fluctuations of genes that are regulated by NF-κB. Moreover, we isolated a homolog of mammalian cullin-4 (Cul4), a component of the ubiquitin E3 ligase family, as a FADDdd-interacting molecule in Xenopus embryos. Thus, our study shows that FADD has multiple functions in embryos; it plays a part in the regulation of NF-κB activation and heart formation, in addition to apoptosis. Furthermore, our findings provide new insights into how Cul4-based ligase is related to FADD signaling in embryogenesis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Antígenos de Diferenciação/fisiologia , Apoptose , Proteína de Domínio de Morte Associada a Fas/fisiologia , Coração/embriologia , NF-kappa B/metabolismo , Receptores Imunológicos/fisiologia , Proteínas de Xenopus/fisiologia , Xenopus/embriologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Blastômeros/enzimologia , Blastômeros/metabolismo , Proteínas Culina/química , Proteínas Culina/genética , Proteínas Culina/metabolismo , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Humanos , Dados de Sequência Molecular , Morfolinos/genética , NF-kappa B/fisiologia , Fragmentos de Peptídeos/química , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Análise de Sequência de DNA , Deleção de Sequência , Transdução de Sinais , Ativação Transcricional , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismoRESUMO
Cognitive and affective impairments are important non-motor features of ischemic stroke (IS) related to white-matter hyperintensity, including periventricular hyperintensity (PVH). To confirm the usefulness of a novel computerized touch panel-type screening test, we investigated cognitive and affective functioning among 142 IS patients and 105 age-and gender-matched normal control subjects. Assessment using the mini-mental state examination, Hasegawa Dementia Scale-Revised, and frontal assessment battery revealed reduced cognitive function in IS patients, with the most severe reduction exhibited by cardiogenic embolism patients, followed by lacunar infarction patients, and atherothrombotic infarction patients. Our novel touch panel screening test revealed a similar pattern of results. In addition, PVH grading, classified using Fazekas' magnetic resonance imaging method, was also correlated with cognitive decline and touch panel screening test performance. In contrast, affective function, assessed with the 15-item Geriatric Depression Scale, vitality index, and apathy scale, was not significantly decreased in IS, and did not correlate with touch panel screening test results or PVH, although the number of microbleeds was correlated with apathy scale results. The present findings revealed that IS and PVH grading were significantly correlated with decline in general cognitive status (mini-mental state examination and Hasegawa Dementia Scale-Revised) and frontal lobe function (frontal assessment battery). Performance on all touch panel screening tests was correlated with IS and PVH grading, but was largely independent of depression or apathy. Touch panel screening tests were easily understood and performed by almost all patients with mild cognitive and motor dysfunction, due to visually clear images and simple methods not involving detailed manual-handling tasks such as writing. Touch panel screening tests may provide a useful tool for the early screening of cognitive function.
Assuntos
Isquemia Encefálica/psicologia , Transtornos Cognitivos/diagnóstico , Cognição/fisiologia , Acidente Vascular Cerebral/psicologia , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Acidente Vascular Cerebral/complicações , TatoRESUMO
Takotsubo cardiomyopathy can induce cerebral embolic stroke because of intracardiac thrombosis, but the timing of cardiogenic embolism relating to takotsubo cardiomyopathy has not been well described. We evaluated a 71-year-old woman with takotsubo cardiomyopathy, who developed cardiogenic cerebral embolism after recovery of cardiac wall motion. Nevertheless, we treated her with anticoagulation therapy. The present clinical observation suggests that attention should be paid to the timing when takotsubo cardiomyopathy resolves against risk of cardiogenic cerebral embolism.
Assuntos
Embolia Intracraniana/etiologia , Acidente Vascular Cerebral/etiologia , Cardiomiopatia de Takotsubo/complicações , Trombose/etiologia , Idoso , Anticoagulantes/uso terapêutico , Angiografia Cerebral/métodos , Imagem de Difusão por Ressonância Magnética , Ecocardiografia , Feminino , Humanos , Embolia Intracraniana/diagnóstico , Embolia Intracraniana/tratamento farmacológico , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Cardiomiopatia de Takotsubo/diagnóstico , Cardiomiopatia de Takotsubo/fisiopatologia , Trombose/diagnóstico , Trombose/tratamento farmacológico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
In October 2005 in Japan, the recombinant tissue plasminogen activator (tPA) alteplase was approved for patients with acute ischemic stroke within 3 hours of onset at a dose of 0.6 mg/kg. The present study was undertaken to assess the safety and efficacy of alteplase in Japan. Between October 2005 and December 2009, a total of 114 consecutive patients admitted to 4 hospitals received intravenous tPA within 3 hours of stroke onset. Clinical backgrounds and outcomes were investigated. The patients were divided into 2 chronological groups: an early group, comprising 45 patients treated between October 2005 and December 2007, and a later group, comprising 69 patients treated between January 2008 and December 2009. The mean time from arrival at the hospital to the initiation of treatment was significantly reduced in the later group, from 82.6 minutes to 70.9 minutes. Intracerebral hemorrhage (ICH) occurred in 26 patients (22.8%); compared with patients without ICH, these patients had a significantly higher prevalence of cardiogenic embolism (88.5% vs 58.0%); greater warfarin use (26.8% vs 6.8%); higher mean National Institutes of Health Stroke Scale (NIHSS) scores on admission (16 vs 10), at 3 days after admission (14 vs 5), and at 7 days after admission (13.5 vs 3); and a lower Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score (7.8 vs 9.1). Patients who received edaravone had a higher prevalence of cardiogenic embolism (70.9% vs 36.4%), a higher recanalization rate (77.7% vs 36.4%), and lower NIHSS scores on admission and at 3 and 7 days after admission compared with those who did not receive edaravone. Our data suggest that administration of intravenous alteplase 0.6 mg/kg within 3 hours of stroke onset is safe and effective, that the NIHSS and Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score are useful predictors of ICH after tPA administration, and that warfarin-treated patients are more likely to develop symptomatic ICH despite an International Normalized Ratio <1.7.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Hospitais , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Hemorragia Cerebral/epidemiologia , Distribuição de Qui-Quadrado , Imagem de Difusão por Ressonância Magnética , Avaliação da Deficiência , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Humanos , Incidência , Coeficiente Internacional Normatizado , Japão/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Tempo para o Tratamento , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento , Varfarina/efeitos adversosRESUMO
BACKGROUND: Alteplase, a recombinant tissue plasminogen activator (tPA), was approved for patients with acute ischemic stroke within 3 hours of stroke onset in Japan in October 2005 at a dose of 0.6 mg/kg. The aim of this study was to assess the safety and efficacy of alteplase in elderly patients in Japan. METHODS: One hundred twenty-nine consecutive patients who were admitted to our 5 hospital groups and who received intravenous tPA within 3 hours of stroke onset between January 2010 and December 2011 were divided into 2 groups by age (<80 years of age [younger group] and >80 years of age [older group]) and by treatment with or without edaravone. Clinical backgrounds and outcomes were investigated. RESULTS: The National Institutes of Health Stroke Scale score on admission was not different in both groups, but the National Institutes of Health Stroke Scale scores 7 days after stroke onset were significantly higher in the older group (score 8; P < .05) than in the younger group (score 4), and the ratio of patients with a modified Rankin Scale score of 4 to 6 was significantly greater in the older group (41.7%; P < .05) than in the younger group (22.2%). However, there was no difference in asymptomatic and symptomatic intracerebral hemorrhage rates between the younger and older groups (asymptomatic 20.2% v 18.8%; symptomatic 2.6% v 2.1%). Patients with edaravone showed a higher recanalization rate (61.9%; P < .01) and a better modified Rankin Scale score at 3 months poststroke (P < .01) than the nonedaravone group. CONCLUSIONS: These data suggest that intravenous alteplase (0.6 mg/kg) within 3 hours of stroke onset was safe and effective, even for very old patients (≥ 80 years of age), but resulted in poor outcomes relating not to tPA but to aging. In addition, edaravone may be a good partner for combination therapy with tPA to enhance recanalization and reduce hemorrhagic transformation.
Assuntos
Antipirina/análogos & derivados , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipirina/administração & dosagem , Antipirina/uso terapêutico , Edaravone , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Estudos Retrospectivos , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Cerebral infarction is a major cause of death or decreasing activities of daily living. This study aimed to investigate the efficacy of commonly used antiplatelet drugs on stroke and motor and cognitive functions in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R). METHODS: Stroke-prone spontaneously hypertensive rats were treated with vehicle, aspirin, clopidogrel, and cilostazol from 8 to 10 weeks of age. Physiological parameters, regional cerebral blood flow, and serum lipids were examined. Motor and cognitive functions were evaluated weekly by the Rotorod and water maze task. Spontaneous infarct volume, oxidative stress markers for lipid, protein, and DNA at the ischemic boundary zone of spontaneous infarction, and the IGF-1R-positive cell ratio in the hippocampus were immunohistochemically examined in brain sections. IGF-1Rß expression in the hippocampus was assessed by Western blotting. RESULTS: The antiplatelet drugs, cilostazol and clopidogrel, reduced the spontaneous infarct volume more than aspirin. Only cilostazol improved motor and cognitive functions with a significant increase (P<0.05) in the memory-related IGF-1R-positive ratio and IGF-1Rß expression in the hippocampus. Cilostazol reduced the 4 oxidative stress markers in affected neurons in stroke-prone spontaneously hypertensive rats regardless of blood pressure, regional cerebral blood flow, or serum lipid levels. CONCLUSIONS: The present results suggest that a possible pleiotropic effect of cilostazol resulted in the reduction of spontaneous infarct volume and preservation of motor and spatial cognitive functions. The increase of IGF-1R-positive cells in the hippocampal CA1 region could partly explain the preservation of spatial cognitive function in stroke-prone spontaneously hypertensive rats.