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Ann Neurol ; 48(2): 148-55, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10939564


Alzheimer's disease (AD) is characterized by the deposition in brain of beta-amyloid (Abeta) peptides, elevated brain caspase-3, and systemic deficiency of cytochrome c oxidase. Although increased Abeta deposition can result from mutations in amyloid precursor protein or presenilin genes, the cause of increased Abeta deposition in sporadic AD is unknown. Cytoplasmic hybrid ("cybrid") cells made from mitochondrial DNA of nonfamilial AD subjects show antioxidant-reversible lowering of mitochondrial membrane potential (delta(gYm), secrete twice as much Abeta(1-40) and Abeta(1-42), have increased intracellular Abeta(1-40) (1.7-fold), and develop Congo red-positive Abeta deposits. Also elevated are cytoplasmic cytochrome c (threefold) and caspase-3 activity (twofold). Increased AD cybrid Abeta(1-40) secretion was normalized by inhibition of caspase-3 or secretase and reduced by treatment with the antioxidant S(-)pramipexole. Expression of AD mitochondrial genes in cybrid cells depresses cytochrome c oxidase activity and increases oxidative stress, which, in turn, lowers delta(psi)m. Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways, which drive caspase 3-mediated Abeta peptide secretion and may account for increased Abeta deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of delta(psi)m and reduction of elevated Abeta secretion.

Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Morte Celular/fisiologia , Células Híbridas/metabolismo , DNA Mitocondrial/metabolismo , Humanos , Imuno-Histoquímica , Neuroblastoma , Células Tumorais Cultivadas
J Neurochem ; 74(4): 1384-92, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10737593


Oxidative stress induced by acute complex I inhibition with 1-methyl-4-phenylpyridinium ion activated biphasically the stress-activated c-Jun N-terminal kinase (JNK) and the early transcription factor nuclear factor-kappaB (NF-kappaB) in SH-SY5Y neuroblastoma cells. Early JNK activation was dependent on mitochondrial adenine nucleotide translocator (ANT) activity, whereas late-phase JNK activation and the cleavage of signaling proteins Raf-1 and mitogen-activated protein kinase (MAPK) kinase (MEK) kinase (MEKK)-1 appeared to be ANT-independent. Early NF-kappaB activation depended on MEK, later activation required an intact electron transport chain (ETC), and Parkinson's disease (PD) cybrid (mitochondrial transgenic cytoplasmic hybrid) cells had increased basal NF-kappaB activation. Mitochondria appear capable of signaling ETC impairment through MAPK modules and inducing protective NF-kappaB responses, which are increased by PD mitochondrial genes amplified in cybrid cells. Irreversible commitment to apoptosis in this cell model may derive from loss of Raf-1 and cleavage/activation of MEKK-1, processes reported in other models to be caspase-mediated. Therapeutic strategies that reduce mitochondrial activation of proapoptotic MAPK modules, i.e., JNK, and enhance survival pathways, i.e., NF-kappaB, may offer neuroprotection in this debilitating disease.

MAP Quinase Quinase Quinase 1 , Mitocôndrias/enzimologia , NF-kappa B/metabolismo , Neurônios/enzimologia , Doença de Parkinson/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , 1-Metil-4-fenilpiridínio/farmacologia , Nucleotídeos de Adenina/metabolismo , Benzotiazóis , Transporte de Elétrons , Ativação Enzimática/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Herbicidas/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , Neuroblastoma , Neurônios/química , Neurônios/citologia , Estresse Oxidativo/fisiologia , Peptídeos/farmacologia , Pramipexol , Proteínas Serina-Treonina Quinases/análise , Proteínas Proto-Oncogênicas c-raf/análise , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Superóxido Dismutase/metabolismo , Tiazóis/farmacologia , Células Tumorais Cultivadas
Ter Arkh ; 69(9): 27-31, 1997.
Artigo em Russo | MEDLINE | ID: mdl-9411821


MR tomography of the brain, MR angiography of extra- and intracranial arteries and veins, duplex scanning of the extracranial arteries and veins were performed according to the technique spin-echo, by the technique 2D, 3D time-to-flight (unit "Magnetom 63 SP", 1.5 T), Acuson 128 technique, respectively, in 21 patients with high and malignant blood hypertension (BH) and 11 healthy controls. In BH patients magnetic resonance has detected signs of hypertensive encephalopathy: dilation of the liquor-conduction system, small hyperintensive foci in the white substance, zones of periventricular hyperintensity. MR angiograms visualized flexures of the extracranial arteries. MR phlebograms were characterized: 1) reduction of or absence of the signal from the blood flow along the cross, sigmoid sinus and internal jugular vein of the hemisphere associated with enlargement of the contralateral structures; 2) lowering of the signal intensity from the blood flow along the upper sagittal sinus; 3) dilation of the emission veins and superficial cerebral veins. These abnormalities should be considered in the treatment of BH.

Encéfalo/patologia , Veias Cerebrais/patologia , Cavidades Cranianas/patologia , Hipertensão/diagnóstico , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética , Doença Aguda , Adolescente , Adulto , Feminino , Humanos , Hipertensão Maligna/diagnóstico , Angiografia por Ressonância Magnética/instrumentação , Angiografia por Ressonância Magnética/métodos , Angiografia por Ressonância Magnética/estatística & dados numéricos , Imagem por Ressonância Magnética/instrumentação , Imagem por Ressonância Magnética/métodos , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino
Ter Arkh ; 69(12): 34-7, 1997.
Artigo em Russo | MEDLINE | ID: mdl-9503531


Ultrasound dopplerography, MR tomography were performed to assess the brain, major cerebral arteries and audiometry was conducted to study cochleovestibular system in 38 patients aged 16-63 years with heterozygous family hypercholesterolemia. Vascular disorders and defects in the white brain matter (in patients with transitory hypertension) were registered. Complications of cerebral atherosclerosis (brain infarction, perception cochleovestibular alterations) contributed to aggravation of ischemic heart disease. Patients with heterozygous family hypercholesterolemia should be observed and treated by cardiologist, neuropathologist and psychoneurologist to prevent cardiocerebral complications.

Artérias Cerebrais , Transtornos Cerebrovasculares/complicações , Hiperlipoproteinemia Tipo II/complicações , Adolescente , Adulto , Velocidade do Fluxo Sanguíneo , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Angiografia Cerebral , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/patologia , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/fisiopatologia , Colesterol/sangue , Feminino , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/complicações , Triglicerídeos/sangue , Ultrassonografia Doppler
Ter Arkh ; 68(9): 26-31, 1996.
Artigo em Russo | MEDLINE | ID: mdl-9005607


NMR tomography (NMRT) of the brain and NMR angiography (NMRA) of the extra- and intracranial arteries were performed on the unit Magnetom 63 SP (1.5 T) Siemens in 13 healthy controls and 87 patients with cerebrovascular diseases initiated by arterial hypertension and atherosclerosis of major cerebral arteries. NMRA image of arterial impairment comprise curved extracranial arteries. NMRT picture of the brain was changed (extension of liquor spaces, small hyperintensive foci in the white matter) in mild and moderate hypertension. Frequency of these phenomena and their severity increase with growing severity of the disease reaching maximum in malignant hypertension. In atherosclerosis of the major cerebral arteries NMRT often detected strokes, for the most part ischemic. A direct relationship between the degree of arterial stenosis and incidence of the strokes was not found.

Encéfalo/patologia , Artérias Carótidas/patologia , Artérias Cerebrais/patologia , Hipertensão/diagnóstico , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética , Adolescente , Adulto , Idoso , Estenose das Carótidas/diagnóstico , Feminino , Humanos , Arteriosclerose Intracraniana/diagnóstico , Angiografia por Ressonância Magnética/instrumentação , Angiografia por Ressonância Magnética/estatística & dados numéricos , Imagem por Ressonância Magnética/instrumentação , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade
Vestn Rentgenol Radiol ; (3): 25-8, 1994.
Artigo em Russo | MEDLINE | ID: mdl-7985367


The authors analyze diagnostic potentialities of magnetic resonance (MR) angiography of the extra- and intracranial arteries in healthy volunteers and patients with arterial hypertension of various origins and course. Fifteen healthy subjects aged 18 to 40 and 33 patients with arterial hypertension were examined; 13 of these patients presented with essential hypertension, eleven with that combined with extracranial arteries atherosclerosis, and nine with nonspecific aortoartheritic. The most informative images were those of extra- and intracranial arteries in three-dimensional reconstruction making use of programs with a decreased magnetization vector angle and a short TR period when the vessel was characterized by a high intensity of the signal against the background of low-intensive adjacent tissues. MR angiography provides diagnostically reliable information on the status of extra- and intracranial arteries, permits imaging of vascular stenoses and occlusions, as well as of aneurysms and arteriovenous malformations. Analysis of MR angiographic and tomographic data permits a sufficiently accurate assessment of the relationships between MR tomographic picture of the brain and changes in extra- and intracranial arteries. MR angiography extends the potentialities of other MR tomographic methods in assessment of changes in small vessels and helps in a number of cases reduce the number of invasive interventions in examination of a patient.

Artérias Carótidas/patologia , Artérias Cerebrais/patologia , Hipertensão/diagnóstico , Angiografia por Ressonância Magnética , Adolescente , Adulto , Artérias Carótidas/anatomia & histologia , Artérias Carótidas/diagnóstico por imagem , Artérias Cerebrais/anatomia & histologia , Artérias Cerebrais/diagnóstico por imagem , Feminino , Humanos , Masculino , Cintilografia , Pentetato de Tecnécio Tc 99m , Doenças Vasculares/diagnóstico