RESUMO
beta-Amyloid cores contain considerable amounts of D-Ser and D-Asp residues in Alzheimer's disease. We investigated the cytotoxic effects of various synthetic beta-amyloids, including D-Ser-substituted derivatives, on primary cultured neurons and nonneuronal HeLa cells. beta 25-35, its D-Ser26-substituted derivative, and beta 1-40 in 10-100 nM specifically suppressed mitochondrial succinate dehydrogenase activity [MTT [3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide] reduction] in HeLa cells, which are dependent on ATP production mainly from glycolysis, but did not exert detectable cytotoxicity, assessed by dye exclusion test, NADH levels, and uptake of [3H]Leu and [3H]Tdr. The beta-amyloids, on the other hand, did exert neurodegenerative effects on rat hippocampal cultured neurons in which ATP is mostly synthesized by the mitochondrion. The activities of beta 25-35 and [D-Ser26] beta 25-35 are dependent on their having beta-structures and not random forms. Although beta 25-35 was degraded rapidly by proteinase(s) in brain extract or leucine aminopeptidase, [D-Ser26] beta 25-35 is fairly resistant. These results indicate that one of the primary targets of beta-amyloids is suppression of mitochondrial succinate dehydrogenase, and the vulnerability of the brain of beta-amyloids can be explained by its large dependence on mitochondrial energy production. Moreover, racemization of serine residues of beta-amyloids may be involved in neurodegeneration and formation of senile plaques through escaping from the degradation process by brain proteinases.
Assuntos
Peptídeos beta-Amiloides/análogos & derivados , Peptídeos beta-Amiloides/farmacologia , Mitocôndrias/enzimologia , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/química , Sequência de Aminoácidos , Peptídeos beta-Amiloides/química , Animais , Química Encefálica , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Sais de Tetrazólio/metabolismo , Tiazóis/metabolismo , Extratos de Tecidos/farmacologiaRESUMO
Serial changes of left ventricular (LV) mass and LV function were evaluated in nine patients with essential hypertension and LV hypertrophy (LVH) after administration of diltiazem (180 mg/day). LV mass and LV function were determined at baseline and at 6 months of therapy by electrocardiogram-gated cardiac CT (ECG-gated CCT) scanning and two-dimensional-guided M-mode echocardiography. At baseline measurements, ECG-gated cardiac scanning clearly showed LVH in two patients in whom no LVH was observed by echocardiography. The systolic and diastolic blood pressures were reduced significantly after 6 months of drug therapy (189-156 mm Hg; p less than 0.01, 111-96 mm Hg; p less than 0.01, respectively). Sequential ECG-gated cardiac scanning revealed a marked reduction in thickness of the interventricular septum (IVS), LV anterior wall (AW), and LV posterior wall (PW) (15.0-12.1 mm; p less than 0.01, 12.5-9.7 mm; p less than 0.01, 10.7-8.3 mm; p less than 0.05, respectively). Simultaneous echocardiographic measurements revealed a reduction in LV mass in six of these patients and a significant reduction in thickness of the IVS (12.1-11.0 mm; p less than 0.05). ECG-gated cardiac scanning demonstrated significant reductions in the thickness of the LVAW, which are difficult to detect by echocardiography. Diltiazem had no effect on the ejection fraction (EF) measured by both methods. In conclusion, ECG-gated cardiac scanning allowed more accurate diagnosis and quantitation of LVH than conventional echocardiography, and LVH in patients with essential hypertension could be reversed by the administration of diltiazem.