Involvement of brain oxidation in the cognitive impairment in a triple transgenic mouse model of Alzheimer's disease: noninvasive measurement of the brain redox state by magnetic resonance imaging.

Oxidative stress is considered to be related to the onset and/or progression of Alzheimer's disease (AD), but there is insufficient evidence of its role(s). In this study, we evaluated the relationships between the brain redox state and cognitive function using a triple transgenic mouse model of AD (3 × Tg-AD mouse). One group of 3 × Tg-AD mice started to receive an α-tocopherol-supplemented diet at 2 months of age and another group of 3 × Tg-AD mice was fed a normal diet. The levels of α-tocopherol, reduced glutathione, oxidized glutathione, and lipid peroxidation were decreased in the cerebral cortex and hippocampus at 4 months of age in the 3 × Tg-AD mice fed a normal diet. These reductions were abrogated by the supplementation of α-tocopherol in the diet. During Morris water maze testing, the 3 × Tg-AD mice did not exhibit cognitive impairment at 4 months of age, but started to show cognitive dysfunction at 6 months of age, and α-tocopherol supplementation suppressed this dysfunction. Magnetic resonance imaging (MRI) using 3-hydroxymethyl-proxyl as a probe showed decreases in the signal intensity in the brains of 3 × Tg-AD mice at 4 months of age, and this reduction was clearly attenuated by α-tocopherol supplementation. Taken together, these findings suggest that oxidative stress can be associated with the cognitive impairment in 3 × Tg-AD mice. Furthermore, MRI might be a powerful tool to noninvasively evaluate the increases in reactive radicals, especially those occurring during the early stages of AD.

Contribution of sustained Ca2+ elevation for nitric oxide production in endothelial cells and subsequent modulation of Ca2+ transient in vascular smooth muscle cells in coculture.

To elucidate the intracellular Ca2+ (Ca2+i ) transient responsible for nitric oxide (NO) production in endothelial cells (ECs) and the subsequent Ca2+i reduction in vascular smooth muscle cells (VSMCs), we administrated four agonists with different Ca2+i-mobilizing mechanisms for both cells in iso- or coculture. We monitored the Ca2+i of both cells by two-dimensional fura-2 imaging, simultaneously measuring NO production as NO2-. The order of potency of the agonists in terms of the peak Ca2+i in ECs was bradykinin (100 nM) > ATP (10 microM) > ionomycin (50 nM) > thapsigargin (1 microM). In contrast, the order in reference to both the extent of Ca2+i reduction in cocultured VSMCs and the elevation in NO production over the level of basal release in ECs completely matched and was ranked as thapsigargin > ionomycin > ATP > bradykinin. Treatment by NG-monomethyl-L-arginine monoacetate but not indomethacin or glybenclamide restored the Ca2+i response in cocultured VSMCs to the isoculture level. In ECs, when the Ca2+ influx was blocked by Ni2+ or by chelating extracellular Ca2+, all four agonists markedly decreased NO production, the half decay time of the Ca2+i degenerating phase, and the area under the Ca2+i curve. The amount of produced NO hyperbolically correlated to the half decay time and the area under the Ca2+i curve but not to the Ca2+i peak level. Thus, the sustained elevation of Ca2+i in ECs, mainly a result of Ca2+ influx, determines the active NO production and subsequent Ca2+i reduction in adjacent VSMCs. Furthermore, L-arginine but not D-arginine or L-lysine at high dose (5 mM) without agonist enhanced the NO production, weakly reduced the Ca2+i in ECs, and markedly decreased the Ca2+i in VSMCs, demonstrating the autocrine and paracrine effects of NO (Shin, W. S., Sasaki, T., Kato, M., Hara, K., Seko, A., Yang, W. D., Shimamoto, N., Sugimoto, T., and Toyo-oka, T. (1992) J. Biol. Chem. 267, 20377-20382).

Preventive effect of a quinonyl derivative of N-acetylmuramyl dipeptide, QMDP-66, against adriamycin-induced ECG abnormalities in rats.

The effects on adriamycin cardiotoxicity of an immunoadjuvant, 2-[2-acetamido-2-deoxy-6-0-[10-(2,3-dimethoxy-5-methyl-1, 4-benzo-quinon-6-yl) decanoyl]-D-glucopyranos-3-0-yl]-D-propionyl-L-valyl D-isoglutamine methyl ester (QMDP-66), and a reference compound, ubiquinone-10, were studied in Wistar Kyoto (WKY) rats. Adriamycin, 1 mg/kg/day intra-peritoneally (i.p.) for 23 days, elicited cardiotoxicity, as judged by widening of the QRS complexes in ECGs. Electron microscopic examination of myocytes from the treated rats revealed many cytoplasmic vacuoles possibly originating from deranged endoplasmic reticula or mitochondria. In addition, the treatment significantly inhibited body weight gain, and decreased ventricular weight. QMDP-66 alone, 1 mg/kg/day i.p. for 23 days, had no effect on the parameters described above. When QMDP-66 (1 mg/kg/day, i.p.) or ubiquinone-10 (3 mg/kg/day, i.p.) was administered together with adriamycin, the widening of the QRS complexes was significantly depressed, and cytoplasmic vacuoles in myocytes were rarely observed. The QMDP-66 or ubiquinone-10 treatment, however, did not alleviate the decrease in body weight gain or ventricular weight due to adriamycin. Heart rate was not significantly changed by any of the treatments. These findings suggest that QMDP-66 is an effective antidote against adriamycin cardiotoxicity.