Measurement of striatal H2O2 by microdialysis following global forebrain ischemia and reperfusion in the rat: correlation with the cytotoxic potential of H2O2 in vitro.

Toxic reactive oxygen species have been implicated as important mediators of tissue injury after reperfusion of ischemic organs. When rats are subject to 30 min global forebrain ischemia, 24 h following this insult, there is substantial loss of medium-sized neurones as revealed by histological sectioning of the striatal region of the forebrain. The goal of this study was to utilize microdialysis to directly measure one of the more stable intermediates of reduced molecular oxygen, H2O2 in the rat striatum following 4-vessel occlusion and reperfusion, and to correlate these levels with H2O2 toxicity to neurones grown in culture. A significant rise in striatal H2O2 levels was observed for about 1 h during reperfusion, amounting to an increase of approximately 100 microM at the peak. In control experiments where the dialysis probe was embedded in cortical regions surrounding the striatum (where there is no neuronal loss due to the ischemic episode), there was no measurable increase in tissue H2O2 levels. H2O2 has been previously shown to be neurotoxic to PC12 cells as well as rat primary hippocampal neurones at comparable concentrations striatal neurones experience during reperfusion. We demonstrate that H2O2 is also neurotoxic to the human cortical neuronal cell line, HCN-1A. These experiments establish an important link between oxidant generation and neuronal loss in this tissue following global forebrain ischemia.

Differential effects of selected dopaminergic agents on locomotor activity in normotensive and spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) exhibit a significantly higher level of spontaneous locomotor activity than age-matched normotensive controls (WKY). The direct-acting dopamine agonists, apomorphine and pergolide, produced a biphasic effect on locomotor activity levels in normotensive controls. Low doses of these agonists decreased activity levels, while higher doses of these agonists dramatically stimulated activity. In marked contrast to these results was the effect observed in the SHR, in which these agonists at all doses tested decreased activity. Amphetamine, a dopamine releaser, stimulated activity levels in both the WKY and SHR; however, the magnitude of the increase was somewhat attenuated in the SHR.

Nylidrin: a potent anti-hypertensive agent in hypertensive rats.

Nylidrin HCl lowered the blood pressure and increased the heart rate of conscious, spontaneously hypertensive rats (SHR), Goldblatt hypertensive rats, and DOCA hypertensive rates. In SHR, the minimum effective dose was 0.5 mg/kg, s.c. At that dose, the anti-hypertensive activity of nylidrin lasted more than 3 hours. Propranolol reversed both effects on blood pressure and heart rate by nylidrin, whereas atenolol, a specific cardiac beta 1 blocker, only blocked or reversed the tachycardia caused by nylidrin but did not block the anti-hypertensive effect of the compound. In normotensive rats of Wistar/Kyoto strain (WKY) and Holtzman strain, nylidrin at 5 or 10 mg/kg, s.c., produced a transient hypotensive effect which lasted less than an hour and tachycardia that persisted for several hours. In WKY, atenolol prolonged the hypotensive activity of the compound by partially reversing the tachycardia. These observations indicate that SHR is more sensitive than WKY to the anti-hypertensive activity of nylidrin, which is probably caused by vasodilatation mediated by beta 2 receptors.

Control of obesity in Avy/a mice by 5alpha-androstan-17-one.

Treating VY/WfL-Avy/a mice with 5 alpha-androston-17-one, a mammalian glucose-6-phosphate dehydrogenase inhibitor, prevented the mice from becoming obese. The weight difference between treated and control Avy/a mice was mainly due to a decreased accumulation of triacylglycerol. The compound did not suppress appetite, had no detectable toxicity and did not affect the lipogenesis rates in the liver and carcass. The weight-controlling effect of 5alpha-androstan-17-one in Avy/a mice was reversible upon withdrawal of treatment.

Dissociation of obesity, hypercholesterolemia and diabetes from atherosclerosis in ob/ob mice.

Genetically obese, diabetic and hypercholesterolemic C57BL/6J-ob/ob mice were placed on Purina Laboratory Chow containing 2% cholesterol for up to 4 months. They developed higher plasma cholesterol levels and accumulated an increased quantity of cholesterol in the liver but failed to develop atherosclerotic lesions in the aorta as would be expected in an obese, diabetic and hypercholesterolemic human adult.

Prevention of obesity in Avy/a mice by dehydroepiandrosterone.

Dehydroepiandrosterone, a mammalian glucose-6-phosphate dehydrogenase inhibitor, prevented Avy/a mice from becoming obese. Decreased accumulation of triacylglycerol accounted for a large portion of the weight difference between treated and control Avy/a mice. Hepatic lipogenesis as measured by 3H2O incorporation into total lipid was less in the dehydroepiandrosterone-treated mice. Dehydroepiandrosterone did not suppress appetite and had no apparent toxic effects at the doses used, and its weight controlling effects were reversible upon withdrawal of treatment.

Triacylglycerol contents and in vivo lipogenesis of ob/ob, db/db and Avy/a mice.

The triacylglycerol content and the in vivo lipogenesis rates of the liver and the carcass of 12 groups of mice were studied. They were mice of three strains and affected by mutations at three loci: C57BL/6J-ob/ob and normal mice; C57BL/KsJ-db/db and normal mice; and VY/WfL-Avy/a and normal mice. Each type of mice was studied at two body weight levels, before and after the mutants became grossly obese. It was found that the C57BL/6J-ob/ob and the C57BL/KsJ-db/db mice had the characteristics of juvenile type obesity. They had higher lipogenesis rates and accumulated more triacylglycerol when they were young. They gained weight rapidly mainly due to the accumulation of more triacylglycerol as they matured. Their total triacylglycerol content could reach 50% of their body weight. At maturity, their lipogenesis rates had decreased to normal. In contrast, the VY/WfL-Avy/a mice had the characteristics of maturity-onset type obesity. When they were young, they did not have higher lipogenesis rates and had only a moderate amount of triacylglycerol stored. They did not gain weight rapidly as they matured. However, when they reached maturity, their lipogenesis rate did not decrease. Their body triacylglycerol content was about 25% of their weight.

An analysis of the relationships among obesity, plasma insulin and hepatic lipogenic enzymes in "viable yellow obese" mice (Avy/a).

The development of obesity, hyperinsulinemia and six hepatic lipogenic enzymes in Avy/a mice were compared to that in a/a mice. Correlation between body weight, liver weight, plasma insulin concentration and activities of hepatic enzymes was analyzed. In the Avy/a mice, body weight, liver weight and plasma insulin level increased steadily as the mice aged. In the a/a mice, the change of these three parameters was much slower. Plasma insulin concentration in a/a mice did not increase until eight months of age. Compared with a/a mice, Avy/a mice had higher 6-phosphogluconate dehydrogenase and fatty acid synthetase activities at two months of age; lower citrate cleavage enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities at three months of age; lower citrate cleavage enzyme and glucose-6-phosphate dehydrogenase and higher acetyl CoA carboxylase activities at five months of age; and higher malic enzyme, citrate cleavage enzyme and 6-phosphogluconate dehydrogenase activities at eight months of age. There were significant correlations between plasma insulin level and body weight and between plasma insulin level and the activities of malic enzyme and citrate cleavage enzyme in Avy/a mice. The correlation between body weight and malic enzyme and citrate cleavage enzyme activities disappeared after the analysis was adjusted for plasma insulin level.