Pharmacological manipulation of the dopaminergic system affects wheel-running activity in differentially active mice.

The genetic factors involved in the regulation of physical activity are not well understood. The dopamine system has been implicated in the control of voluntary locomotion and wheel running (WR) in mice and is thus a likely candidate as a genetic/biological system important to the regulation of physical activity. This study evaluated the effects of four different dopaminergic acting drugs on WR in differentially active inbred strains of mice. High active C57L/J (n=7, 3 controls, 4 experimental) and low active C3H/HeJ (n=8, 3 controls, 5 experimental) were analyzed for baseline wheel-running indices of distance (km/day), duration (mins/day), and speed (m/min) for 21 days. Experimental mice received increasing doses over four days of each of the following drugs: SKF 81297 (D1 agonist), SCH 23390 (D1 antagonist), GBR 12783 (DAT inhibitor), and AMPT (tyrosine hydroxylase inhibitor). Each drug dose response treatment was separated by three days of recovery (no drug injections). WR indices were monitored during drug treatments and during drug wash-out phases. SKF 81297 significantly reduced (p=0.0004) WR in the C57L/J mice, but did not affect WR in the C3H/HeJ mice. GBR 12783 significantly increased (p=0.0005) WR in C3H/HeJ mice, but did not affect WR in C57L/J mice. Only duration (not overall WR) was significantly reduced in C57L/J mice in response to SCH 23390 (p=0.003) and AMPT (p=0.043). SCH 23390 (p=0.44) and AMPT (p=0.98) did not significantly affect WR in C3H/HeJ mice. These results suggest that genetic differences in dopamine signaling may play a role in the WR response to dopaminergic-acting drugs in inbred strains of mice. The high activity in the C57L/J strain appears most responsive to D1-like receptor acting drugs, while in the C3H/HeJ strain, dopamine re-uptake appears to have an influence on activity level.

Antibodies to oxidised low-density lipoproteins and cardiolipin in pre-eclampsia and eclampsia.

The objective of this study was to test the hypothesis that autoantibodies to phospholipids and to oxidised low-density lipoprotein (ox-LDL) are increased in pre-eclamptic and eclamptic women compared with normal pregnancy. Serum concentrations of autoantibodies to ox-LDL and to cardiolipin were measured in 21 non-pregnant controls, 29 pregnant controls, 21 pre-eclamptic and six eclamptic women. Concentrations of IgG antibodies to ox-LDL and to cardiolipin were not significantly different in women with eclampsia as compared with the non-pregnant controls, pregnant controls and pre-eclampsia. Concentrations of IgM antibodies to cardiolipin were significantly lower in women with pre-eclampsia compared with non-pregnant controls and eclampsia. All three pregnant states differ markedly from the non-pregnant controls, of whom only 5% (1 of 21) had "high positive" IgG antibodies. These results suggest that ACAs rise as a result of the pregnant state rather than as a result of preeclampsia or eclampsia. According to these results, there is no evidence of increased production of serum autoantibodies against modified LDL in African women with pre-eclampsia, which may reflect reduced lipid peroxidation involving lipoproteins or no link at all. In addition, IgG and IgM anticardiolipin antibodies have no diagnostic value in preeclampsia and eclampsia.

Oxidative stress in pre-eclampsia.

BACKGROUND: The objective of this study was to test the hypothesis that maternal plasma, cord plasma and placental tissue lipid peroxidation products are increased and antioxidants are decreased in women with pre-eclampsia. METHODS: Placenta, maternal and cord plasma were collected at delivery from 29 normal, 21 pre-eclamptic and six eclamptic women. Plasma was collected from 21 non-pregnant matched controls. The analyses were measured by HPLC and colorimetric assay. RESULTS: Plasma maternal concentrations of uric acid, LPO, MDA, ascorbic acid, vitamin E and cholesterol were not significantly different in pre-eclampsia as compared with normal pregnancy. Plasma concentrations of ascorbic acid and vitamin E were not significantly different in normal pregnancy as compared with the non-pregnant controls. Cord plasma concentrations of MDA were significantly higher in eclampsia (1.16+/-0.26 micromol/l) as compared with normal pregnancy (0.79+/-0.05 micromol/l, p<0.02) and pre-eclampsia (0.83+/-0.05 micromol/l, p<0.05). Cord plasma concentrations of vitamin E were significantly higher in eclampsia (21.3+/-7.5 micromol/l) as compared with normal pregnancy (10.2+/-1.1 micromol/l, p<0.01) and pre-eclampsia (10.4+/-1.8 micromol/l, p<0.04). Placental concentrations of LPO, MDA and ascorbic acid were not significantly different in pre-eclampsia as compared with normal pregnancy. Plasma cord concentrations of LPO and placental concentrations of vitamin E were undetected for normal pregnant, pre-eclamptic and eclamptic women respectively. Uric acid concentrations were significantly increased in eclampsia as compared with the non-pregnant controls (p<0.0001), normal pregnant controls (p<0.0001) and pre-eclampsia (p<0.008). CONCLUSIONS: The findings in this study do not show any evidence of deficiency in the maternal protective antioxidant systems or increased production of lipid peroxidation products, LPO and MDA in African women with pre-eclampsia as compared with normal pregnancy. However, there was evidence of increased cord plasma concentrations of MDA and vitamin E in eclampsia as compared with normal pregnancy and pre-eclampsia. The placenta may be effective in removing MDA. The antioxidant uric acid serves as a protective role whilst the antioxidant and oxidant capacity in the different study groups remained unchanged.

Systemic inflammatory indices in pre-eclampsia and eclampsia.

The objective of this study was to test the hypothesis that TNF-alpha, TNFp55 receptor and sICAM-1 are markers of immune activation, protective response to concentrations of TNF-alpha and endothelial cell activation, respectively, in pre-eclampsia. In addition, MPO and sL-selectin were selected as blood discriminators of neutrophil activation. This was a cross-sectional study comparing 21 non-pregnant controls, 29 normal pregnant controls, 21 pre-eclamptic and six eclamptic women. Blood concentrations of TNF-alpha, sTNFp55 receptor, sICAM-1, sL-selectin, myeloperoxidase, leucocyte count, neutrophil count, C-reactive protein and gamma-glutamyl transferase were estimated. The neutrophil count was significantly decreased in pre-eclampsia compared with normal pregnancy (9.12+/-0.95 vs. 12.52+/-0.80 x 10(9)/l, P<0.01). Serum concentrations of sL-selectin were significantly higher in non-pregnant controls compared with pregnant controls (P<0.0001), pre-eclampsia (P<0.0001) and eclampsia (P<0.0001). Serum concentrations of TNF-alpha, sTNFp55 receptor, sICAM-1, sL-selectin and MPO were not significantly different in women with pre-eclampsia compared with normal pregnancy. Serum concentrations of TNF-alpha, sTNFp55, sICAM-1, sL-selectin and MPO did not discriminate between normal and pre-eclamptic pregnancies. The high neutrophil count in normal and eclamptic pregnancies and the lack of shedded L-selectin suggests that neutrophil exudation to inflammatory sites was increased in women with an accompanying inflammatory response.

The response of the dietary anti-oxidants vitamin E and vitamin C to oxidative stress in pre-eclampsia.

The relationship of oxidants and anti-oxidants in preeclampsia with reference to the dietary anti-oxidants vitamin C and vitamin E was investigated. Three groups of patients were studied in the third trimester of pregnancy: normotensives ( n = 32), mild pre-eclamptics ( n = 15) and severe pre-eclamptics ( n = 31) with a group of healthy non-pregnant women ( n = 18) serving as a control. Total anti-oxidant concentration, the concentrations of vitamin C, vitamin E, superoxide dismutase, uric acid and the concentration of total oxidant activity, as reflected by lipid peroxides, were measured in plasma or red blood cells. Total anti-oxidants and vitamin C concentrations were significantly lower in pre-eclamptic patients than in pregnant controls (P < 0.05), with the concentrations in the pregnant controls being significantly lower than in the non-pregnant controls (P < 0.05). There was no significant difference in vitamin E concentration for all four groups. Superoxide dismutase activity was significantly lower in the normal pregnancy group. Lipid peroxides were significantly increased in the three pregnant groups (P < 0.05) with no differences noted between these groups. The relationship of oxidants to anti-oxidants in pregnancy and pre-eclampsia is dependent on many factors but balance appears to be upset in pre-eclampsia. The reduction in anti-oxidant concentrations in pre-eclampsia suggests either a primary deficit or consumption of the anti-oxidants measured. Of the dietary anti-oxidants studied, vitamin C was most affected in pre-eclampsia.