Development of an animal model for gestational hypermethioninemia in rat and its effect on brain Na⁺,K⁺-ATPase/Mg²âº-ATPase activity and oxidative status of the offspring.

In the present study we developed a chemically induced experimental model for gestational hypermethioninemia in rats and evaluated in the offspring the activities of Na(+),K(+)-ATPase and Mg(2+)-ATPase, as well as oxidative stress parameters, namely sulfhydryl content, thiobarbituric acid-reactive substances and the antioxidant enzymes superoxide dismutase and catalase in encephalon. Serum and encephalon levels of methionine and total homocysteine were also evaluated in mother rats and in the offspring. Pregnant Wistar rats received two daily subcutaneous injections of methionine throughout the gestational period (21 days). During the treatment, a group of pregnant rats received dose 1 (1.34 µmol methionine/g body weight) and the other one received dose 2 (2.68 µmol methionine/g body weight). Control group received saline. After the rats give birth, a first group of pups was killed at the 7th day of life and the second group at the 21th day of life for removal of serum and encephalon. Mother rats were killed at the 21th day postpartum for removal of serum and encephalon. Both doses 1 and 2 increased methionine levels in encephalon of the mother rats and dose 2 increased methionine levels in encephalon of the offspring. Maternal hypermethioninemia also decreased the activities of Na(+),K(+)-ATPase, Mg(2+)-ATPase and catalase, as well as reduced total sulfhydryl content in the encephalon of the pups. This chemical model seems to be appropriate for studies aiming to investigate the effect of maternal hypermethioninemia on the developing brain during gestation in order to clarify possible neurochemical changes in the offspring.

Chronic variable stress induces oxidative stress and decreases butyrylcholinesterase activity in blood of rats.

Depressive disorders, including major depression, are serious and disabling, whose mechanisms are not clearly understood. Since life stressors contribute in some fashion to depression, chronic variable stress (CVS) has been used as an animal model of depression. In the present study we evaluated some parameters of oxidative stress [thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx)], and inflammatory markers (interleukin 6, C reactive protein, tumor necrosis factor-alpha and nitrites), as well as the activity of butyrylcholinesterase in blood of rats subjected to chronic stress. Homocysteine and folate levels also were measured. Stressed animals were submitted to different mild stressors for 40 days. After CVS, a reduction in weight gain was observed in the stressed group, as well as an increase in immobility time in the forced swimming test as compared with controls. Stressed animals presented a significant increase on TBARS and SOD/CAT ratio, but stress did not alter GPx activity and any inflammatory parameters studied. CVS caused a significant inhibition on serum butyrylcholinesterase activity. Stressed rats had higher plasmatic levels of homocysteine without differences in folate levels. Although it is difficult to extrapolate our findings to the human condition, the alterations observed in this work may be useful to help to understand, at least in part, the pathophysiology of depressive disorders.

Lower in vivo brain extracellular GABA concentration in diabetic rats during forced swimming.

Diabetic rats are more immobile during the forced-swimming test (FST) and GABAergic drugs reverse this behavior. We investigated if there is in vivo changes of GABA levels of diabetic rats during the FST. In vivo basal striatal GABA levels of streptozotocin diabetic rats are similar to non-diabetic rats. Non-diabetic rats presented a significant increase in GABA levels after the FST while the increase was delayed and lower in diabetic rats. These results suggest that diabetes may change GABA homeostasis and modify behavioral responses in an animal model of depression.

Development of an animal model for chronic mild hyperhomocysteinemia and its response to oxidative damage.

The purpose of this study was to develop a chronic chemically induced model of mild hyperhomocysteinemia in adult rats. We produced levels of Hcy in the blood (30µM), comparable to those considered a risk factor for the development of neurological and cardiovascular diseases, by injecting homocysteine subcutaneously (0.03µmol/g of body weight) twice a day, from the 30th to the 60th postpartum day. Controls received saline in the same volumes. Using this model, we evaluated the effect of chronic administration of homocysteine on redox status in the blood and cerebral cortex of adult rats. Reactive oxygen species and thiobarbituric acid reactive substances were significantly increased in the plasma and cerebral cortex, while nitrite levels were reduced in the cerebral cortex, but not in the plasma, of rats subjected to chronic mild hyperhomocysteinemia. Homocysteine was also seen to disrupt enzymatic and non-enzymatic antioxidant defenses in the blood and cerebral cortex of rats. Since experimental animal models are useful for understanding the pathophysiology of human diseases, the present model of mild hyperhomocysteinemia may be useful for the investigation of additional mechanisms involved in tissue alterations caused by homocysteine.