Dopamine induces proteasome inhibition in neural PC12 cell line.

The autoxidation and enzymatic catabolism of dopamine results in the generation of reactive oxygen species (ROS), which may possibly contribute to oxidative stress in multiple neurodegenerative disorders. Recent studies indicate that proteasome inhibition occurs in numerous neurodegenerative conditions, possibly as the result of oxidative stress, although the effects of dopamine on proteasome activity have not been determined. In the present study we examined the effects of dopamine on proteasome activity in the neural PC12 cell line. Application of dopamine induced a dose- and time-dependent decrease in proteasome activity, which occurred prior to cell death. Application of an antioxidant (gluthathione monoethyl ester), monoamine oxidase inhibitors (deprenyl, clogyline, paragyline), or an inhibitor of dopamine uptake (nomifensine) attenuated dopamine toxicity and dopamine-induced proteasome impairment. Application of the proteasome inhibitor lactacystin increased the toxicity of dopamine and the levels of protein oxidation following administration of dopamine. Together, these data indicate that dopamine induces proteasome inhibition that is dependent, in part, on ROS and dopamine uptake, and suggest a possible role for proteasome inhibition in dopamine toxicity.

Development and characterization of a model of eosinophil-mediated cardiomyopathy in rats infected with Toxocara canis.

This study begins testing the hypothesis that a causal relationship exists between hypereosinophilia and cardiac dysfunction. Rats infected with the nematode Toxocara canis develop marked hypereosinophilia, with peak blood eosinophil levels of approximately 3,500 eosinophils/mm3 whole blood observed approximately 14 days postinfection. Corresponding to the increase in blood eosinophils of infected animals was a decrease in cardiac performance. By 14 days postinfection, cardiac work had declined approximately 25% while negative first derivative of pressure (-dP/dt) fell approximately 10%. As the extent of hypereosinophilia declined from a peak of approximately 3,500 eosinophils/mm3 whole blood to a new steady state of approximately 1,000 eosinophils/mm3, the degree of cardiac dysfunction also was reduced. Cardiac work was 10-15% less in rats 28-42 days postinfection while -dP/dt was 5% depressed in these animals. Myocardial dysfunction was also observed following exposure of perfused hearts obtained from uninfected rats to buffer containing activated eosinophils. The hearts exposed to activated eosinophils exhibited marked histological alterations, characterized by distention of the intermyocyte space, increased pericapillary space, and focal losses of striated staining pattern. These changes were associated with the accumulation of eosinophils within the myocardium, as evidenced by the cytochemical demonstration of eosinophil peroxidase activity within the heart. The data support the hypothesis that hypereosinophilia can lead to cardiac dysfunction.