The Neurotoxins Rotenone, Paraquat and Manganese Exert Different Effects on Human Isolated Lymphocytes

Aims: To examine the effects of the neurotoxins rotenone, paraquat and manganese on human circulating lymphocytes. Methods: Lymphocytes were isolated by density-gradient centrifugation from peripheral venous blood. Cell viability, proliferation, interferon (IFN)-γ and interleukin (IL)-4 production, proteasome 20S and caspase 3 and 9 activity were measured in cells at rest and after stimulation with anti-CD3/anti-CD28 antibodies. Results: Rotenone and manganese concentration-dependently reduced anti-CD3/anti-CD28-induced cell proliferation and IFN-γ production. Manganese also inhibited IL-4 production while paraquat had no major effect on proliferation or on IFN-γ or IL-4 production. Proteasome 20S activity was reduced by paraquat and manganese but not by rotenone, while caspase 9 activity was extensively inhibited by rotenone and manganese and only slightly affected by paraquat, and caspase 3 activity was not affected by any of the neurotoxins tested. Conclusions: Rotenone is widely used in animal models of neurodegeneration and its immune effects should be therefore further assessed in vivo. In addition, circulating lymphocytes warrant further evaluation as early markers of manganese exposure.