A model of MPP+ induced generation of two waves of ROS in dopaminergic neurons and mechanisms of blockade by losartan. MPTP is converted to MPP+ in astrocytes by monoamine oxidase B . Specific uptake of MPP+ released from astrocytes into dopaminergic neurons occurs via a cell membrane dopamine transporter (DAT). After entering the cytosol, MPP+ binds and inhibits mitochondrial complex I, leading to an increase in mitochondrial ROS (First Wave), which, in turn, leads to the activation of the extramitochondrial NADPH oxidase complex to generate superoxide (Second Wave). The Second Wave of ROS can be blocked by pharmacological and genetic inhibition of NADPH oxidase, as well as inhibition of protein synthesis by cyclohexamide (c-hex), and by losartan blockade of AT1 receptor. Cell surface Nox2-generated superoxide is readily dismutated to H2O2, which can act either extracellularily or cross into the cytosol of dopaminergic neurons for propagation of the two-wave cascade. Reaction of superoxide with nitric oxide can generate highly cytotoxic peroxynitrite, which has been reported for its neurotoxicity in models of PD [74, 75].