Nox2 interaction with p22phox forms a cytochrome b558 complex, which is towards necessary for NADPH oxidase activity for production of superoxide through recruit ment of a small GTPase Rac2, and of p47phox and p67phox to the plasma membrane. Formation of the NADPH oxidase complex may involve alternative iso forms of the component subunits. The current database of the human genome contains seven members of the NADPH oxidase family. The members include Nox1 5, together with two dual oxidases that Inhibitors,Modulators,Libraries contain both NADPH oxidase and peroxidase like domains. the tissue distribution of these seven family members varies significantly. The gene encoding Nox5 is not present in rodents. Although several pharmacological inhibitors of NADPH oxidase exist, their specificity, efficacy, and safety differ widely.

Inhibitors,Modulators,Libraries An alternative and potentially sounder approach to suppression of NADPH oxidase generated superoxide utilizes angiotensin II type 1 receptor blockers, exemplified by the original compound in this class, losartan. This is possible because generation of superoxide from NADPH oxidase is promoted by angio tensin II binding to the AT1 receptor, leading to induc tion of protein kinase C induced Nox2 signaling. Antagonists of the AT1 receptor such as candesartan and losartan suppress angiotensin II induced increases in superoxide production and Nox2 expression. Postmortem analysis of the midbrain of PD patients has provided evidence of microglial activation in this pathogenic Inhibitors,Modulators,Libraries process. This activation of microglia, the macrophage like, resident immune cells of the brain, and ROS production has been associated with the neurodegeneration characteristic of PD.

In response to brain injury and immunological challenges, microglia become readily activated and produce a wide array of cytokines and cytotoxic factors, including ROS as well as TNF a, eicosanoids, IL 1b, Inhibitors,Modulators,Libraries and nitric oxide. In one model of dopaminergic degeneration, activation of microglia by Inhibitors,Modulators,Libraries the inflammatory factor lipopolysacchar ide is rapid and is followed by a delayed, progressive, and selective destruction of nigral dopamine neurons both in vitro and in vivo. Microglial activation sig nificantly enhances MPP damage to dopaminergic neurons in a primary neuron glia cell culture model of dopaminer gic cell death. However, this occurs not by direct activation of microglia by MPP, but rather as a result of microglial stimulation by factors released from an initial die off of dopaminergic neurons.

As a result of this sequential neuronal glial interaction, the primary damage TSA to even a few dopaminergic neurons leads to extensive microglia enhanced neurodegeneration. Importantly, these findings suggest that ROS responses in dopaminergic neurons, themselves, are a necessary initial step in a cascade that leads to the flagrant neuro nal cell loss in response to MPP treatment.