Microglial NADPH oxidase is a novel target for femtomolar neuroprotection against oxidative stress.

Inflammation has been increasingly recognized to contribute to the pathogenesis of Parkinson's disease. Several compounds are neuroprotective at femtomolar concentrations through the inhibition of inflammation. However, the mechanisms mediating femtomolar-acting compounds are poorly understood. Here we show that both gly-gly-phe (GGF), a tri-peptide contained in the dynorphin opioid peptide, and naloxone are neuroprotective at femtomolar concentrations against LPS-induced dopaminergic neurotoxicity through the reduction of microglial activation. Mechanistic studies demonstrated the critical role of NADPH oxidase in the GGF and naloxone inhibition of microglial activation and associated DA neurotoxicity. Pharmacophore analysis of the neuroprotective dynorphin peptides and naloxone revealed common chemical properties (hydrogen bond acceptor, hydrogen bond donor, positive ionizable, hydrophobic) of these femtomolar-acting compounds. These results support a common high-affinity site of action for several femtomolar-acting compounds, where NADPH oxidase is the critical mechanism governing neuroprotection, suggesting a novel avenue of anti-inflammatory and neuroprotective therapy.