There has been some discussion here on how people with PD lose dopamine producing neurons. And some believe that these neurons have gone dormant.
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.—Qin, L., Block, M. L., Liu, Y., Bienstock, R. J., Pei, Z., Zhang, W., Wu, X., Wilson, B., Burka, T., Hong, J.-S. Microglial NADPH oxidase is a novel target for femtomolar neuroprotection against oxidative stress.
Parkinson’s disease (PD) is characterized by the specific and progressive death of dopaminergic neurons in the substantia nigra (SN); other neuronal cell types are much less affected. Recent reports have linked inflammation to neurodegenerative disease, where microglia, cells of myeloid lineage responsible for innate immunity in the brain, are considered to be the major cell type underlying the inflammation-mediated neurotoxicity (7 8 9) . The activation of microglia is a complex process involving the release of several soluble proinflammatory factors [tumor necrosis factor {alpha} (TNF-{alpha}), PGE2, IL-1] and free radicals (nitric oxide, superoxide) (7) . Current replacement therapy with L-dopa is able to alleviate disease symptoms, but is unable to alter the disease course. Thus, therapeutic interventions designed to inhibit the microglial inflammatory response offer hope for attenuation of the neurodegenerative disease process. The current anti-inflammatory treatments available, including steroids and nonsteroidal anti-inflammatory drugs, are limited by the ability to influence only a small portion of the microglial response (10) . Thus, identification of compounds acting on novel targets to inhibit the release of a wide range of proinflammatory factors from overactivated microglia is of paramount importance. In the ensuing study, we report that femtomolar concentrations of naloxone and the peptide fragment glycine-glycine-phenylalanine (GGF) attenuate a broad spectrum of the microglia inflammatory response (reactive oxygen species (ROS) and proinflammatory factors) and are neuroprotective with extremely potent efficacy through the inhibition of microglial NADPH oxidase.
http://www.fasebj.org/cgi/content/full/19/6/550