euk-189 and Parkinson-Disease

We previously demonstrated that elevation of astrocytic monoamine oxidase B (MAO-B) levels in a doxycycline (dox)-inducible transgenic mouse model following 14 days of dox induction results in several neuropathologic features similar to those observed in the Parkinsonian midbrain (Mallajosyula et al., 2008). These include a specific, selective and progressive loss of dopaminergic neurons of the substantia nigra (SN), selective decreases in mitochondrial complex I (CI) activity and increased oxidative stress. Here, we report that the temporal sequence of events following MAO-B elevation initially involves increased oxidative stress followed by CI inhibition and finally neurodegeneration. Furthermore, dox removal (DR) at days 3 and 5 of MAO-B induction was sufficient to arrest further increases in oxidative stress as well as subsequent neurodegenerative events. In order to assess the contribution of MAO-B-induced oxidative stress to later events, we compared the impact of DR which reverses the MAO-B increase with treatment of animals with the lipophilic antioxidant compound EUK-189. EUK-189 was found to be as effective as DR in halting downstream CI inhibition and also significantly attenuated SN DA cell loss as a result of astrocytic MAO-B induction. This suggests that MAO-B-mediated ROS contributes to neuropathology associated with this model and that antioxidant treatment can arrest further progression of dopaminergic cell death. This has implications for early intervention therapies.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Astrocytes; Disease Models, Animal; Disease Progression; Dopamine; Doxycycline; Electron Transport Complex I; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Diseases; Monoamine Oxidase; Nerve Degeneration; Neurons; Organometallic Compounds; Oxidative Stress; Parkinson Disease; Prognosis; Salicylates; Substantia Nigra; Time Factors; Treatment Outcome

Environmental paraquat and neonatal iron exposure have both separately been suggested as potential risk factors for sporadic forms of Parkinson's disease (PD). In this study, we demonstrate that combined environmental exposure to these two agents results in modulations in microglial activation state. Apocynin, an NADPH oxidase inhibitor, was found to attenuate the release of superoxide from microglia stimulated by combined paraquat and iron and blocked paraquat-induced dopaminergic neuronal death. Furthermore, pretreatment with the synthetic superoxide dismutase/catalase mimetic, EUK-189, significantly decreased microglial activation mediated by combined paraquat and iron treatment. These findings support the notion that environmental PD risk factors may act synergetically to produce neurodegeneration associated with the disorder and that iron and paraquat may act via common oxidative stress-mediated mechanism involving microglial activation.

Topics: Biomimetics; Cell Death; Cell Differentiation; Dopamine; Environmental Exposure; Humans; Infant, Newborn; Iron; Microglia; Neurons; Organometallic Compounds; Oxidative Stress; Paraquat; Parkinson Disease; Salicylates; Superoxide Dismutase

Extensive epidemiological data in humans and studies in animal models of Parkinson's disease (PD) suggest that sporadic forms of the disorder are not strictly genetic in nature but most likely because of combined environmental exposures over the period of the life-span coupled with increased genetic susceptibilities. Environmental paraquat and neonatal iron exposure have both been separately suggested as potential risk factors for sporadic forms of the disease. In this study, we demonstrate that combined environmental exposure to these two agents results in accelerated age-related degeneration of nigrostriatal dopaminergic neurons. Furthermore, pretreatment with the synthetic superoxide dismutase/catalase mimetic, EUK-189, significantly attenuated neuronal death mediated by combined paraquat and iron treatment. These findings support the notion that environmental PD risk factors may act synergistically to produce neurodegeneration associated with the disorder and that iron and paraquat may act via common oxidative stress-mediated mechanisms.

Topics: Aging; Animals; Cell Line; Cells, Cultured; Drug Synergism; Environmental Exposure; Herbicides; Iron; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neurons; Neuroprotective Agents; Organometallic Compounds; Paraquat; Parkinson Disease; Rats; Salicylates; Substantia Nigra; Superoxide Dismutase

Exposure of mice to the herbicide paraquat has been demonstrated to result in the selective loss of dopaminergic neurons of the substantia nigra, pars compacta (SNpc) akin to what is observed in Parkinson disease (PD). In this study, we investigate the efficacy of two synthetic superoxide dismutase/catalase mimetics (EUK-134 and EUK-189) in protecting against paraquat-induced dopaminergic cell death in both the rat dopaminergic cell line 1RB3AN27 (N27) and primary mesencephalic cultures in vitro and in adult mice in vivo. Our data demonstrate that pretreatment with either EUK-134 or EUK-189 significantly attenuates paraquat-induced neurotoxicity in vitro in a concentration-dependent manner. Furthermore, systemic administration of EUK-189 decreases paraquat-mediated SNpc dopaminergic neuronal cell death in vivo. These findings support a role for oxidative stress in paraquat-induced neurotoxicity and suggest novel therapeutic approaches for neurodegenerative disorders associated with oxidative stress such as PD.

Topics: Animals; Antioxidants; Blotting, Western; Catalase; Cells, Cultured; Dopamine; Immunohistochemistry; Male; Manganese; Manganese Compounds; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Models, Chemical; Neurons; Neuroprotective Agents; Organometallic Compounds; Oxidative Stress; Paraquat; Parkinson Disease; Rats; Salicylates; Substantia Nigra; Superoxide Dismutase; Time Factors