euk-189 and Disease-Models--Animal

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

Animal models, and human postmortem studies, of prion disease have demonstrated the presence of heightened oxidative stress in the brain, with additional findings supporting the likelihood that the normal isoform of prion protein directly contributes to neuronal antioxidant defences. Although such data are consistent with the postulate that oxidative stress plays a salient pathogenic role in prion disease, it remains possible that oxidative damage represents a secondary or relatively less important phenomenon in neurons already rendered dysfunctional from other primary insults. To provide further insights into the relative pathogenic importance of oxidative stress, we employed a potent manganese-superoxide dismutase/catalase mimetic, EUK-189, as a therapeutic in our mouse model of human prion disease. A significant but relatively modest prolongation of survival in EUK-189-treated mice was observed, which correlated with reductions in oxidative, especially nitrative, damage to proteins when compared to untreated disease controls. Lesion profiling also revealed reductions in spongiform change in specific brain regions of terminally sick EUK-189-treated mice. Our results are consistent with heightened oxidative stress playing a pathogenic role in prion disease but underscore the need for more biologically potent and, most likely, broader spectrum antioxidant treatments if more successful amelioration is to be achieved.

Topics: Animals; Antioxidants; Biomimetics; Blotting, Western; Brain; Catalase; Disease Models, Animal; Humans; Immunohistochemistry; Mice; Organometallic Compounds; Prion Diseases; Prions; Protein Carbonylation; Salicylates; Superoxide Dismutase

Ataxia-telangiectasia is caused by mutations in the ATM gene, the protein product of which is essential for effective response to double-stranded DNA breaks. Loss of ATM function explains most aspects of the disease, but not the cerebellar neurodegeneration characteristic of the disease. Mice lacking ATM provide an excellent model of the human disorder. In addition to deficient response to DNA damage, these mice exhibit oxidative stress, which we hypothesized is the cause of cerebellar dysfunction. We show that treatment with a catalytic antioxidant corrects the neurobehavioral deficit in these mice.

Topics: Animals; Antioxidants; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Brain; Catalysis; Cell Cycle Proteins; Disease Models, Animal; DNA-Binding Proteins; Fatty Acids; Mice; Mice, Knockout; Organometallic Compounds; Oxidation-Reduction; Protein Serine-Threonine Kinases; Rotarod Performance Test; Salicylates; Tumor Suppressor Proteins