title: Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: implications for early intervention on disease progression.
abstract: We previously demonstrated that elevation of astrocytic monoamine oxidase B (MAO-B) levels in adoxycycline (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.
authors.affiliation: Buck Institute for Age Research, Novato, CA 94945, USA.
authors.forename: Almas
authors.initials: A
authors.lastname: Siddiqui
authors.forename: Jyothi K
authors.initials: JK
authors.lastname: Mallajosyula
authors.forename: Anand
authors.initials: A
authors.lastname: Rane
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen