Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: Implications for early intervention on disease progression

NEUROBIOLOGY OF DISEASE

卷:40

Article

Siddiqui, Almas¹  Mallajosyula, Jyothi K.²  Rane, Anand¹  Andersen, Julie K.¹ 

[1] Buck Inst Age Res, Novato, CA 94945 USA

[2] ISIS Pharmaceut, Carlsbad, CA 92008 USA

关键词: Monoamine oxidase B;    Parkinson's disease;    Substantia nigra;    Mitochondrial complex I;    Tyrosine hydroxylase;    Reactive oxygen species;   

DOI  :  10.1016/j.nbd.2010.07.004

来源: Elsevier

【 摘 要 】

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 (Cl) 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 Cl 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. (c) 2010 Elsevier Inc. All rights reserved.

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