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
Almas SiddiquiJulie K Andersen

Abstract

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 astro...Continue Reading

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Citations

Aug 14, 2012·Parkinson's Disease·M Y InyushinW D Wessinger
Apr 2, 2014·The Journal of Infectious Diseases·Kelly A MeulendykeM Christine Zink
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Jun 16, 2021·Current Pharmaceutical Design·Md Sohanur RahmanGhulam Md Ashraf

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