Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: implications for early intervention on disease progression.
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.
Siddiqui
Almas
A
Buck Institute for Age Research, Novato, CA 94945, USA.
Mallajosyula
Jyothi K
JK
Rane
Anand
A
Andersen
Julie K
JK
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000172:deficiency / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases; D008995:Monoamine Oxidase / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012459:Salicylates / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D000975:Antioxidants; C436526:EUK-189; D009942:Organometallic Compounds; D012459:Salicylates; D008995:Monoamine Oxidase; D042967:Electron Transport Complex I; D004318:Doxycycline; D004298:Dopamine