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

Neurobiol Dis. 2010 Nov;40(2):444-8. doi: 10.1016/j.nbd.2010.07.004. Epub 2010 Jul 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antioxidants / pharmacology
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Dopamine / metabolism
  • Doxycycline / pharmacology
  • Electron Transport Complex I / deficiency
  • Electron Transport Complex I / metabolism
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism
  • Mesencephalon / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondrial Diseases
  • Monoamine Oxidase / metabolism*
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / pathology*
  • Neurons / metabolism
  • Neurons / pathology
  • Organometallic Compounds / pharmacology
  • Oxidative Stress / drug effects*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Prognosis
  • Salicylates / pharmacology
  • Substantia Nigra / drug effects
  • Substantia Nigra / pathology*
  • Time Factors
  • Treatment Outcome


  • Anti-Bacterial Agents
  • Antioxidants
  • EUK-189
  • Organometallic Compounds
  • Salicylates
  • Monoamine Oxidase
  • Electron Transport Complex I
  • Doxycycline
  • Dopamine

Supplementary concepts

  • Mitochondrial complex I deficiency