Elsevier

Neurobiology of Disease

Volume 40, Issue 2, November 2010, Pages 444-448
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2010.07.004Get rights and content

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 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.

Research highlights

►Monoamine Oxidase-B mouse model serves as a novel tool to understand ROS mediated PD pathogenesis. ►Inducible expression of the MAO-B in-vivo allows us to study the exact timing of events. ►MAOB inhibitors and antioxidant drug therapies may be beneficial in preventing disease progression if given early.

Introduction

Monoamine oxidase B (MAO-B) is found in the brain primarily in non-neuronal cells such as astrocytes and radial glia [20], [40], [41]. Age-related increases in its levels have been suggested to play a role in neurodegeneration associated with PD [9], [10], [20], [31], [33]. This is believed to be as a consequence of increased oxidative stress; substrate oxidation by the enzyme is accompanied stoichiometrically by the reduction of oxygen to H2O2 [5], [39]. We previously demonstrated that elevations in astrocytic MAO-B levels in an inducible transgenic mouse model results in a selective loss of dopaminergic SN neurons and that severity of this loss was age-dependent [22]. Cell loss was accompanied by increased oxidative stress and selective inhibition of mitochondrial CI activity, all key features of human Parkinson's disease (PD). Reversing MAO-B induction after 14 days was not sufficient to reverse any of the observed effects when examined 2 weeks later. However, what is not clear from our earlier studies is whether reversing the MAO-B increase at earlier time points would be sufficient to prevent subsequent events or the mechanisms involved. We set out in this current set of studies to investigate the exact timing of events and whether reversal of MAO-B induction at earlier time points was capable of halting or delaying the observed neuropathological progression.

Section snippets

Induction of astrocytic MAO-B levels via dox feeding and impact of dox removal

Dox-inducible astrocytic MAO-B expressing transgenics were generated in the C57Bl/6 background as previously described [22]. Mice were housed according to standard animal care protocols, fed ad libitum, kept on a 12-h light/dark cycle, and maintained in a pathogen-free environment in the Buck Institute Vivarium. Astroglial-specific transgene expression was induced by feeding adult (3–4 months old) males doxycycline at 0.5 g/kg/day provided in pre-mixed Purina chow (Research Diets) for the

Astrocytic MAO-B increase results in subsequent increases in ROS, CI inhibition, and neurodegeneration which could be reversed via dox removal (DR) at days 3–5

Approximately 10–15% of nerve terminals in the striatum (ST) originate from SN dopaminergic neurons [25], [26], [29]. Enrichment of striatal dopaminergic nerve terminal (synaptosomal) populations therefore allows us to measure the impact of astrocytic MAO-B induction directly within dopaminergic nigrostriatal neurons at various time points on both ROS levels and CI activity [22]. ROS levels were measured in isolated ST dopaminergic versus nondopaminergic synaptosomes 3 h following injection of

Discussion

Increased brain MAO-B levels have been hypothesized to play a role in neuropathies associated with PD [4], [5], [15], [23], [27], [42]. It was recently reported that rasagaline (Azilect), a selective irreversible inhibitor of MAO-B, resulted in a delay in disease development in patients who initiated drug treatment at the earlier stages which is consistent with a neuroprotective effect (although this is confounded by the mild improvements and questions about differences with drug dosage). It is

Acknowledgments

These studies were funded by R01 NS045615 (JKA) and a grant from the National Parkinson's Foundation (JKM).

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