Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease.

Géraldine H Petit,Patrik Brundin,Elijahu Berkovich,Mark Hickery,Pekka Kallunki,Karina Fog,Cheryl Fitzer-Attas

doi:10.1371/journal.pone.0060691

Géraldine H Petit, Patrik Brundin + Show 5 more

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https://doi.org/10.1371/journal.pone.0060691

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Abstract

Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.

Highlights

Parkinson’s disease (PD) patients exhibit motor dysfunction, and multiple non-motor symptoms [1]
To investigate the effect of an accumulation of wild-type asynuclein, we studied a transgenic mouse model of PD expressing human wild-type a-synuclein under the control of the mouse asynuclein promoter, which is likely to lead to an expression pattern of the human a-synuclein that is similar to the pattern of endogenous mouse a-synuclein expression
We found no changes in olfactory bulb (OB) neurogenesis that could explain the olfactory deficits

Summary

Introduction

Parkinson’s disease (PD) patients exhibit motor dysfunction, and multiple non-motor symptoms [1]. Braak et al (2003) have suggested that these a-synuclein aggregates appear before the onset of motor symptoms. Either these protein aggregates or changes in OB neurogenesis might contribute to olfactory deficits in PD. Rasagiline (N-propargyl-1-(R)-aminoindan) is an irreversible monoamine oxidase (MAO)-B inhibitor, prescribed as monotherapy in early-stage PD and as an adjunct to levodopa in moderate to advanced PD [10]. It reduces motor deficits and ameliorates motor fluctuations [11,12,13]. We monitored the effects of rasagiline on these deficits and OB neurogenesis

Materials and Methods

Findings

Discussion