The preclinical investigations of inflammation and excitotoxicity in mouse models of Parkinson's disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder that manifests as a result of degeneration of the nigrostriatal system. While L-Dopa still remains the most effective symptomatic treatment, its benefits are limited as it is associated with the development of L-Dopa-induced dyskinesias (LIDs). Furthermore, there is currently no treatment that has proved effective in halting the nigrostriatal degeneration, thus alternative therapeutic targets are needed. To identify such targets, we first established the MPTP mouse model of PD to allow for the investigation of both pathological and behavioural outcomes. In contrast to previous studies, we demonstrated no significant effect of MPTP on motor function at 1 week and 3 months post-MPTP, despite stereological quantification showing a decrease in dopamine cells with increasing MPTP dose, suggesting the MPTP model is more appropriate for identifying effects on cell survival. A screen of novel therapeutic agents and genetic modifications in mice in the MPTP model revealed the growth factor activin A and the kainate receptor subunits GluK1 and GluK3 as the most promising neuroprotective targets. We showed activin A increased survival of dopamine neurons at 1 and 8 weeks following MPTP. Interestingly, animals receiving activin A did not have a corresponding increase in dopamine levels and striatal terminal protection. This nigral protective effect of activin A was replicated in the 6-OHDA model of PD. Animals receiving activin A also had lower numbers of astrocytes and microglia following MPTP and LPS, suggesting that activin A’s neuroprotective effects may be driven by its anti-inflammatory properties. In addition, activin A was shown to increase the efficacy of low doses of L-Dopa in 6-OHDA-lesioned mice, suggesting activin A may act as an L-DOPA-sparing agent. We also showed that blocking GluK1 or GluK3, through the use of selective antagonists or knockout animals, increased survival of dopaminergic neurons following MPTP, however there was no corresponding increase in dopamine levels and striatal terminal protection. Our results indicate that activin A, GluK1 and GluK3 are potential neuroprotective targets for PD.