Inflammatory-environment interactions as an approach to modelling Parkinson's disease

Abstract

It has been over 50 years since the first demonstration that levodopa was capable of reversing the motor dysfunction associated with Parkinson’s disease. In the intervening decades, although levodopa has remained the most effective treatment for the motor symptoms of Parkinson’s disease, it is limited by serious side effects and the fact that it provides symptomatic relief only. One of the main reasons suggested for the paucity of drug discovery for Parkinson’s disease is the lack of a relevant animal model for the disease. Parkinson’s disease is thought to be the net result of a combination of multiple risk factors encountered over a lifetime, such as genetic predisposition, exposure to pesticides and bacterial or viral infections. Therefore the overarching aim of this project was to develop a novel model of Parkinson’s disease incorporating both inflammatory and environmental exposures. This would serve to shed further light on the role of relevant inflammatory-environment interactions in Parkinson’s disease, and would also provide a novel inflammatory-environment model.

In order to facilitate development of a novel inflammatory-environment model, we characterised the temporal changes that occur in the inflammatory system in neurotoxic, environmental, inflammatory and genetic models of Parkinson’s disease, with a particular focus on the pathogen-recognition Toll-like receptors (TLRs). We then went on to assess the impact of dual exposure of rats to a bacterial-like (i.e. lipopolysaccharide (LPS)) or viral-like (i.e. Poly I:C) inflammagen, followed by the environmental pesticide, rotenone. Finally, we investigated the impact of dual exposure of rats to rotenone, followed by Poly I:C or LPS.

All Parkinsonian-associated toxins resulted in an increase in TLR3 and TLR4, and other inflammatory toxins, with varying temporal patterns. With the dual exposure inflammatory-environment studies we found that exposing rats to either Poly I:C or LPS followed by rotenone did not exacerbate the Parkinsonism caused by either toxin alone. In contrast, dual exposure to rotenone followed by LPS significantly exacerbated the motor dysfunction and neuroinflammation compared to that caused by either inflammagen or environmental factors alone.

Overall, this research has shown that different Parkinson’s-associated challenges can induce different temporal neuroinflammatory responses, indicating the importance of the choice of toxin in preclinical Parkinson’s disease studies, and of time-point for secondary challenge administration in dual exposure studies. We have also shown that dual exposure of rats to the environmental pesticide, rotenone, and the bacterial endotoxin, LPS, induced a relevant model of Parkinson’s disease that may provide a suitable tool for testing novel neuroprotective therapies for this condition.