Exacerbation of neurodegeneration by inflammation

A patho-physiological feature ubiquitously found in animal models and Parkinson's Disease (PD) patients is brain inflammation, in particular, microglial activation. However, the functional role of microglial activation is under dispute. We have found that microglia is activated to a particular state during neurodegeneration with increased transcription but no translation of pro-inflammatory cytokines. We and others (in other neurodegenerative diseases) have defined this microglial state of activation as „primed“. We have hypothesized that a sub-toxic inflammatory stimulus could shift this primed state to a pro-inflammatory state and exacerbate the ongoing neurodegeneration, leading to an exacerbation of PD motor symptoms and disease progression. Rats previously injected with 6-hydroxydopamine (6-OHDA) in the striatum were injected with a sub-toxic dose of bacterial lipopolysaccharide in the substantia nigra (SN) or adenoviral vectors producing human IL-1 beta intravenously, as pro-inflammatory stimuli. Contrary to controls, both animal groups revealed end-stage microglial activation (stage-4) in the SN. Significant exacerbation of neurodegeneration was observed in both models when the pro-inflammatory stimulus was present. The central stimulus significantly manifested earlier and exacerbating behavioral deficits and increased expression of IL-1beta in the SN. By functional experiments, we have found that central IL-1 is a key mediator of this exacerbating effect, while nitric oxide plays only a minor role, downstream of IL-1. For the first time we demonstrate that a non-degenerative central or peripheral inflammatory stimulus produced an increase in 6-OHDA-mediated neurodegeneration, establishing that inflammation could be a risk factor for the progression of PD.