Exacerbation of neurodegeneration by inflammation

FERNANDO J. PITOSSI

Congreso; MEETING GERMAN ENDOCRINOLOGY SOCIETY; 2010

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.