IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Exacerbation of neurodegeneration by inflammation
Autor/es:
FERNANDO J. PITOSSI
Reunión:
Congreso; MEETING GERMAN ENDOCRINOLOGY SOCIETY; 2010
Resumen:
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.