Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation

ANA LAURA DE LELLA EZCURRA; MARIELA CHERTOFF; CARINA CINTIA FERRARI; MARIANA GRACIARENA; FERNANDO JUAN PITOSSI

NEUROBIOLOGY OF DISEASE

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2010 vol. 37 p. 630 - 640

0969-9961

Inflammation, and in particular microglia activation, is regarded as a constant component of brain pathology in Parkinson´s disease (PD). Microglial activation has been found in the substantia nigra (SN), one of the main brain regions affected in PD, for many years after the initiation of the disease. Although many studies point towards a deleterious role of inflammation on PD, the functional role of many of its main components has not been clarified yet. For example, tumor necrosis factor-alpha (TNF-a), a key pro-inflammatory cytokine, has been shown to exert toxic or no effects on the viability of dopaminergic neurons. No study has evaluated the effects of the long-lasting TNF-a expression in the SN, an experimental set-up most probably resembling the clinical situation. The aim of this study was to investigate the effects of the chronic expression of TNF-a in the adult SN at different time points. Adenoviral expression of low TNF-a levels (17-19 pg/mg) lasted for 14 days in the SN and did not induce interleukin-1beta (IL-1b) expression. Long-lasting TNF-a expression caused dopaminergic cell death from day 14, increasing at 21 and 28 days compared with control animals injected with adenovectors expressing b-galactosidase. TNF-a overexpression elicited irreversible, unilateral akinesia starting at 14 days, but not earlier. These effects were accompanied by microglial activation to stage 4 and/or monocyte/macrophage recruitment from the periphery from day 7 post adenovector inoculations. Thus, we conclude that extended duration of the expression of TNF-a is necessary and sufficient for a univocal toxic effect of TNF-a on dopaminergic neurons and motor disabilities. This study provides an animal model to study early events that lead to TNF-a-mediated neuronal demise in the SN. In addition, the cellular components of the inflammation elicited by TNF-a and the lack of IL-1b expression support the growing idea of a distinct cytokine network in the brain.