Chronic overexpression of TNF causes progressive neurodegeneration in the substantia nigra.

ANA DE LELLA EZCURRA,; MARIELA CHERTOFF; FERNANDO PITOSSI

ARGENTINA

Congreso; III Congreso Iberoamericano de Neuroinmunomodulación; 2009

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:ES; mso-fareast-language:ES;} @page Section1 {size:595.3pt 841.9pt; margin:70.9pt 79.4pt 70.9pt 79.4pt; mso-header-margin:35.45pt; mso-footer-margin:35.45pt; mso-paper-source:0;} div.Section1 {page:Section1;} -->   Parkinson’s disease (PD) is characterized by neuronal death in the substantia nigra (SN). Expression of Tumor Necrosis Factor-alpha (TNF) has been observed in PD, but its function is unclear. Our objective is to study the effects of the chronic overexpression of TNF in the SN of adult rats. We injected an adenovector expressing mouse TNF (AdTNF) directly in the SN, using as a control the same dose of an adenovirus expressing b-galactosidase. We confirmed expression of mouse TNF in the SN at 7 and 14 days p.i. using ELISA. Starting at 14 days, the number of dopaminergic neurons in the injected SN was lower in animals expressing TNF than in controls. This neurodegenerative effect was increased at 21 days and maintained at 28 days p.i. The cylinder test showed motor deficits (reduction in the use of the contralateral paw) in animals injected with AdTNF 20 and 27 days p.i. Finally, we observed an inflammatory infiltrate (mainly macrophages) and microglial activation (demonstrated by immunostaining against MHCII and GSA lectin) in response to TNF. These results show a progressive neurodegenerative effect of chronic overexpression of TNF in the SN, which causes forelimb akinesia and an inflammatory response in the brain.