Protective effects of TNF in an animal model of Parkinson ´s Disease

MARIELA CHERTOFF; ANA DE LELLA EZCURRA; A. SCHOENENBERG; U. EISEL; CARINA FERRARI; FERNANDO PITOSSI

Buzios

Congreso; I Congreso IBRO/LARC de Neurociencias; 2008

Parkinson's disease (PD) is a slowly progressive disorder, mainly characterized by the selective loss of dopaminergic neurons of the substantia nigra (SN). Overexpression of tumor necrosis factor alpha (TNF) has been associated with neurotoxicity in brain parenchyma and it is upregulated in neurodegenerative disorders. On the other hand, TNF can have also beneficial effects in models of stroke, Multiple Sclerosis or retinal ischemia. Because of its diverse bioactivities, the functional role of TNF on neuronal tissues remains unclear. Objectives: To study the functional role of the chronic TNF expression on dopaminergic neurons and understand the mechanism mediating TNF protection. Methods: We used knock-in mice to express constitutive levels of TNF in the SN of adult mice. Animals were treated with 4ug 6-hydroxidopamine in the striatum. We performed tyrosin-hydroxilase-positive cell and area counting, Nissl staining, GFAP and Tomato lectin immunohistochemistry in wt and k-in animals either naïve or after 6-OHDA treatment. Besides, we analyzed genes related to TNF mechanism of action such as the Manganese Superoxide Dismutase (MnSOD), the neuronal nitric oxide synthase (nNOS) and insulin-like growth factor 1 (IGF-1) by Western blot or real-time PCR. Results: The k-in mice increased the TNF mRNA levels in the SN compared to wild type (wt) mice. TNF reduced the nigral and striatal neurodegeneration after 20 days of 6-hydroxydopamine (6-OHDA) in k-in mice vs wt animals. There was no evidence for inflammatory response in naive animals; k-in animals had astrocytosis in the SN pars reticulate.  In the SN of naïve animals, the IGF-1 and MnSOD expression and nNOS activity were increased in k-in vs wt animals. However, the total activity of SOD was not changed. After 20 days of 6-OHDA, both SOD and nNOS activities were increased in k-in treated animals vs. wt, with similar MnSOD protein levels. Conclusions: These results suggest that TNF might produce a protective effect by upregulation of the survival pathway such as IGF-1 or astrocyte activation and activation of the antioxidant capacity by the modulation of the MnSOD and nNOS activities, supporting the concept of the beneficial role of cytokines on the central nervous system under certain conditions.