Two faces of TNF on the viability of dopaminergic neurons in the substantia nigra

M CHERTOFF; A DE LELLA EZCURRA; U EISEL; F PITOSSI

ARGENTINA

Congreso; Primer Reunión Conjunta del Taller Argentino de Neurociencias y la Sociedad Argentina de Investigación en Neurociencia Argentina,; 2009

Taller Argentino de Neurociencias y la Sociedad Argentina de Investigación en Neurociencia Argentina,

<!-- /* Font Definitions */ @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-1610611985 1073750139 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin-top:0cm; margin-right:0cm; margin-bottom:10.0pt; margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-fareast-font-family:Calibri; mso-bidi-font-family:"Times New Roman"; mso-ansi-language:ES-AR; mso-fareast-language:EN-US;} p.MsoBodyTextIndent, li.MsoBodyTextIndent, div.MsoBodyTextIndent {mso-style-link:" Car Car"; margin-top:0cm; margin-right:0cm; margin-bottom:6.0pt; margin-left:14.15pt; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-fareast-font-family:Calibri; mso-bidi-font-family:"Times New Roman"; mso-ansi-language:ES-AR; mso-fareast-language:EN-US;} span.CarCar {mso-style-name:" Car Car"; mso-style-locked:yes; mso-style-link:"Sangría de texto normal"; mso-ansi-font-size:11.0pt; mso-bidi-font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-fareast-font-family:Calibri; mso-hansi-font-family:Calibri; mso-ansi-language:ES-AR; mso-fareast-language:EN-US; mso-bidi-language:AR-SA;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Tumor necrosis factor-alpha (TNF) has been implicated in several human neurodegenerative diseases of the central nervous system, such as Parkinson‘s disease. In order to understand the functional role of chronic TNF on dopaminergic neurons in the substantia nigra (SN), we utilized a combination of adenoviral vectors, the CRE/loxP system and hypomorphic mice to express three different levels of TNF in the SN of adult mice: basal, low and upregulated levels of TNF. The expression of low level of TNF did not produce inflammatory infiltrate or microglial activation, although astrocytosis has been observed in the SNr of k-in mice.  Low TNF expression induced TNF-R1, GDNF and IGF-1 in the SN and increased SOD activity in the Striatum (ST). Low TNF reduced the nigral neurodegeneration mediated by intrastriatal 6-hydroxydopamine administration without an inflammatory response. The injection of the adenovirus which express CRE recombinase, allowed us to upregulate the TNF level due to the excision of an interference cassette. In consequence, the SN of k-in mice injected with AdCRE showing high TNF expression level induced progressive neuronal loss, glial activation and an inflammatory response composed almost exclusively by monocyte/macrophages. This approach allowed us to clarify the functional role of TNF in the SN according to its levels of expression and characterize its cellular and molecular environment, supporting the concept of a dual role of TNF on several CNS diseases. Protective effects of low TNF level may be mediated by TNF-R1, GDNF, IGF-1 and SOD activity. On the other hand, neurodegenerative effects could be mediated, at least in part, by activated glia.