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Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation.
Neurobiol Dis. 2010 Mar; 37(3):630-40.ND

Abstract

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-alpha), 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-alpha 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-alpha in the adult SN at different time points. Adenoviral expression of low TNF-alpha levels (17-19 pg/mg) lasted for 14 days in the SN and did not induce interleukin-1beta (IL-1beta) expression. Long-lasting TNF-alpha expression caused dopaminergic cell death from day 14, increasing at 21 and 28 days compared with control animals injected with adenovectors expressing beta-galactosidase. TNF-alpha 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-alpha is necessary and sufficient for a univocal toxic effect of TNF-alpha on dopaminergic neurons and motor disabilities. This study provides an animal model to study early events that lead to TNF-alpha-mediated neuronal demise in the SN. In addition, the cellular components of the inflammation elicited by TNF-alpha and the lack of IL-1beta expression support the growing idea of a distinct cytokine network in the brain.

Authors+Show Affiliations

Institute Leloir Foundation and IIBBA-CONICET, Patricias Argentinas 435, Buenos Aires, Argentina.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19969084

Citation

De Lella Ezcurra, Ana Laura, et al. "Chronic Expression of Low Levels of Tumor Necrosis Factor-alpha in the Substantia Nigra Elicits Progressive Neurodegeneration, Delayed Motor Symptoms and Microglia/macrophage Activation." Neurobiology of Disease, vol. 37, no. 3, 2010, pp. 630-40.
De Lella Ezcurra AL, Chertoff M, Ferrari C, et al. Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. Neurobiol Dis. 2010;37(3):630-40.
De Lella Ezcurra, A. L., Chertoff, M., Ferrari, C., Graciarena, M., & Pitossi, F. (2010). Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. Neurobiology of Disease, 37(3), 630-40. https://doi.org/10.1016/j.nbd.2009.11.018
De Lella Ezcurra AL, et al. Chronic Expression of Low Levels of Tumor Necrosis Factor-alpha in the Substantia Nigra Elicits Progressive Neurodegeneration, Delayed Motor Symptoms and Microglia/macrophage Activation. Neurobiol Dis. 2010;37(3):630-40. PubMed PMID: 19969084.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. AU - De Lella Ezcurra,Ana Laura, AU - Chertoff,Mariela, AU - Ferrari,Carina, AU - Graciarena,Mariana, AU - Pitossi,Fernando, Y1 - 2009/12/05/ PY - 2009/07/05/received PY - 2009/11/24/revised PY - 2009/11/26/accepted PY - 2009/12/9/entrez PY - 2009/12/9/pubmed PY - 2010/6/9/medline SP - 630 EP - 40 JF - Neurobiology of disease JO - Neurobiol Dis VL - 37 IS - 3 N2 - 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-alpha), 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-alpha 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-alpha in the adult SN at different time points. Adenoviral expression of low TNF-alpha levels (17-19 pg/mg) lasted for 14 days in the SN and did not induce interleukin-1beta (IL-1beta) expression. Long-lasting TNF-alpha expression caused dopaminergic cell death from day 14, increasing at 21 and 28 days compared with control animals injected with adenovectors expressing beta-galactosidase. TNF-alpha 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-alpha is necessary and sufficient for a univocal toxic effect of TNF-alpha on dopaminergic neurons and motor disabilities. This study provides an animal model to study early events that lead to TNF-alpha-mediated neuronal demise in the SN. In addition, the cellular components of the inflammation elicited by TNF-alpha and the lack of IL-1beta expression support the growing idea of a distinct cytokine network in the brain. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/19969084/Chronic_expression_of_low_levels_of_tumor_necrosis_factor_alpha_in_the_substantia_nigra_elicits_progressive_neurodegeneration_delayed_motor_symptoms_and_microglia/macrophage_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(09)00340-4 DB - PRIME DP - Unbound Medicine ER -