Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra.
The functional role of the long-lasting inflammation found in the substantia nigra (SN) of Parkinson's disease (PD) patients and animal models is unclear. Proinflammatory cytokines such as interleukin-1beta (IL-1beta) could be involved in mediating neuronal demise. However, it is unknown whether the chronic expression of cytokines such as IL-1beta in the SN can alter neuronal vitality. The aim of this study was to investigate the effects of the chronic expression of IL-1beta in the adult rat SN using a recombinant adenovirus expressing IL-1beta. The chronic expression of IL-1beta for 60 days induced dopaminergic cell death in the SN and unilateral akinesia starting only at 21 days post-injection. Microglial cell activation and inflammatory cell infiltrate were associated with dopaminergic cell death and motor disabilities. Astrocytic activation was delayed and associated with scar formation. The chronic expression of a single proinflammatory cytokine as IL-1beta in the SN elicited most of the characteristics of PD, including progressive dopaminergic cell death, akinesia and glial activation. Our data suggest that IL-1beta per se is able to mediate inflammatory-mediated toxic effects in the SN if its expression is sustained. This model will be helpful to identify possible therapeutic targets related to inflammation-derived neurodegeneration in the SN.
Ferrari
Carina Cintia
CC
Institute Leloir, IIBBA-CONICET, FBMC-FCEyN. Avenue Patricias Argentinas 435 (1405), Buenos Aires, Argentina.
Pott Godoy
María Clara
MC
Tarelli
Rodolfo
R
Chertoff
Mariela
M
Depino
Amaicha Mara
AM
Pitossi
Fernando Juan
FJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004298:Dopamine / Q000502:physiology; D005822:Genetic Vectors; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008262:Macrophage Activation / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000502:physiology; D009069:Movement Disorders / Q000235:genetics* / Q000473:pathology*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology*; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010302:Parkinson Disease, Secondary / Q000235:genetics / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology*
D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D004298:Dopamine