Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra

Abstract

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.