Evidence suggests that chronic neuroinflammation is associated with the pathophysiology of Parkinsonís disease by creating an environment that is detrimental for dopaminergic (DA) neuronal cell survival. Neuroinflammation may also hinder the development of effective cell replacement therapies by interfering with the re-innervation process and survival of the transplanted neurones. Nurr1 is a nuclear receptor expressed in the embryonic ventral midbrain and is essential for the generation, development, terminal differentiation, and maintenance of DA neurons. Nurr1 is also expressed in astrocytes and microglia where it has been shown to inhibit the expression of pro-inflammatory mediators and to alleviate inflammation-induced DA neuronal death . Thus, Nurr1 may have the capacity for indirect anti-inflammatory effects that are favourable to DA survival as well as direct beneficial effects on DA neuronal development for cell replacement therapy for Parkinsonís disease.
The aim of this study was to elucidate the effect of the pro-inflammatory cytokine TNFα on Nurr1 expression and survival of DA neuronal precursor cells. Proliferating cells prepared from rat embryonic mesencephalic cultures were treated with a high (100 ng/ml; H) or low concentration (100 pg/ml; L) of TNFα. Treatment with TNFα (H) induced apoptotic cell death of neuronal precursors and DA neurones accompanied by increased Tnfr1 expression. Treatment with TNFα (L) resulted in a 30% decrease in DA neuronal survival at 1h, up to 100% at 24h while precursor cells remained relatively healthy for 24h. These results suggest that Tnfα cytotoxicity is mediated by Ttnfr1-induced apoptosis in neuronal precursors and DA neurones when treated with TNFα (H). Assessment of Nurr 1 expression revealed that neuronal precursors and DA neurones show an early increase (15 min) of Nurr1 expression which was returned to basal levels at 60 min after treatment with TNFα (L) which may represent a cellular attempt to prevent cytotoxicity in response to a pro-inflammatory stimulus.