Tumor necrosis factor α is toxic to embryonic mesencephalic dopamine neurons

Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD), This observation provides a basis for associating TNF alpha with neurodegeneration, but a specific toxicity in dopamine (DA) neurons has not been firmly established. Therefore, we investigated TNF alpha -induced toxicity in DA neurons by utilizing primary cultures of embryonic rat mesencephalon. Exposure to TNF alpha resulted in a dose-dependent decrease in DA neurons as evidenced by decreased numbers of tyrosine hydroxylase-immunoreactive (THir) cells. TNF alpha toxicity was selective for DA neurons in that neither glial cell counts nor the total number of neurons was decreased and no general cytotoxicity was evidenced by lactate dehydrogenase assay. Many of the cells which remained immunoreactive for TH had shrunken and rounded cell bodies with broken, blunted, or absent processes. However, TNF alpha -treated cultures also contained some THir cells which appeared to be undamaged and possibly resistant to TNF alpha -induced toxicity. Additionally, immunocytochemistry revealed basal expression of TNF alpha receptor 1 (p55, R1) and TNF alpha receptor 2 (p75, R2) on all cells within the mesencephalic cultures to some degree, even though only DA neurons were affected by TNF alpha treatment. These data strongly suggest that TNF alpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD. (C) 2001 Academic Press.