Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons

Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF alp ha) are increased in postmortem brain and cerebral spinal fluid from patien ts with Parkinson's disease (PD), This observation provides a basis for ass ociating TNF alpha with neurodegeneration, but a specific toxicity in dopam ine (DA) neurons has not been firmly established. Therefore, we investigate d TNF alpha -induced toxicity in DA neurons by utilizing primary cultures o f embryonic rat mesencephalon. Exposure to TNF alpha resulted in a dose-dep endent 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 ne urons was decreased and no general cytotoxicity was evidenced by lactate de hydrogenase assay. Many of the cells which remained immunoreactive for TH h ad shrunken and rounded cell bodies with broken, blunted, or absent process es. However, TNF alpha -treated cultures also contained some THir cells whi ch appeared to be undamaged and possibly resistant to TNF alpha -induced to xicity. 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 neuro ns were affected by TNF alpha treatment. These data strongly suggest that T NF alpha mediates cell death in a sensitive population of DA neurons and su pport the potential involvement of proinflammatory cytokines in the degener ation of DA neurons in PD. (C) 2001 Academic Press.