Dysfunction of rat forebrain astrocytes in culture alters cytokine and neurotrophic factor release

Altered glial cell function occurring in substantia nigra in Parkinson' disease may lead to the release of cytokines and impairment of neurotrophic factor production, which in turn, may cause dopaminergic apoptosis. To evaluate this concept, primary cultures of rat brain astrocytes were activated with lipopolysaccharide (LPS), depleted of glutathione with L-buthionine-[S,R]-sulfoximine or subjected to complex I inhibition with 1-methyl-4-phenylpyridinium. The effects on tumour necrosis factor-alpha (TNF-alpha) release, dopamine-stimulated glial cell line derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) release were determined. LPS activation or inhibition complex I activity, but not glutathione depletion, stimulated TNF-alpha release. Glutathione depletion or complex I inhibition, but not LPS-induced activation, impaired dopamine-stimulated GDNF release. None of these treatments altered BDNF release. Thus, altered glial function leading to TNF-alpha-mediated or GDNF withdrawal-induced dopaminergic apoptosis may contribute to nigral degeneration in Parkinson's disease.