5-ethynyl-2--deoxyuridine and 9-methyl-beta-carboline

Beta-carbolines (BCs) are potential endogenous and exogenous neurotoxins that may contribute to the pathogenesis of Parkinson's disease. However, we recently demonstrated protective and stimulatory effects of 9-methyl-BC (9-me-BC) in primary dopaminergic culture. In the present study, treatment with 9-me-BC unmasked a unique tetrad of effects. First, tyrosine hydroxylase (TH) expression was stimulated in pre-existing dopa decarboxylase immunoreactive neurons and several TH-relevant transcription factors (Gata2, Gata3, Creb1, Crebbp) were up-regulated. Neurite outgrowth of TH immunoreactive (THir) neurons was likewise stimulated. The interaction with tyrosine kinases (protein kinase A and C, epidermal growth factor-receptor, fibroblast growth factor-receptor and neural cell adhesion molecule) turned out to be decisive for these observed effects. Second, 9-me-BC protected in acute toxicity models THir neurons against lipopolysaccharide and 2,9-dime-BC(+) toxicity. Third, in a chronic toxicity model when cells were treated with 9-me-BC after chronic rotenone administration, a pronounced regeneration of THir neurons was observed. Fourth, 9-me-BC inhibited the proliferation of microglia induced by toxin treatment and installed an anti-inflammatory environment by decreasing the expression of inflammatory cytokines and receptors. Finally, 9-me-BC lowered the content of alpha-synuclein protein in the cultures. The presented results warrant the exploration of 9-me-BC as a novel potential anti-parkinsonian medication, as 9-me-BC interferes with several known pathogenic factors in Parkinson's disease as outlined above. Further investigations are currently under way.

Topics: Animals; Anti-Inflammatory Agents; Carbolines; Cells, Cultured; Cytokines; Deoxyuridine; Dopa Decarboxylase; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Mammalian; Female; Gene Expression Regulation; L-Lactate Dehydrogenase; Lipopolysaccharides; Mesencephalon; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Piperazines; Pregnancy; Receptors, Cytokine; Regeneration; RNA, Messenger; Statistics, Nonparametric; Tyrosine 3-Monooxygenase