The exceptional properties of 9-methyl-beta-carboline: stimulation, protection and regeneration of dopaminergic neurons coupled with anti-inflammatory effects.
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.
Polanski
Witold
W
Department of Neurology, Technical University of Dresden, Dresden, Germany.
Enzensperger
Christoph
C
Reichmann
Heinz
H
Gille
Gabriele
G
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D004296:Dopa Decarboxylase / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D018709:Statistics, Nonparametric; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C461261:(1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate); C529608:9-methyl-beta-carboline; D000893:Anti-Inflammatory Agents; D002243:Carbolines; D016207:Cytokines; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010879:Piperazines; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; D004296:Dopa Decarboxylase; C031086:5-ethynyl-2'-deoxyuridine; D004298:Dopamine; D003857:Deoxyuridine