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The exceptional properties of 9‐methyl‐β‐carboline: stimulation, protection and regeneration of dopaminergic neurons coupled with anti‐inflammatory effects
Author(s) -
Polanski Witold,
Enzensperger Christoph,
Reichmann Heinz,
Gille Gabriele
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06725.x
Subject(s) - dopaminergic , tyrosine hydroxylase , biology , receptor , neurotoxin , microglia , pharmacology , microbiology and biotechnology , dopamine , immunology , endocrinology , inflammation , biochemistry
J. Neurochem. (2010) 113 , 1659–1675. Abstract β‐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 α‐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.