Indole-N-methylated β-carbolinium ions as potential brain-bioactivated neurotoxins

Collins, Michael A.; Neafsey, Edward J.; Matsubara, Kazuo; Cobuzzi, Robert J.; Rollema, Hans

doi:10.1016/0006-8993(92)90576-u

Cited by 91 publications

(24 citation statements)

References 27 publications

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“…(2008) have shown that 9‐me‐BC‐treatment decreased necrosis and also apoptosis by reducing caspase 3 activity. Although 2,9‐dime‐BC + has also been shown to inhibit complex I of the mitochondrial respiratory chain (Collins et al. 1992), 9‐me‐BC completely protected dopaminergic neurons during the co‐treatment scheme (Fig.…”

Section: Discussionmentioning

confidence: 99%

The exceptional properties of 9‐methyl‐β‐carboline: stimulation, protection and regeneration of dopaminergic neurons coupled with anti‐inflammatory effects

Polanski

Enzensperger

Reichmann

et al. 2010

Journal of Neurochemistry

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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.

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Section: Discussionmentioning

confidence: 99%

The exceptional properties of 9‐methyl‐β‐carboline: stimulation, protection and regeneration of dopaminergic neurons coupled with anti‐inflammatory effects

Polanski

Enzensperger

Reichmann

et al. 2010

Journal of Neurochemistry

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“…N2-methylating activity of norharman was reported in rat brain [85] and it has been hypothesised that the N2-methyl derivative is further methylated at the N9 position. Both metabolites, N2-methylnorharman and N2,N9-dimethylnorharmonium cation have been detected in rat and human brain samples [12].…”

Section: Metabolismmentioning

confidence: 99%

“…In this study, smoking or coffee drinking was not accounted for. It was proposed that carbolines, especially N2-methylated metabolites, may play a role in the pathogenesis of Parkinson's disease [9,12].…”

Section: β-Carbolines and Diseasementioning

confidence: 99%

“…Molecular similarity to the Parkinson-inducing neurotoxin N-methyl-4-phenylpyridinium and the observation that harman induced tremor in mice as well as parkinsonism-like effects has resulted in a number of studies investigating the possibility of these compounds as endogenously formed factors that are involved in the induction of idiopathic Parkinson's disease [9,10]. Here, the N-methylated derivatives or metabolites of ␤-carbolines have been in the focus [11,12].…”

Section: Introductionmentioning

confidence: 97%

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Exposure to β-carbolines norharman and harman

Pfau

Skog

2004

Journal of Chromatography B

198

170

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“…1(c) and (d)). [15][16][17][18][19][20][21][22][23][24][25] Some are reported to be increased in PD and/or their N-methylating enzyme increased. They all inhibit complex 1, the chief biochemical event in both MPTP poisoning and in PD.…”

Section: Mpp+ Like Compoundsmentioning

confidence: 99%