9-Methyl-β-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture

Hamann, Juliane; Wernicke, Catrin; Lehmann, Jochen; Reichmann, Heinz; Rommelspacher, Hans; Gille, Gabriele

doi:10.1016/j.neuint.2007.08.018

Cited by 39 publications

(66 citation statements)

References 56 publications

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“…GAS1 is a protein involved with two major signaling pathways, namely GDNF and SHH, and in this paper, we have analyzed a potential interaction between the two intracellular signaling cascades. Abnormal SHH signaling has been associated with the origin and maintenance of neuroblastomas, and several of the components of this pathway have been detected in primary human neuroblastomas and cell lines, including SH-SY5Y [33][34][35][36]. In the present work, we detected the expression of the mRNAs for SHH, PTCH1 and GLI1, in both SH-SY5Y cells and cells expressing GAS1 mRNA antisense, in conditions of proliferation and after serum withdrawal ( Supplementary Fig.…”

Section: Discussionsupporting

confidence: 60%

GAS1 induces cell death through an intrinsic apoptotic pathway

et al. 2012

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Growth Arrest Specific 1 (GAS1) is a protein expressed when cells are arrested and during development. When ectopically expressed, GAS1 induces cell arrest and apoptosis of different cell lines, and we have previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity inhibiting the GDNF-mediated intracellular survival signaling. In the present work, we have dissected the molecular pathway leading to cell death. We employed the SH-SY5Y human neuroblastoma cell line that expresses GAS1 when deprived of serum. We observed, as we have previously described, that the presence of GAS1 reduces RET phosphorylation and inhibits the activation of AKT. We have now determined that the presence of GAS1 also triggers the dephosphorylation of BAD, which, in turn, provokes the release of Cytochrome-c from the mitochondria to the cytosol activating caspase-9, prompting the activity of caspase-3 and resulting in apoptosis of the cells. The apoptotic process is intrinsic, because there is no activation of caspase-8, thus this is consistent with apoptosis induced by the lack of trophic support. Interestingly, in cells where GAS1 has been silenced there is a significant delay in the onset of apoptosis.

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Section: Discussionsupporting

confidence: 60%

GAS1 induces cell death through an intrinsic apoptotic pathway

et al. 2012

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“…9-Me-BC exerted neurostimulatory, neuroprotective, neuroregenerative and anti-inflammatory effects in primary dopaminergic culture [22,61]. While toxic effects of 9-methylated b-carbolines were reported in former in vivo studies with mice [62], recent research has confirmed the neuroprotective properties of 9-me-BC in a rat model [63].…”

Section: Review Polanski Reichmann and Gillementioning

confidence: 97%

“…Stimulation, protection & regeneration of dopaminergic neurons by 9-methyl-b-carboline 9-methyl-b-carboline is taken up by the DAT into dopaminergic neurons and reaches maximum uptake kinetics after approximately 3 h [61]. After treatment of primary dopaminergic cell cultures with 9-me-BC for 48 h, an increased number of tyrosine hydroxylase immunoreactive (THir) neurons were observed [22].…”

Section: Reviewmentioning

confidence: 99%

“…Dopaminergic neurotrophic/morphogenic factors, such as sonic hedgehog (Shh) [71], wingless-type mouse mammary tumor virus (MMTV) integration site family, member 1 (Wnt1) [72] and member 5a (Wnt5a) [73], as well as the dopaminergic transcription factors engrailed homeobox 1 (En1) [74], nuclear receptor related 1 (Nurr1) [75] and paired-like homeodomain transcription factor 3 (Pitx3) [76], and the dopaminergic markers aldehyde dehydrogenase 1a1 (Aldh1), DAT and TH, have also been shown to be upregulated by 9-me-BC [61]. Importantly, recent studies demonstrated that Nurr1 is required not only during the development process of dopaminergic neurons, but is also essential for the maintenance of maturing and adult dopaminergic neurons [77].…”

Section: Reviewmentioning

confidence: 99%

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Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?

Polanski

Reichmann

Gille

2011

Expert Review of Neurotherapeutics

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β-carbolines are potential endogenous and exogenous neurotoxins that may contribute to the pathogenesis of Parkinson's disease (PD). 9-methyl-β-carboline exhibits multimodal effects that could be beneficial in the treatment of PD. It shows stimulatory effects to dopaminergic neurons by increasing the expression of tyrosine hydroxylase and its transcription factors in pre-existing dopa decarboxylase immunoreactive neurons. Furthermore, 9-methyl-β-carboline has emerged as a substance with the rare property of a protective and regenerative/restorative potential for dopaminergic neurons by inducing gene expression of several neurotrophic factors and decreasing apoptotic cell signals. It reduces protein levels of α-synuclein and inhibits monoamine oxidase A and B. Finally, 9-methyl-β-carboline acts on multiple targets in the inflammatory cascade by inhibiting the proliferation of microglia, by decreasing chemotactic cytokines and by creating an anti-inflammatory environment in the CNS. This article summarizes our current knowledge of 9-methyl-carboline and discusses its potential role as a new drug for the treatment of PD.

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“…Dif--carboline studies found 3 false negative citations in 2 publications (Hamann et al, 2006;2008). All three were 9-methyl-beta-carboline xHCl, which belongs to the -carboline compound class, yet is not a neurotoxic, but a neuroprotective member of this class (Hamann et al, 2008). Hence, primary mesencephalon cells from mouse brain do not have any 'real' false negatives in the endpoint categories 'mitochondrial dysfunction/oxidative stress/apoptosis'.…”

Section: Mousementioning

confidence: 99%

Literature review and appraisal on alternative neurotoxicity testing methods

Masjosthusmann

Barenys

El‐Gamal

et al. 2018

EFSA Supporting Publications

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The goal of this review was the evaluation of information on assessment methods in the field of alternative neurotoxicity (NT) testing. We therefore performed a systematic and comprehensive collection of scientific literature (in English) from the past 27 years until mid of 2017 on state of the art alternative testing methods including in vitro test methods, in silico methods and alternative non-mammalian models. This review identified a variety of test methods that have the ability to predict NT of chemicals based on predefined key NT endpoint categories (27). Those endpoint categories were derived from the Mode of Action (MoA) of known human neurotoxicants. Pre-evaluated MoAs of human neurotoxicants allowed the identification of performance characteristics with regard to the ability of a test system to correctly predict a chemical effect on an endpoint category. The most predictive in vitro model that covers a large variety of endpoint categories are primary rodent cells or tissues. Human based systems derived from induced pluripotent stem cells (iPSC) are promising and warrant human relevance. There is however not yet sufficient data on these models to demonstrate their suitability to reliably substitute primary rodent cells for NT testing purposes. Test methods for glia toxicity are rare and glia endpoint categories are clearly underrepresented. Therefore, a focus for future method development should be placed on glia, astrocytes, oligodendrocytes and microglia based models, preferably in a co-culture se up. The review on in silico methods, resulted into 54 QSARs publications, relevant for NT, of which 39 on blood brain barrier (BBB) permeation. The QSARs available in the publications were developed from data on drugs and chemicals, but there appears a limited set of experimental data for chemicals and pesticides on blood-brain barrier passage. The evaluation of NT methods using alternative whole organism approaches demonstrated a majority of data for C. elegans (nematode species), represented with high true prediction (96%). The main endpoint category was inhibition of cholinergic transmission, with specific endpoints for AChE activity and motor activity, the latter confirming the added value of a whole organism approach among alternative models. Though D. rerio, the zebrafish model appeared a www.efsa.europa.eu/publications 2 EFSA Supporting publication 2018:EN-1410The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights ...

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9-Methyl-β-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture

Cited by 39 publications

References 56 publications

GAS1 induces cell death through an intrinsic apoptotic pathway

GAS1 induces cell death through an intrinsic apoptotic pathway

Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?

Literature review and appraisal on alternative neurotoxicity testing methods

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