Dopamine transporter‐mediated cytotoxicity of β‐carbolinium derivatives related to Parkinson's disease: relationship to transporter‐dependent uptake

Storch, Alexander; Hwang, Yu-I; Gearhart, Debra A.; Beach, Joseph Warren; Neafsey, Edward J.; Collins, Michael A.; Schwarz, Johannes

doi:10.1111/j.1471-4159.2004.02397.x

Cited by 46 publications

(29 citation statements)

References 47 publications

(131 reference statements)

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“…Our previous investigation showed that this meroterpenoid bakuchiol analog BU is a potent monoamine transporter inhibitor with selectivity for DAT and NET [9]. DAT has been proven to catalyze the reuptake of MPP + , 1-benzyl-1,2,3,4-tetrahydroisoquinoline derivatives [19], and b-carboline [20], in addition to regulating synaptic DA content. DAT thus may be considered a molecular gate for neurotoxins.…”

Section: Discussionmentioning

confidence: 99%

In vitro dopaminergic neuroprotective and in vivo antiparkinsonian-like effects of Δ3,2-hydroxybakuchiol isolated from Psoralea corylifolia (L.)

Zhao

Zheng²,

Qin

et al. 2009

Cell. Mol. Life Sci.

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Cocktail recipes containing Psoralea corylifolia seeds (PCS) are used to empirically treat Parkinson disease. A PCS isolate Delta(3),2-hydroxybakuchiol (BU) can inhibit dopamine uptake in dopamine transporter (DAT) transfected Chinese hamster ovary (CHO) cells, and dopamine reuptake blockade may provide an alternative approach for ameliorating parkinsonism. Here, we assessed the potential dopaminergic neuroprotective, and antiparkinsonian-like activity of BU. BU sample size was increased by using a scale-up extraction paradigm. Pharmacologically, BU significantly protected SK-N-SH cells from 1-methyl-4-phenylpyridinium (MPP(+)) insult, produced striking inhibitory actions on dopamine/norepinephrine uptake and WIN35,428 binding in synaptosomes on in vivo administration, and significantly preventing poor performance on rotarod and dopaminergic loss in substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice. BU acts by protecting dopaminergic neurons from MPP(+) injury and preventing against MPTP-induced behavioral and histological lesions in the Parkinson's disease (PD) model, possibly by inhibiting monoamine transporters. These findings suggest that BU could be meaningful in PD treatment.

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Section: Discussionmentioning

confidence: 99%

In vitro dopaminergic neuroprotective and in vivo antiparkinsonian-like effects of Δ3,2-hydroxybakuchiol isolated from Psoralea corylifolia (L.)

Zhao

Zheng²,

Qin

et al. 2009

Cell. Mol. Life Sci.

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“…␤-Carbolines are considered as natural or environmental analogs of MPP ϩ and have been implicated as environmental risk factors for Parkinson's disease (Nagatsu, 1997;Collins and Neafsey, 2000;Storch et al, 2004). These compounds produce neurotoxicity by inhibiting complex I of the mitochondrial respiratory chain.…”

Section: Discussionmentioning

confidence: 99%

“…␤-Carbolines are structurally related to MPP ϩ and possess a pyridinium-like structure attached to an aromatic heterocyclic indole ring (category 3). They are considered as natural or environmental analogs of MPP ϩ and have been implicated as environmental risk factors for Parkinson's diseases (Nagatsu, 1997;Collins and Neafsey, 2000;Storch et al, 2004). On the basis of the current data and previously reported PMAT inhibitors and noninhibitors, we used computer-aided modeling to generate three-dimensional qualitative and quantitative pharmacophore models with the aim of characterizing the substrate-inhibitor interaction site in PMAT.…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis and Structure-Activity Relationship Modeling of the Substrate/Inhibitor Interaction Site of Plasma Membrane Monoamine Transporter

Pan

Cui

et al. 2011

J Pharmacol Exp Ther

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Plasma membrane monoamine transporter (PMAT) is a new polyspecific transporter that interacts with a wide range of structurally diverse organic cations. To map the physicochemical descriptors of cationic compounds that allow interaction with PMAT, we systematically analyzed the interactions between PMAT and three series of structural analogs of known organic cation substrates including phenylalkylamines, n-tetraalkylammonium (n-TAA) compounds, and ␤-carbolines. Our results showed that phenylalkylamines with a distance between the aromatic ring and the positively charged amine nitrogen atom of ϳ6.4 Å confer optimal interactions with PMAT, whereas studies with n-TAA compounds revealed an excellent correlation between IC 50 values and hydrophobicity. The five ␤-carbolines that we tested, which possess a pyridinium-like structure and are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium, inhibited PMAT with high affinity (IC 50 values of 39.1-65.5 M). Cytotoxicity analysis further showed that cells expressing PMAT are 14-to 15-fold more sensitive to harmalan and norharmanium, suggesting that these two ␤-carbolines are also transportable substrates of PMAT. We then used computer-aided modeling to generate qualitative and quantitative three-dimensional pharmacophore models on the basis of 23 previously reported and currently identified PMAT inhibitors and noninhibitors. These models are characterized by a hydrogen bond donor and two to three hydrophobic features with distances between the hydrogen bond donor and hydrophobic features ranging between 5.20 and 7.02 Å. The consistency between the mapping results and observed PMAT affinity of a set of test compounds indicates that the models performed well in inhibitor prediction and could be useful for future virtual screening of new PMAT inhibitors.

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“…Beta-carbolines can also be synthesised endogenously in mammals from indolamines and further metabolised by condensation or sequential N-methylation, forming bioactive 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) or 2,9-di-N-methylated carbolinium ions (2,9-dimethyl-beta-norharmanium), respectively. The potential involvement of beta-carbolines in PD pathogenesis was observed when it was found that human PD patients had higher levels of 2,9-dimethyl-beta-norharmanium and other beta-carboline derivatives in the cerebral spinal fluid and plasma than that of control patients (Akundi et al, 2004;Hamann et al, 2006;Storch et al, 2004a The 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.…”

Section: Beta-carbolinesmentioning

confidence: 99%

“…It has been suggested that beta-carbolines, similar to another MPTP-similar chemical group isoquinolines (see Results Section 1.5.8), are taken up into dopaminergic neurons via DAT and elicit specific neurotoxicity as human embryonic kidney HEK-293 cell line overexpressing DAT showed higher degree of cytotoxicity triggered by 2[N]-methylated compounds than the parental HEK-293 cells alone (Storch et al, 2004a). Lastly, also similar to isoquinolines, not all beta-carbolines are neurotoxic as there are a few studies showing the neuroprotective effects both in vitro and in vivo of 9-methyl-beta-carboline such as protection against rotenone-or MPP+-induced neurodegeneration, reduced activation of microglia and its pro-inflammatory response and reduction of alpha-synuclein level (Polanski et al, 2010;Wernicke et al, 2010).…”

Section: Beta-carbolinesmentioning

confidence: 99%

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

Choi¹,

Polcher²,

Joas³

2016

EFSA Supporting Publications

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This report presents the outcomes of a systematic review (SR) identifying the mechanisms and chemicals involved in the pathogenesis of Parkinson's disease (PD) and childhood leukaemia (CL). This work serves as a basis for defining and mapping the causal linkages between a molecular initiating event (MIE) and a final adverse outcome (AO) that are relevant for the development of a prototype adverse outcome pathway (AOP) for assessing risk factors for PD and CL. Search for literature from 1990 to present was conducted using Web of Science, PubMed and TOXNET, and relevant references were selected using established inclusion/exclusion criteria and ranked using a set of quality control factors.For PD, 7,384 individual references were identified to be relevant for PD pathogenesis and chemicals associated with PD. Dopaminergic neurodegeneration in the substantia nigra leading to locomotor deficits was identified as the AO in PD. Other identified key events in PD pathogenesis include mitochondrial dysfunction, cellular accumulation of alpha-synuclein and oxidative stress. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and paraquat are some chemicals identified to be associated with PD pathogenesis.For CL, 1,988 individual references were identified to be relevant for CL pathogenesis and chemicals associated with CL. Chromosomal translocation, genetic damage/mutation and hyperdiploidy are considered as driving forces of CL. Except for infant leukaemia, CL pathogenesis requires a 'two-hit' model with an initiating event occurring in utero followed by a secondary hit potentially occurring after birth. Potential MIEs leading to these driving mechanisms include aberrant DNA topoisomerase II activity and erroneous DNA repair. Epigenetics appears to also play an influential role in CL pathogenesis. Benzene, bioflavonoids and organophosphates are some chemicals identified to be implicated in CL pathogenesis.The challenges of developing AOPs for these two diseases and the data gaps identified from the outcomes of this SR are also elaborated in this report. The 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 of the authors. KEY WORDSSystematic Review, Parkinson Disease, Childhood Leukaemia, Pathogenesis, Chemicals, Pesticides, Adverse Outcome Pathway SUMMARYThe aim of this project was to perform a systematic review (SR) to collect relevant publications related to the mechanisms involved in the pathogenesis of Parkinson's disease (PD)...

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Dopamine transporter‐mediated cytotoxicity of β‐carbolinium derivatives related to Parkinson's disease: relationship to transporter‐dependent uptake

Cited by 46 publications

References 47 publications

In vitro dopaminergic neuroprotective and in vivo antiparkinsonian-like effects of Δ3,2-hydroxybakuchiol isolated from Psoralea corylifolia (L.)

In vitro dopaminergic neuroprotective and in vivo antiparkinsonian-like effects of Δ3,2-hydroxybakuchiol isolated from Psoralea corylifolia (L.)

Molecular Analysis and Structure-Activity Relationship Modeling of the Substrate/Inhibitor Interaction Site of Plasma Membrane Monoamine Transporter

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

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