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1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) Alters Cell Cycle Progression in Human Neuroblastoma Cell Lines

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Abstract

1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline, abbreviated as TaClo, is an endogenous neurotoxin capable of formation in the brain through the condensation of neuronal tryptamine with ingested exogenous toxins such as trichloroethylene or chloral hydrate. Due to its structural resemblance to 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), and similar ability to inhibit mitochondrial complex I, TaClo has been implicated in the etiology of Parkinson’s disease. Previous studies have shown the cytotoxicity of TaClo in various cell culture models. In this study, we were interested in identifying the early molecular events within the cell upon exposure to TaClo, a potent mitochondrial toxin. We found increased phosphorylation of 5′-adenosine monophosphate-activated protein kinase (AMPK), induction of autophagy, and a dependence on glycolysis as some of the downstream events to TaClo treatment. Furthermore, TaClo-treated cells undergo accelerated late proliferation but form daughter cells containing fewer neurites, leading to their eventual apoptosis. We also found that TaClo inhibits neuronal prostaglandin E2 synthesis which may play an important role in synaptic plasticity. These results show that TaClo-mediated inhibition of mitochondrial complex I have multiple effects on cellular physiology which are in line with other mitochondrial effectors of Parkinson’s disease.

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Acknowledgements

The technical assistance of Ulrike Gotzinger-Berger, Brigitte Gunter, and Raina Seupel is sincerely acknowledged. This work was supported in part by the EU grant QLK3-CT2000 00463 (to B.L.F.) and South Asian University Start Up fund (to R.S.A.). E.C.J was supported by the Alexander von Humboldt Foundation (Bonn, Germany).

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Authors and Affiliations

  1. Neuroinflammation Research Group, South Asian University, Chanakyapuri, New Delhi, India

    Rakesh Kumar Sharma & Ravi Shankar Akundi

  2. Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    Eduardo Candelario-Jalil

  3. Institute of Organic Chemistry, University of Würzburg, Würzburg, Germany

    Doris Feineis & Gerhard Bringmann

  4. Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, Freiburg, Germany

    Bernd L. Fiebich

  5. Faculty of Life Sciences and Biotechnology, South Asian University, Chanakyapuri, New Delhi, 110021, India

    Ravi Shankar Akundi

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  1. Rakesh Kumar Sharma
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  2. Eduardo Candelario-Jalil
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  3. Doris Feineis
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Sharma, R.K., Candelario-Jalil, E., Feineis, D. et al. 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) Alters Cell Cycle Progression in Human Neuroblastoma Cell Lines. Neurotox Res 32, 649–660 (2017). https://doi.org/10.1007/s12640-017-9782-1

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