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Novel neurotoxic peptides from Protopalythoa variabilis virtually interact with voltage-gated sodium channel and display anti-epilepsy and neuroprotective activities in zebrafish

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Abstract

We previously reported a novel toxic peptide identified from the anthozoan Protopalythoa variabilis transcriptome which is homologous to a novel structural type of sodium channel toxin isolated from a parental species (Palythoa caribaeorum). The peptide was named, according to its homologous, as Pp V-shape α-helical peptide (PpVα) in the present study. Through molecular docking and dynamics simulation, linear and hairpin folded PpVα peptides were shown to be potential voltage-gated sodium channel blockers. Nowadays, sodium channel blockers have been the mainstream of the pharmacological management of epileptic seizures. Also, sodium channel blockers could promote neuronal survival by reducing sodium influx and reducing the likelihood of calcium importation resulting in suppressing microglial activation and protecting dopaminergic neurons from degeneration. The folded PpVα peptide could decrease pentylenetetrazol (PTZ)-induced c-fos and npas4a expression level leading to reverse PTZ-induced locomotor hyperactivity in zebrafish model. In vitro, the folded PpVα peptide protected PC12 cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity via activating heme oxygenase-1 (HO-1) and attenuating inducible nitric oxide synthase (iNOS) expression. In vivo, PpVα peptide suppressed the 6-OHDA-induced neurotoxicity on the locomotive behavior of zebrafish and, importantly, prevented the 6-OHDA-induced excessive ROS generation and subsequent dopaminergic neurons loss. This study indicates that the single S–S bond folded PpVα peptide arises as a new structural template to develop sodium channel blockers and provides an insight on the peptide discovery from cnidarian transcriptome to potentially manage epilepsy and neurodegenerative disorders.

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Acknowledgements

Research at University of Macau was supported by grants from the Science and Technology Development Fund (FDCT) of Macao SAR (Ref. no. 069/2015/A2 and no. 134/2014/A3) and Research Committee, University of Macau (MYRG2016-00133-ICMS-QRCM, MYRG2015-00182-ICMS-QRCM, and MYRG2016-00129-ICMS-QRCM). Research work at the Institute for Marine Sciences, Federal University of Ceará, was supported by the Brazilian National Council for Scientific and Technological Development—CNPq, under the auspices of the Marine Biotechnology Network Initiative (Grant no. 408835/2013-3 to G.R.-B.), the Ministry of Science, Technology, Innovation & Communication (MCTI-C) of the Federal Government of Brazil. J.-E.RLM was a former doctoral fellowship recipient from the Coordination for the improvement of Higher Education Personnel (CAPES, the Ministry of Education, Brazil).

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  1. Qiwen Liao and Shengnan Li contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China

    Qiwen Liao, Shengnan Li, Xiufen Wang & Simon Ming-Yuen Lee

  2. Department of Computer and Information Science, Faculty of Science and Technology, University of Macau, Macau, China

    Shirley Weng In Siu

  3. Laboratory of Biochemistry and Biotechnology, Institute for Marine Sciences, Federal University of Ceará, Fortaleza, Brazil

    Jean-Étienne R. L. Morlighem & Gandhi Rádis-Baptista

  4. Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Clarence Tsun Ting Wong

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  1. Qiwen Liao
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Liao, Q., Li, S., Siu, S.W.I. et al. Novel neurotoxic peptides from Protopalythoa variabilis virtually interact with voltage-gated sodium channel and display anti-epilepsy and neuroprotective activities in zebrafish. Arch Toxicol 93, 189–206 (2019). https://doi.org/10.1007/s00204-018-2334-5

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