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Effects of C-Terminal-Ethyl-Esterification in a Snake-Venom-Based Peptide Against the Neurotoxicity of Acrolein in PC12 Cells

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Abstract

We have recently reported the neurotrophic and neuroprotective effects of the snake-venom-based synthetic tripeptide BTX-I in PC12 cells treated with acrolein. In the present study, this peptide was chemically modified to increase its neurotrophic/neuroprotective activity. Esterification (ethyl or methyl), PEGylation and amidation were introduced at the C-terminus; acetylation was introduced at the N-terminus. The modified peptides protected PC12 cells from the decrease in viability and neuritogenesis induced by acrolein; however, only the ethyl-esterified peptide (named BTX-II) significantly increased neuritogenesis in comparison with the original peptide BTX-I. Moreover, BTX-II increased the expression of proteins related to (i) axonal/synaptic plasticity (synapsin I, β-III-Tubulin), and (ii) energy metabolism (AMPK-α and SIRT I) in PC12 cells treated with acrolein. In addition, BTX-II upregulated the expression of genes that encode apolipoprotein E (ApoE) and Mitogen-Activated Protein Kinase 3 (Mapk3), which are associated with cognitive improvements in animal models of Alzheimer’s disease (AD). In conclusion, ethyl-esterification at the C-terminus of the snake-venom-based tripeptide [Glu-Val-Trp] improved the neurotrophic and neuroprotective potential in relation to the original tripeptide.

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Acknowledgements

The authors thank FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, Grant numbers: 2015/4808-2, 2011/23236-4), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant number: 305823/2019-1) for the financial support.

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  1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil

    Carolina P. Bernardes, Neife A. G. Santos, Tassia R. Costa, Danilo L. Menaldo, Flavia M. Sisti, Martin K. Amstalden, Lusânia M. G. Antunes, Suely V. Sampaio & Antonio C. Santos

  2. Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, FMRP, Ribeirão Preto, SP, Brazil

    Diego L. Ribeiro

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  1. Carolina P. Bernardes
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All authors have equally contributed to this study.

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Correspondence to Antonio C. Santos.

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Bernardes, C.P., Santos, N.A.G., Costa, T.R. et al. Effects of C-Terminal-Ethyl-Esterification in a Snake-Venom-Based Peptide Against the Neurotoxicity of Acrolein in PC12 Cells. Int J Pept Res Ther 29, 41 (2023). https://doi.org/10.1007/s10989-023-10517-2

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