Fiscalin Derivatives as Potential Neuroprotective Agents

Sandra Barreiro; Bárbara Silva; Solida Long; Madalena Pinto; Fernando Remião; Emília Sousa; Renata Silva

doi:10.3390/pharmaceutics14071456

Fiscalin Derivatives as Potential Neuroprotective Agents

Pharmaceutics. 2022 Jul 12;14(7):1456. doi: 10.3390/pharmaceutics14071456.

Authors

Sandra Barreiro^{1

2}, Bárbara Silva^{1

2}, Solida Long^{3

4}, Madalena Pinto^{4

5}, Fernando Remião^{1

2}, Emília Sousa^{4

5}, Renata Silva^{1

2}

Affiliations

¹ Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
² UCIBIO-Applied Molecular Biosciences Unit, Requimte, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
³ Department of Bioengineering, Royal University of Phnom Penh, Russian Confederation Blvd., Phnom Penh 12156, Cambodia.
⁴ CIIMAR-Centro Interdisciplinar de Investigação Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal.
⁵ Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.

Abstract

Neurodegenerative diseases (ND) share common molecular/cellular mechanisms that contribute to their progression and pathogenesis. In this sense, we are here proposing new neuroprotection strategies by using marine-derived compounds as fiscalins. This work aims to evaluate the protective effects of fiscalin derivatives towards 1-methyl-4-phenylpyridinium (MPP⁺)- and iron (III)-induced cytotoxicity in differentiated SH-SY5Y cells, an in vitro disease model to study ND; and on P-glycoprotein (P-gp) transport activity, an efflux pump of drugs and neurotoxins. SH-SY5Y cells were simultaneously exposed to MPP⁺ or iron (III), and noncytotoxic concentrations of 18 fiscalin derivatives (0-25 μM), being the cytotoxic effect of both MPP⁺ and iron (III) evaluated 24 and 48 h after exposure. Fiscalins 1a and 1b showed a significant protective effect against MPP⁺-induced cytotoxicity and fiscalins 1b, 2b, 4 and 5 showed a protective effect against iron (III)-induced cytotoxicity. Fiscalins 4 and 5 caused a significant P-gp inhibition, while fiscalins 1c, 2a, 2b, 6 and 11 caused a modest increase in P-gp transport activity, thus suggesting a promising source of new P-gp inhibitors and activators, respectively. The obtained results highlight fiscalins with promising neuroprotective effects and with relevance for the synthesis of new derivatives for the treatment/prevention of ND.

Keywords: P-glycoprotein; cytotoxicity; fiscalins; neurodegeneration; neurodegenerative diseases; neuroprotection.

Grants and funding

This work was financed by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB. In addition, this work was supported by national funds through FCT within the scope of UIDB/04423/2020, UIDP/04423/2020 (Group of Natural Products and Medicinal Chemistry-CIIMAR), and under the projects PTDC/SAU-PUB/28736/2017 (reference POCI-01–0145-FEDER-028736), and PTDC/CTA-AMB/0853/2021 cofinanced by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds supported by NORTE2020, through ERDF, and CHIRALSINTESE_APSFCT_IINFACTS_2021. This work was also funded by the structured program of R&D&I ATLANTIDA-Platform for the monitoring of the North Atlantic Ocean and tools for the sustainable exploitation of the marine resources (reference NORTE-01-0145-FEDER-000040), supported by the North Portugal Regional Operational Program (NORTE2020), through the European Regional Development Fund (ERDF).