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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 <b>1a</b> and <b>1b</b> showed a significant protective effect against MPP⁺-induced cytotoxicity and fiscalins <b>1b</b>, <b>2b</b>, <b>4</b> and <b>5</b> showed a protective effect against iron (III)-induced cytotoxicity. Fiscalins <b>4</b> and <b>5</b> caused a significant P-gp inhibition, while fiscalins <b>1c</b>, <b>2a</b>, <b>2b</b>, <b>6</b> and <b>11</b> 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.