Caniferolide A, a Macrolide from Streptomyces caniferus, Attenuates Neuroinflammation, Oxidative Stress, Amyloid-Beta, and Tau Pathology in Vitro

Abstract

The macrolide caniferolide A was isolated from extracts of a culture of the marine-derived actinomyceteStreptomyces caniferus, and its ability to ameliorate Alzheimer’s disease (AD) hallmarks was determined. The compound reducedneuroinflammatory markers in BV2 microglial cells activated with lipopolysaccharide (LPS), being able to block NFκB-p65translocation to the nucleus and to activate the Nrf2 pathway. It also produced a decrease in pro-inflammatory cytokines (IL-1β,IL-6, and TNF-α), reactive oxygen species (ROS) and nitric oxide release and inhibited iNOS, JNK, and p38 activities.Moreover, the compound blocked BACE1 activity and attenuated Aβ-activation of microglia by drastically diminishing ROSlevels. The phosphorylated state of the tau protein was evaluated in SH-SY5Y tau441 cells. Caniferolide A reduced Thr212 andSer214 phosphorylation by targeting p38 and JNK MAPK kinases. On the other side, the antioxidant properties of themacrolide were determined in an oxidative stress model with SH-SY5Y cells treated with H2O2. The compound diminishedROS levels and increased cell viability and GSH content by activating the nuclear factor Nrf2. Finally, the neuroprotectiveability of the compound was confirmed in two trans-well coculture systems with activated BV2 cells (both with LPS and Aβ)and wild type and transfected SH-SY5Y cells. The addition of caniferolide A to microglial cells produced a significant increase inthe survival of neuroblastoma in both cases. These results indicate that the compound is able to target many pathologicalmarkers of AD, suggesting that caniferolide A could be an interesting drug lead for a polypharmacological approach to theillnessThe research leading to these results has received funding from the following FEDER cofunded-grants, Consellería de Cultura, Educación e Ordenación Universitaria Xunta de Galicia, 2017 GRC GI-1682 (ED431C 2017/01); CDTI and Technological Funds, supported by Ministerio de Economía, Industria y Competitividad, AGL2014-58210-R, AGL2016-78728-R (AEI/FEDER, UE), ISCIII/PI16/01830, RTC-2016-5507-2, and ITC-20161072; and European Union POCTEP 0161-Nanoeaters-1-E-1, Interreg AlertoxNet EAPA-317-2016, Interreg Agritox EAPA-998-2018, H2020 778069-EMERTOX, and FP7 PharmaSea (Grant Agreement 312184).This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular pharmaceutics, copyright © 2019 American Chemical Society, after peer review and technical editing by the publisher.S