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 actinomycete Streptomyces caniferus, and its ability to ameliorate Alzheimer’s disease (AD) hallmarks was determined. The compound reduced neuroinflammatory markers in BV2 microglial cells activated with lipopolysaccharide (LPS), being able to block NFκB-p65 translocation 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 ROS levels. The phosphorylated state of the tau protein was evaluated in SH-SY5Y tau441 cells. Caniferolide A reduced Thr212 and Ser214 phosphorylation by targeting p38 and JNK MAPK kinases. On the other side, the antioxidant properties of the macrolide were determined in an oxidative stress model with SH-SY5Y cells treated with H2O2. The compound diminished ROS levels and increased cell viability and GSH content by activating the nuclear factor Nrf2. Finally, the neuroprotective ability 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 in the survival of neuroblastoma in both cases. These results indicate that the compound is able to target many pathological markers of AD, suggesting that caniferolide A could be an interesting drug lead for a polypharmacological approach to the illness.

Exploitation of Marine Molecules to Manage Alzheimer’s Disease

“…Caniferolide A is a macrolide-type compound isolated from extracts of a marine culture of Streptomyces caniferus , a Gram-positive bacterium included in the phylum Actinobacteria [ 142 ]. Studies show that this compound alleviates the distinctive characteristics of AD [ 25 ]. Caniferolide A ( Figure 2 G) leads to the reduction in neuroinflammatory markers in BV2 glial cells activated with lipopolysaccharide (LPS), being able to block the translocation of FFKB-p65 to the nucleus and activate the Nrf2 pathway [ 25 ].…”

“…Studies show that this compound alleviates the distinctive characteristics of AD [ 25 ]. Caniferolide A ( Figure 2 G) leads to the reduction in neuroinflammatory markers in BV2 glial cells activated with lipopolysaccharide (LPS), being able to block the translocation of FFKB-p65 to the nucleus and activate the Nrf2 pathway [ 25 ]. It also was found to cause decreases in proinflammatory cytokines (IL-1b, IL-6, and TNF-alpha), reactive oxygen species (ROS), and the release of nitric oxide (NO) and inhibit the activities of iNOS, JNK, and p38.…”

“…Caniferolide A reduced the phosphorylation of Thr212 and Ser 214 by targeting the p38 and JNK MAPK kinases. On the other hand, the antioxidant properties of the macrolide were determined in an oxidative stress model with SH-SY5Y cells treated with hydrogen peroxide [ 25 ]. The compound decreased ROS levels and increased cell viability and GSH content by activating the nuclear factor Nrf2.…”

“…The effectiveness of all these molecules varies between patients and stages of the disease, and in many cases, these drugs have adverse effects (nausea, vomiting, and diarrhea). For all these reasons, numerous efforts have been made in developing new therapeutic agents to find new drugs of value against AD [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. It is widely known that the development of AD is linked to amyloid-β peptides and tau aggregation.…”

A Decade of Antifungal Leads from Natural Products: 2010–2019

“…Like the astolides, the caniferolides displayed potent antifungal activity with MICs of 0.5-2 μg/mL against C. albicans and 2-8 μg/mL against Aspergillus fumigatus, as well as similar levels of cytotoxicity against human tumor cell lines. Caniferolide A was also shown to have in vitro activity against targets relevant to Alzheimer's disease [25]. Enduspeptides A-C (27)(28)(29) are depsipeptides that differ in the acyl chain attached to the threonine residue and were isolated from a Streptomyces sp.…”