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7-O-Esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo. | LitMetric

AI Article Synopsis

  • Alzheimer's disease (AD) is a complex and common form of dementia with no current cures or treatments to slow its progression, sparking interest in natural products as potential neuroprotectants due to their health benefits and low toxicity.
  • This study focuses on the creation of new compounds, specifically 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin, which are hybrids of the flavonoid taxifolin and phenolic acids, showing enhanced neuroprotective effects in vitro against various forms of cell damage and inflammation.
  • In animal studies, these compounds not only improved memory performance in a mouse model of AD but also demonstrated a stronger impact than their individual components, suggesting that these natural

Article Abstract

Alzheimer's disease (AD) is a multifactorial disease and the most common form of dementia. There are no treatments to cure, prevent or slow down the progression of the disease. Natural products hold considerable interest for the development of preventive neuroprotectants to treat neurodegenerative disorders like AD, due to their low toxicity and general beneficial effects on human health with their anti-inflammatory and antioxidant features. In this work we describe regioselective synthesis of 7-O-ester hybrids of the flavonoid taxifolin with the phenolic acids cinnamic and ferulic acid, namely 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin. The compounds show pronounced overadditive neuroprotective effects against oxytosis, ferroptosis and ATP depletion in the murine hippocampal neuron HT22 cell model. Furthermore, 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin reduced LPS-induced neuroinflammation in BV-2 microglia cells as assessed by effects on the levels of NO, IL6 and TNFα. In all in vitro assays the 7-O-esters of taxifolin and ferulic or cinnamic acid showed strong overadditive activity, significantly exceeding the effects of the individual components and the equimolar mixtures thereof, which were almost inactive in all of the assays at the tested concentrations. In vivo studies confirmed this overadditive effect. Treatment of an AD mouse model based on the injection of oligomerized Aβ peptide into the brain to cause neurotoxicity and subsequently memory deficits with 7-O-cinnamoyltaxifolin or 7-O-feruloyltaxifolin resulted in improved performance in an assay for short-term memory as compared to vehicle and mice treated with the respective equimolar mixtures. These results highlight the benefits of natural product hybrids as a novel compound class with potential use for drug discovery in neurodegenerative diseases due to their pharmacological profile that is distinct from the individual natural components.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928325PMC
http://dx.doi.org/10.1016/j.redox.2019.101378DOI Listing

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