The antioxidant 2,3-dichloro,5,8-dihydroxy,1,4-naphthoquinone inhibits acetyl-cholinesterase activity and amyloid β42 aggregation: A dual target therapeutic candidate compound for the treatment of Alzheimer's disease.

Abstract

Alzheimer's disease is characterized by amyloid β aggregation and cholinergic neurodegeneration. In the present study, pure DDN (2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone) was examined, for the first time, for its dual potential as inhibitor of acetylcholinesterase (AChE) and Aβ42 aggregation. Such investigation was encouraged by the in vitro high antioxidant potential of DDN. Indeed, it revealed interesting antioxidant activity with IC50 values of 9.8 and 4.3 µM for ABTS and reducing power, respectively. The ability of DDN to counteract Aβ42 aggregation was evaluated by thioflavine-T assay. Strong inhibition of Aβ42 aggregation of more than 90% at 25 µM was measured. Moreover, results showed that DDN inhibited AChE (IC50 = 14.5 µM). To better understand the interactions between DDN and AChE, molecular docking was performed. Obtained data predicted a high interaction characterized by hydrogen bonding at TYR337 as for galanthamine (positive control). Several residues involved in AChE hydrophobic interactions were similarly implicated in binding of this domain to DDN (ASP74, THR83, and TYR124). All these data would be useless if DDN could not pass the blood-brain barrier. So, DDN was loaded into alginate microspheres to enhance its stability and bioavailability. Thereafter, drug release profiles were assessed using immersion cell apparatus.

• Authors: Imen Khelifi, Audrey Tourrette, Zohra Dhouafli, Jalloul Bouajila, Thomas Efferth, Sara Abdelfatah, Riadh Ksouri, El Akrem Hayouni
• Journal: Biotechnology and applied biochemistry (Biotechnol Appl Biochem) Vol. 67 Issue 6 Pg. 983-990 (Nov 2020) ISSN: 1470-8744 [Electronic] United States
• PMID: 31820491 (Publication Type: Journal Article)
• Copyright: © 2019 International Union of Biochemistry and Molecular Biology, Inc.

Chemical References

• Amyloid beta-Peptides
• Cholinesterase Inhibitors
• GPI-Linked Proteins
• Naphthoquinones
• Peptide Fragments
• Protein Aggregates
• amyloid beta-protein (1-42)
• ACHE protein, human
• Acetylcholinesterase

Topics

• Acetylcholinesterase (chemistry)
• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (chemistry)
• Cholinesterase Inhibitors (chemistry, therapeutic use)
• GPI-Linked Proteins (chemistry)
• Humans
• Naphthoquinones (chemistry, therapeutic use)
• Peptide Fragments (chemistry)
• Protein Aggregates (drug effects)