Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates.

Abstract

Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 (Aβ1-42) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against Aβ1-42-induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by Aβ1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.

• Authors: Hasan Turkez, Ivana Cacciatore, Mehmet Enes Arslan, Erika Fornasari, Lisa Marinelli, Antonio Di Stefano, Adil Mardinoglu
• Journal: Biomolecules (Biomolecules) Vol. 10 Issue 5 (05 09 2020) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 32397415 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Antioxidants
• Peptides, Cyclic
• Piperazines
• Mitomycin
• 8-Hydroxy-2'-Deoxyguanosine
• Acetylcholinesterase
• Amyloid Precursor Protein Secretases
• histidyl-proline diketopiperazine

Topics

• 8-Hydroxy-2'-Deoxyguanosine (metabolism)
• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy, pathology)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (toxicity)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Cell Death (drug effects)
• Cell Line, Tumor
• Gene Expression Regulation (drug effects)
• Humans
• Isomerism
• Lymphocytes (drug effects, metabolism)
• Metaphase (drug effects)
• Mitomycin (pharmacology)
• Models, Biological
• Necrosis
• Neurons (drug effects, metabolism, pathology)
• Neuroprotection (drug effects)
• Oxidation-Reduction
• Oxidative Stress (drug effects)
• Peptides, Cyclic (chemistry, pharmacology, therapeutic use)
• Piperazines (chemistry, pharmacology, therapeutic use)