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Article

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

1
Department of Medical Biology, Faculty of Medicine, Atatürk University, 25240 Erzurum, Turkey
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Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, via dei Vestini 31, 66100 Chieti Scalo (CH), Italy
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Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, 25050 Erzurum, Turkey
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Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden
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Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 9RT, UK
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(5), 737; https://doi.org/10.3390/biom10050737
Received: 28 March 2020 / Revised: 26 April 2020 / Accepted: 29 April 2020 / Published: 9 May 2020
(This article belongs to the Section Natural and Bio-inspired Molecules)
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 (1-42) 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 1-42-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 1-42 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. View Full-Text
Keywords: histidyl-proline diketopiperazine; Alzheimer’s disease; amyloid-beta 1-42; neuroprotection; novel therapeutics histidyl-proline diketopiperazine; Alzheimer’s disease; amyloid-beta 1-42; neuroprotection; novel therapeutics
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MDPI and ACS Style

Turkez, H.; Cacciatore, I.; Arslan, M.E.; Fornasari, E.; Marinelli, L.; Di Stefano, A.; Mardinoglu, A. Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates. Biomolecules 2020, 10, 737. https://doi.org/10.3390/biom10050737

AMA Style

Turkez H, Cacciatore I, Arslan ME, Fornasari E, Marinelli L, Di Stefano A, Mardinoglu A. Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates. Biomolecules. 2020; 10(5):737. https://doi.org/10.3390/biom10050737

Chicago/Turabian Style

Turkez, Hasan, Ivana Cacciatore, Mehmet Enes Arslan, Erika Fornasari, Lisa Marinelli, Antonio Di Stefano, and Adil Mardinoglu. 2020. "Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates" Biomolecules 10, no. 5: 737. https://doi.org/10.3390/biom10050737

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