title: Curcumin/melatonin hybrid 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide ameliorates AD-like pathology in the APP/PS1 mouse model.
abstract: In our efforts to develop hybrid compounds of curcumin and melatonin as potential disease-modifying agents for Alzheimer's disease (AD), a potent lead hybrid compound, Z-CM-I-1, has been recently identified and biologically characterized in vitro. In this work, we report the in vivo effects of Z-CM-I-1 on AD pathologies in an APP/PS1 transgenic AD model. Our studies demonstrated that Z-CM-I-1 significantly decreased the accumulation of Aβ in the hippocampus and cortex regions of the brain and reduced inflammatory responses and oxidative stress after treatment for 12 weeks at 50 mg/kg per dose via oral administration. Furthermore, Z-CM-I-1 significantly improved synaptic dysfunction evidenced by the increased expression of synaptic marker proteins, PSD95 and synaptophysin, indicating its protective effects on synaptic degeneration. Lastly, we demonstrated that Z-CM-I-1 significantly increased the expression level of complexes I, II, and IV of the mitochondria electron transport chain in the brain tissue of APP/PS1 mice. Collectively, these results clearly suggest that Z-CM-I-1 is orally available and exhibits multifunctional properties in vivo on AD pathologies, thus strongly encouraging further development of this lead compound as a potential disease-modifying agent for AD patients.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Gorka
authors.initials: G
authors.lastname: Gerenu
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Chojnacki
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Saathoff
authors.affiliation: Alzheimer Disease Research Unit, Alzheimer Center Reina Sofía Foundation, CIEN Foundation, Carlos III Institute of Health, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-Martín
authors.affiliation: College of Sciences, University of Texas, San Antonio, Texas, USA.
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003374:Coumarins / Q000494:pharmacology*; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008550:Melatonin / Q000494:pharmacology*; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D009154:Mutation; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010421:Pentanoic Acids / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D003374:Coumarins; D045222:Electron Transport Chain Complex Proteins; D007211:Indoles; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D010421:Pentanoic Acids; D053764:Presenilin-1; C000607493:Z-CM-I-1; D008550:Melatonin
keywords: Alzheimer’s disease; Hybrid compounds; curcumin; melatonin; neuroprotectants