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A 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


Year of Publication:
Contact PI Name:
Shijun Zhang
Contact PI Affiliation:
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA
Gorka Gerenu, Kai Liu, Jeremy E. Chojnacki, John M. Saathoff, Pablo Martínez-Martín, George Perry, Xiongwei Zhua, Hyoung-gon Lee
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Commonwealth of Virginia
Alzheimer's and Related Diseases Research Award Fund (ARDRAF), Virginia Commonwealth University
Study Goal and Principal Findings:

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 region of the brain tissue, 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Z-CM-I-1 (Curcumin/Melatonin Hybrid)
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Load
Postsynaptic Density Protein 95 (PSD95)
Mitochondrial Proteins
Activated Microglia
4-hydroxy-2-nonenal (HNE)