Journal
ACS CHEMICAL NEUROSCIENCE
Volume 6, Issue 8, Pages 1393-1399Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00082
Keywords
Hybrid compounds; neuroprotectants; curcumin; melatonin; Alzheimer's disease
Funding
- Alzheimer's & Related Diseases Research Award Fund, Commonwealth of Virginia
- NIA of the NIH [R01AG041161]
- Semmes Foundation
- National Institute on Minority Health and Health Disparities [G12MD007591]
- Virginia and Buddy Spitz
- Mapfre-Reina Sofia postdoctoral award by the Mapfre-Reina Sofia-CieN foundation
- NATIONAL INSTITUTE ON AGING [R01AG041161] Funding Source: NIH RePORTER
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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 A beta 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/PSI 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.
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