title: The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.
abstract: With the trend of an increasing aged population worldwide, Alzheimer's disease (AD), an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC) inhibitor, suberoylanilidehydroxamic acid (SAHA), may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Pharmacy, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Center of Excellence in Neuroscience, Texas Tech University Health Sciences Center, El Paso, Texas, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Camarillo
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yina
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Center of Excellence in Neuroscience, Texas Tech University Health Sciences Center, El Paso, Texas, United States of America.
authors.forename: Chun
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Jiang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050882:CREB-Binding Protein / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D018450:Disease Progression; D004357:Drug Synergism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009757:Nylons / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D009757:Nylons; D011758:Pyrroles; C585734:SAHA-PIP-delta; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D003474:Curcumin