Searching for disease modifiers-PKC activation and HDAC inhibition - a dual drug approach to Alzheimer's disease that decreases Abeta production while blocking oxidative stress.
A series of benzolactam compounds were synthesized, some of which caused a concentration-dependent increase in sAPPalpha and decrease in Abeta production in the concentration range of 0.1-10 microM. Moreover, some compounds showed neuroprotective effects in the 10-20 microM range in the HCA cortical neuron model of oxidative stress and no toxicity in measurements of neuron viability by MTT assay, even at the highest concentrations tested (20 microM). Alzheimer's disease (AD) is a well-studied neurodegenerative process characterized by the presence of amyloid plaques and neurofibrillary tangles. In this study, a series of protein kinase C (PKC) activators were investigated, some of which also exhibit histone deacetylase (HDAC) inhibitory activity, under the hypothesis that such compounds might provide a new path forward in the discovery of drugs for the treatment of AD. The PKC-activating properties of these drugs were expected to enhance the alpha-secretase pathway in the processing of amyloid precursor protein (APP), while their HDAC inhibition was anticipated to confer neuroprotective activity. We found that benzolactams 9 and 11-14 caused a concentration-dependent increase in sAPPalpha and decrease in beta-amyloid (Abeta) production in the concentration range of 0.1-10 microM, consistent with a shift of APP metabolism toward the alpha-secretase-processing pathway. Moreover, compounds 9-14 showed neuroprotective effects in the 10-20 microM range in the homocysteate (HCA) cortical neuron model of oxidative stress. In parallel, we found that the most neuroprotective compounds caused increased levels of histone acetylation (H4), thus indicating their likely ability to inhibit HDAC activity. As the majority of the compounds studied also show nanomolar binding affinities for PKC, we conclude that it is possible to design, de novo, agents that combine both PKC-activating properties along with HDAC inhibitory properties. Such agents would be capable of modulating amyloid processing while showing neuroprotection. These findings may offer a new approach to therapies that exhibit disease-modifying effects, as opposed to symptomatic relief, in the treatment of AD.
Kozikowski
Alan P
AP
Drug Discovery Program, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA. kozikowa@uic.edu
Chen
Yihua
Y
Subhasish
Tapadar
T
Lewin
Nancy E
NE
Blumberg
Peter M
PM
Zhong
Zhenyu
Z
D'Annibale
Melissa A
MA
Wang
Weng-Long
WL
Shen
Yong
Y
Langley
Brett
B
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D056572:Histone Deacetylase Inhibitors; D007769:Lactams; D018696:Neuroprotective Agents; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D053829:Amyloid Precursor Protein Secretases; C543273:HDAC7 protein, human; D006655:Histone Deacetylases