Abstract
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 α-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 sAPPα and decrease in β-amyloid (Aβ) production in the concentration range of 0.1-10 μm, consistent with a shift of APP metabolism toward the α-secretase- processing pathway. Moreover, compounds 9-14 showed neuroprotective effects in the 10-20 μm 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1095-1105 |
| Number of pages | 11 |
| Journal | ChemMedChem |
| Volume | 4 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 6 2009 |
| Externally published | Yes |
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Keywords
- Alzheimer's disease
- Amyloid β
- HDAC inhibition
- Neuroprotection
- PKC activation
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry
- Molecular Medicine
Cite this
Searching for disease modifiers - PKC activation and HDAC inhibition - A dual drug approach to Alzheimer's disease that decreases Aβ production while blocking oxidative stress. / Kozikowski, Alan P.; Chen, Yihua; Subhasish, Tapadar; Lewin, Nancy E.; Blumberg, Peter M.; Zhong, Zhenyu; D'Annibale, Melissa A.; Wang, Weng Long; Shen, Yong; Langley, Brett.
In: ChemMedChem, Vol. 4, No. 7, 06.07.2009, p. 1095-1105.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Searching for disease modifiers - PKC activation and HDAC inhibition - A dual drug approach to Alzheimer's disease that decreases Aβ production while blocking oxidative stress
AU - Kozikowski, Alan P.
AU - Chen, Yihua
AU - Subhasish, Tapadar
AU - Lewin, Nancy E.
AU - Blumberg, Peter M.
AU - Zhong, Zhenyu
AU - D'Annibale, Melissa A.
AU - Wang, Weng Long
AU - Shen, Yong
AU - Langley, Brett
PY - 2009/7/6
Y1 - 2009/7/6
N2 - 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 α-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 sAPPα and decrease in β-amyloid (Aβ) production in the concentration range of 0.1-10 μm, consistent with a shift of APP metabolism toward the α-secretase- processing pathway. Moreover, compounds 9-14 showed neuroprotective effects in the 10-20 μm 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.
AB - 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 α-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 sAPPα and decrease in β-amyloid (Aβ) production in the concentration range of 0.1-10 μm, consistent with a shift of APP metabolism toward the α-secretase- processing pathway. Moreover, compounds 9-14 showed neuroprotective effects in the 10-20 μm 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.
KW - Alzheimer's disease
KW - Amyloid β
KW - HDAC inhibition
KW - Neuroprotection
KW - PKC activation
UR - http://www.scopus.com/inward/record.url?scp=67749147448&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67749147448&partnerID=8YFLogxK
U2 - 10.1002/cmdc.200900045
DO - 10.1002/cmdc.200900045
M3 - Article
C2 - 19396896
AN - SCOPUS:67749147448
VL - 4
SP - 1095
EP - 1105
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 7
ER -