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

Alan P. Kozikowski, Yihua Chen, Tapadar Subhasish, Nancy E. Lewin, Peter M. Blumberg, Zhenyu Zhong, Melissa A. D'Annibale, Weng Long Wang, Yong Shen, Brett Langley

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1095-1105
Number of pages11
JournalChemMedChem
Volume4
Issue number7
DOIs
StatePublished - Jul 6 2009
Externally publishedYes

Fingerprint

Histone Deacetylases
Oxidative stress
Protein Kinase C
Alzheimer Disease
Oxidative Stress
Chemical activation
Amyloid
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Pharmaceutical Preparations
Processing
Acetylation
Neurofibrillary Tangles
Aptitude
Amyloid Plaques
Neuroprotective Agents
Drug Discovery
Metabolism
Histones
Neurons

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 journalArticle

Kozikowski, AP, Chen, Y, Subhasish, T, Lewin, NE, Blumberg, PM, Zhong, Z, D'Annibale, MA, Wang, WL, Shen, Y & Langley, B 2009, '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', ChemMedChem, vol. 4, no. 7, pp. 1095-1105. https://doi.org/10.1002/cmdc.200900045
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. / 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. In: ChemMedChem. 2009 ; Vol. 4, No. 7. pp. 1095-1105.
@article{544814316f784e1b9443b6013f9a2dca,
title = "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",
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.",
keywords = "Alzheimer's disease, Amyloid β, HDAC inhibition, Neuroprotection, PKC activation",
author = "Kozikowski, {Alan P.} and Yihua Chen and Tapadar Subhasish and Lewin, {Nancy E.} and Blumberg, {Peter M.} and Zhenyu Zhong and D'Annibale, {Melissa A.} and Wang, {Weng Long} and Yong Shen and Brett Langley",
year = "2009",
month = "7",
day = "6",
doi = "10.1002/cmdc.200900045",
language = "English (US)",
volume = "4",
pages = "1095--1105",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "7",

}

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 -