title: A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson's Disease.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by motor and non-motor symptoms, resulting from the degeneration of nigrostriatal dopaminergic neurons and peripheral autonomic neurons. Given the limited success of neurotrophic factors in clinical trials, there is a need to identify new small molecule drugs and drug targets to develop novel therapeutic strategies to protect all neurons that degenerate in PD. Epigenetic dysregulation has been implicated in neurodegenerative disorders, while targeting histone acetylation is a promising therapeutic avenue for PD. We and others have demonstrated that histone deacetylase inhibitors have neurotrophic effects in experimental models of PD. Activators of histone acetyltransferases (HAT) provide an alternative approach for the selective activation of gene expression, however little is known about the potential of HAT activators as drug therapies for PD. To explore this potential, the present study investigated the neurotrophic effects of CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), which is a potent small molecule activator of the histone acetyltransferase p300/CBP, in the SH-SY5Y neuronal cell line. We report that CTPB promoted the survival and neurite growth of the SH-SY5Y cells, and also protected these cells from cell death induced by the neurotoxin 6-hydroxydopamine. This study is the first to investigate the phenotypic effects of the HAT activator CTPB, and to demonstrate that p300/CBP HAT activation has neurotrophic effects in a cellular model of PD.
authors.affiliation: Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland. shane.hegarty@ucc.ie.
authors.forename: Shane V
authors.initials: SV
authors.lastname: Hegarty
authors.affiliation: Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Eimear
authors.initials: E
authors.lastname: O'Leary
authors.affiliation: Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Solger
authors.affiliation: School of Biochemistry and Cell Biology, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Stanicka
authors.affiliation: Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Aideen M
authors.initials: AM
authors.lastname: Sullivan
authors.affiliation: Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland.|The Irish Centre for Fetal and Neonatal Translational Research (INFANT), Cork University Maternity Hospital, Cork, Ireland.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
mesh_terms: D000978:Antiparkinson Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D000071446:Neuronal Outgrowth / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D000978:Antiparkinson Agents; D001549:Benzamides; C475167:N-(4-chloro-3-trifluoromethylphenyl)-2-ethoxy-6-pentadecylbenzamide; D018696:Neuroprotective Agents; D016627:Oxidopamine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases
keywords: CTPB; Epigenetic regulation; Neuronal survival and growth; Neurotrophic therapy; Parkinson’s disease; p300/CBP histone acetyltransferase