title: Hydroxamic acid-based histone deacetylase (HDAC) inhibitors can mediate neuroprotection independent of HDAC inhibition.
abstract: Histone deacetylase (HDAC) inhibition improves function and extends survival in rodent models of a host of neurological conditions, including stroke, and neurodegenerative diseases. Our understanding, however, of the contribution of individual HDAC isoforms to neuronal death is limited. In this study, we used selective chemical probes to assess the individual roles of the Class I HDAC isoforms in protecting Mus musculus primary cortical neurons from oxidative death. We demonstrated that the selective HDAC8 inhibitor PCI-34051 is a potent neuroprotective agent; and by taking advantage of both pharmacological and genetic tools, we established that HDAC8 is not critically involved in PCI-34051's mechanism of action. We used BRD3811, an inactive ortholog of PCI-34051, and showed that, despite its inability to inhibit HDAC8, it exhibits robust neuroprotective properties. Furthermore, molecular deletion of HDAC8 proved insufficient to protect neurons from oxidative death, whereas both PCI-34051 and BRD3811 were able to protect neurons derived from HDAC8 knock-out mice. Finally, we designed and synthesized two new, orthogonal negative control compounds, BRD9715 and BRD8461, which lack the hydroxamic acid motif and showed that they stably penetrate cell membranes but are not neuroprotective. These results indicate that the protective effects of these hydroxamic acid-containing small molecules are likely unrelated to direct epigenetic regulation via HDAC inhibition, but rather due to their ability to bind metals. Our results suggest that hydroxamic acid-based HDAC inhibitors may mediate neuroprotection via HDAC-independent mechanisms and affirm the need for careful structure-activity relationship studies when using pharmacological approaches.
authors.affiliation: Burke Medical Research Institute, White Plains, New York 10605, Department of Natural Sciences, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, Lebanese American University, Byblos, Lebanon, sama.sleiman01@lau.edu.lb rrr2001@med.cornell.edu.
authors.forename: Sama F
authors.initials: SF
authors.lastname: Sleiman
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: David E
authors.initials: DE
authors.lastname: Olson
authors.affiliation: Department of Natural Sciences, Lebanese American University, Byblos, Lebanon, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Megan W
authors.initials: MW
authors.lastname: Bourassa
authors.affiliation: Department of Natural Sciences, Lebanese American University, Byblos, Lebanon, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Saravanan S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gale
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, and.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595.
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.affiliation: Burke Medical Research Institute, White Plains, New York 10605, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, sama.sleiman01@lau.edu.lb rrr2001@med.cornell.edu.
authors.forename: Rajiv R
authors.identifier: http://orcid.org/0000-0002-9081-2701
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy
chemical_list: D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents
keywords: HDAC inhibitors; HDAC8; PCI-34051; hydroxamic acids; neuroprotection; oxidative stress