title: Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity.
abstract: The importance of white matter (WM) injury to stroke pathology has been underestimated in experimental animal models and this may have contributed to the failure to translate potential therapeutics into the stroke clinic. Histone deacetylase (HDAC) inhibitors are neuroprotective and also promote neurogenesis. These properties make them ideal candidates for stroke therapy. In a pure WM tract (isolated mouse optic nerve), we show that pan- and class I-specific HDAC inhibitors, administered before or after a period of oxygen and glucose deprivation (OGD), promote functional recovery of axons and preserve WM cellular architecture. This protection correlates with the upregulation of an astrocyte glutamate transporter, delayed and reduced glutamate accumulation during OGD, preservation of axonal mitochondria and oligodendrocytes, and maintenance of ATP levels. Interestingly, the expression of HDACs 1, 2, and 3 is localized to astrocytes, suggesting that changes in glial cell gene transcription and/or protein acetylation may confer protection to axons. Our findings suggest that a therapeutic opportunity exists for the use of HDAC inhibitors, targeting mitochondrial energy regulation and excitotoxicity in ischemic WM injury.
authors.affiliation: Department of Neurology and Neurological Surgery, University of Washington School of Medicine, Seattle, Washington 98104, USA. selva@u.washington.edu
authors.forename: Selva
authors.initials: S
authors.lastname: Baltan
authors.forename: Sean P
authors.initials: SP
authors.lastname: Murphy
authors.forename: Camelia A
authors.initials: CA
authors.lastname: Danilov
authors.forename: Amelia
authors.initials: A
authors.lastname: Bachleda
authors.forename: Richard S
authors.initials: RS
authors.lastname: Morrison
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D056572:Histone Deacetylase Inhibitors; D018698:Glutamic Acid; D000255:Adenosine Triphosphate