Inhibition of histone deacetylation protects wild-type but not gelsolin-deficient neurons from oxygen/glucose deprivation.
Histone acetylation and deacetylation participate in the epigenetic regulation of gene expression. In this paper, we demonstrate that pre-treatment with the histone deacetylation inhibitor trichostatin A (TSA) enhances histone acetylation in primary cortical neurons and protects against oxygen/glucose deprivation, a model for ischaemic cell death in vitro. The actin-binding protein gelsolin was identified as a mediator of neuroprotection by TSA. TSA enhanced histone acetylation of the gelsolin promoter region, and up-regulated gelsolin messenger RNA and protein expression in a dose- and time-dependent manner. Double-label confocal immunocytochemistry visualized the up-regulation of gelsolin and histone acetylation within the same neuron. Together with gelsolin up-regulation, TSA pre-treatment decreased levels of filamentous actin. The neuroprotective effect of TSA was completely abolished in neurons lacking gelsolin gene expression. In conclusion, we demonstrate that the enhancement of gelsolin gene expression correlates with neuroprotection induced by the inhibition of histone deacetylation.
Meisel
Andreas
A
Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Harms
Christoph
C
Yildirim
Ferah
F
Bösel
Julian
J
Kronenberg
Golo
G
Harms
Ulrike
U
Fink
Klaus B
KB
Endres
Matthias
M
D000107:Acetylation / Q000187:drug effects; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D003640:Dealkylation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018260:Gelsolin / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D005947:Glucose / Q000172:deficiency / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000860:Hypoxia / Q000473:pathology*; D007118:Immunoassay; D015151:Immunoblotting; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology
D002843:Chromatin; D004791:Enzyme Inhibitors; D018260:Gelsolin; D006657:Histones; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C012589:trichostatin A; D005947:Glucose