HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats.
Traumatic brain injury (TBI) produces a rapid and robust inflammatory response in the brain characterized in part by activation of microglia. A novel histone deacetylase (HDAC) inhibitor, 4-dimethylamino-N-[5-(2-mercaptoacetylamino)pentyl]benzamide (DMA-PB), was administered (0, 0.25, 2.5, 25 mg/kg) systemically immediately after lateral fluid percussion TBI in rats. Hippocampal CA2/3 tissue was processed for acetyl-histone H3 immunolocalization, OX-42 immunolocalization (for microglia), and Fluoro-Jade B histofluorescence (for degenerating neurons) at 24 h after injury. Vehicle-treated TBI rats exhibited a significant reduction in acetyl-histone H3 immunostaining in the ipsilateral CA2/3 hippocampus compared to the sham TBI group (p<0.05). The reduction in acetyl-histone H3 immunostaining was attenuated by each of the DMA-PB dosage treatment groups. Vehicle-treated TBI rats exhibited a high density of phagocytic microglia in the ipsilateral CA2/3 hippocampus compared to sham TBI in which none were observed. All doses of DMA-PB significantly reduced the density of phagocytic microglia (p<0.05). There was a trend for DMA-PB to reduce the number of degenerating neurons in the ipsilateral CA2/3 hippocampus (p=0.076). We conclude that the HDAC inhibitor DMA-PB is a potential novel therapeutic for inhibiting neuroinflammation associated with TBI.
Zhang
Bin
B
Department of Pharmacology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Jinan, Shandong, 250012 P.R. China.
West
Eric J
EJ
Van
Ken C
KC
Gurkoff
Gene G
GG
Zhou
Jia
J
Zhang
Xiu-Mei
XM
Kozikowski
Alan P
AP
Lyeth
Bruce G
BG
D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects*; D009930:Organic Chemicals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C533964:4-dimethylamino-N-(5-(2-mercaptoacetylamino)pentyl)benzamide; D001549:Benzamides; D039481:CD11b Antigen; D005452:Fluoresceins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009930:Organic Chemicals; C435731:fluoro jade