title: Valproate protects the retina from endoplasmic reticulum stress-induced apoptosis after ischemia-reperfusion injury.
abstract: Valproate (VPA) is commonly used in the treatment of bipolar disorder and epilepsy. The mechanism underlying its clinical efficacy is complicated, including its ability to inhibit histone deacetylase (HDAC). Here, we show that VPA promoted endoplasmic reticulum (ER) chaperone expression and attenuated ER-induced apoptosis after ischemia/reperfusion (I/R) injury in retina. Male Wistar rats were randomly divided into four groups: sham (group A), sham+VPA (group B), I/R+vehicle (group C), and I/R+VPA (group D). VPA was administered subcutaneously at 300mg/kg twice daily before insult. Morphological changes were analyzed on stained histological sections and flat-mounted retinas labeled by Fluoro-gold. Western blot analysis was used to determine protein levels of GRP78, CHOP, caspase-12 and acetylation of histone H3 in each group. In group C, the severe retinal damage was shown in histological sections, however, the damage was reduced by VPA in group D. Significant loss of retinal ganglion cells (RGCs) was observed in group C, whereas, the density of RGCs was significantly higher in group D at 7days post-insult. VPA increased GRP78 expression and acetylation of histone H3, attenuated upregulation of CHOP and activation of caspase-12 in group D. Our results suggest that VPA can protect ischemic retinas from ER stress-induced apoptosis by mechanisms that may involve HDAC inhibition.
authors.affiliation: Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China. Electronic address: zzz2011413@163.com.
authors.forename: ZhenZhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China. Electronic address: nedvedtnt@126.com.
authors.forename: NianTin
authors.initials: N
authors.lastname: Tong
authors.affiliation: Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China. Electronic address: gyydr@126.com.
authors.forename: YuanYuan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China. Electronic address: qiuqh9@163.com.
authors.forename: QingHua
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China. Electronic address: yll144@yahoo.com.cn.
authors.forename: LiLi
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Pathology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China. Electronic address: lvxiuhong123@163.com.
authors.forename: XiuHong
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China. Electronic address: wxw.2011413@gmail.com.
authors.forename: XingWei
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053454:Caspase 12 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology*; D012160:Retina / Q000187:drug effects* / Q000648:ultrastructure; D012165:Retinal Ganglion Cells / Q000187:drug effects; D016707:Tissue Fixation; D051742:Transcription Factor CHOP / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000927:Anticonvulsants; D053454:Caspase 12; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D018696:Neuroprotective Agents; D051742:Transcription Factor CHOP; D014635:Valproic Acid; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP