Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China.
Department of Pathology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China.
Neurosci Lett. 2011 Oct 24;504(2):88-92. doi: 10.1016/j.neulet.2011.09.003. Epub 2011 Sep 12.
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.
丙戊酸（VPA）常用于治疗双相情感障碍和癫痫。其临床疗效的机制很复杂，包括抑制组蛋白去乙酰化酶（HDAC）的能力。在这里，我们表明 VPA 可促进内质网（ER）伴侣蛋白的表达，并减轻缺血/再灌注（I/R）损伤后 ER 诱导的视网膜细胞凋亡。雄性 Wistar 大鼠随机分为四组：假手术（A 组）、假手术+VPA（B 组）、I/R+载体（C 组）和 I/R+VPA（D 组）。在损伤前，每天两次通过皮下注射 300mg/kg 的 VPA。通过染色的组织学切片和平铺的 Fluoro-gold 标记视网膜来分析形态变化。Western blot 分析用于确定每组中 GRP78、CHOP、caspase-12 和组蛋白 H3 乙酰化的蛋白水平。在 C 组中，组织学切片显示出严重的视网膜损伤，然而，在 D 组中，VPA 减轻了损伤。在 C 组中观察到视网膜神经节细胞（RGC）大量丢失，而在损伤后 7 天，D 组的 RGC 密度明显更高。VPA 增加了 GRP78 的表达和组蛋白 H3 的乙酰化，减轻了 D 组中 CHOP 的上调和 caspase-12 的激活。我们的结果表明，VPA 可以通过可能涉及 HDAC 抑制的机制来保护缺血性视网膜免受 ER 应激诱导的细胞凋亡。
