Abnormal innervation patterns in the anorectum of ETU-induced fetal rats with anorectal malformations |
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Authors: | Wang Weilin Jia Huimin Zhang Hailan Chen Qingjiang Zhang Tao Bai Yuzuo Yuan Zhengwei |
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Institution: | a Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China b Department of Pathology, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Wujin Road 85, Shanghai 200080, China |
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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 300 mg/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 7 days 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. |
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Keywords: | VPA valproate RGCs retinal ganglion cells I/R ischemia-reperfusion HDAC histone deacetylase UPR unfolded protein response CHOP C/EBP homologous protein ER endoplasmic reticulum IPL inner plexiform layer INL inner nuclear layer ORL outer retinal layer |
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