Valproate protects the retina from endoplasmic reticulum stress-induced apoptosis after ischemia–reperfusion injury

• Published in: Neuroscience letters Vol. 504; no. 2; pp. 88 - 92
• Main Authors: Zhang, ZhenZhen, Tong, NianTin, Gong, YuanYuan, Qiu, QingHua, Yin, LiLi, Lv, XiuHong, Wu, XingWei
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 24.10.2011; Elsevier
• Subjects: Animals; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Caspase 12 - metabolism; Cell Death - drug effects; CHOP; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Heat-Shock Proteins - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Ischemia/reperfusion; Male; Medical sciences; Neuropharmacology; Neuroprotective Agents; Pharmacology. Drug treatments; Rats; Rats, Wistar; Reperfusion Injury - pathology; Retina; Retina - drug effects; Retina - ultrastructure; Retinal Ganglion Cells - drug effects; Tissue Fixation; Transcription Factor CHOP - metabolism; Valproate; Valproic Acid - pharmacology; Vertebrates: nervous system and sense organs; RGCs; IPL; VPA; INL; ORL; Retina; I/R; ER; Ischemia/reperfusion; Valproate; Endoplasmic reticulum stress; UPR; CHOP; HDAC; Anticonvulsant; Valproic acid; Stress; Eye; Visual system; Cell death; Lesion; Endoplasmic reticulum; Apoptosis
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2011.09.003

▸ Valproate (VPA), a histone deacetylase inhibitor has neuroprotective effects. ▸ VPA increased the expression of GRP78 in retina after ischemia. ▸ Hyperacetylation of histone H3 was induced by VPA in retina. ▸ VPA suppressed the upregulation of CHOP and caspase-12 in retina after ischemia. ▸ VPA reduced endoplasmic reticulum stress-induced apoptosis in ischemic retina. 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.