Acute retinal necrosis in a patient with cervical malignant tumor treated with sintilimab: a case report and literature review.

Acute retinal necrosis (ARN) is an inflammatory disease that is primarily caused by herpesvirus infection, most commonly varicella-zoster virus (VZV), followed by herpes simplex virus (HSV) and occasionally cytomegalovirus (CMV). Sintilimab is an immune checkpoint inhibitor (ICI) that can enhance the body's anti-tumor immune response. However, treatment with ICIs may lead to reactivation of the VZV. Here, we present a case of ARN caused by VZV infection in a patient receiving sintilimab for cervical cancer. A 64-year-old female patient developed vision loss and floaters with left eye redness for one week after 22 cycles of sintilimab for cervical cancer. Based on clinical manifestations, ophthalmological examination, and vitreous humor biopsy, the patient was diagnosed with acute retinal necrosis syndrome secondary to VZV. After receiving systemic antiviral and anti-inflammatory therapy, retinal necrosis lesions and visual function improved. In conclusion, clinicians should be aware of the risk of ARN when using sintilimab and should actively monitor patients for prompt diagnosis and optimal management of this rare adverse drug reaction.

miR-410 Regulates Helper T Cell Differentiation in Ovalbumin-Induced Asthma through the PI3K-AKT-VEGF Signaling Pathway.

INTRODUCTION: Asthma has been attributed to Th1/Th2 imbalance and inappropriate Th2 responses to environmental allergens. MicroRNAs (miRNAs), 21 to 23 RNA molecules, are first found in mammals and have been implicated in various biological activities. Our previous study found that miR-410 effectively ameliorates airway inflammation in the ovalbumin (OVA)-induced asthma murine model. However, the role of miR-410 in regulating helper T (Th) cell differentiation is not clear. In the present study, we aimed to explore the regulatory effects of miR-410 on the differentiation of Th cells through both in vivo and in vitro studies. METHODS: Dual-luciferase reporter assay was used to find if miR-410 has any direct binding position with VEGF mRNAs. PBMC and CD4+ T cells were isolated and stimulated with OVA. The miR-410 mimics and inhibitors were transfected into CD4+ T cells. The differentiation of Th cells was evaluated by enzyme-linked immunosorbent assay (ELISA) for the concentration of IL-4, IFN-γ, and TGF-ß levels in supernatants. Western Blot was used to detect protein expression and phosphorylation of PI3K and AKT. BALB/c mice were kept in a specific pathogen-free condition and received sterile OVA-free food and water. OVA-induced asthmatic mice model was established. ELISA was used to measure the bronchoalveolar lavage fluid (BALF) concentrations of IL-4, IFN-γ, TGF-ß, and VEGF. Hematoxylin and eosin staining and immunohistochemical staining were conducted to analyze inflammatory cell infiltration, pathological changes, and the expression of VEGF. RESULTS: Dual-luciferase reporter assay showed that miR-410 has no direct binding position with VEGF mRNAs. In the OVA-primed mononuclear cells compared to normal cells, IFN-γ and TGF-ß were decreased while IL-4 and VEGF were increased. This change was reversed while miRNA-410 mimics were transfected into CD4+ T cells. Besides, the OVA-primed CD4+ T cells treated with miR-410 decrease the proliferation of cytokine of Th2 cells as well as phosphorylation of PI3K, and AKT. In OVA-induced asthma mice, IFN-γ and TGF-ß were decreased in BALF while the IL-4 and VEGF were increased. OVA-induced mice with asthma treated with miR-410 mimics showed marked reductions in the infiltration of inflammatory cells as well as IL-4 and VEGF in BALF. The immunohistochemical staining of the expression of VEGF also decreased in OVA-induced asthma mice with the instillation of miR-410. CONCLUSIONS: In this study, we revealed that miR-410 could regulate the differentiation of Th cells via the PI3K-AKT-VEGF signaling pathway in asthma.

Clinical Manifestations of Supra-Large Range Nonperfusion Area in Diabetic Retinopathy.

Objective: We describe the clinical manifestations of supra-large range nonperfusion area (SLRNPA) in diabetic retinopathy (DR). Methods: This was a retrospective case-control study. A total of 260 eyes of 236 patients with DR who underwent pars plana vitrectomy in the Department of Ophthalmology of Qingdao Municipal Hospital from February 2016 to June 2019 were enrolled. Fundus fluorescein angiography was performed after surgery to determine whether SLRNPA or non-SLRNPA in DR was present. All demographic and clinical data were carefully collected. Results: Forty-one eyes of 22 patients were diagnosed with SLRNPA in DR (15.77% of all eyes). Compared to non-SLRNPA, SLRNPA patients were more likely to be male and younger with earlier DR onset, a smoking history, other comorbidities, and a higher HbA1c level. SLRNPA in DR eyes exhibited more neovascular glaucoma (NVG) and diabetic keratopathy (DK) than did other eyes. Such eyes were more likely to require anti-VEGF therapy before surgery or a silicone oil or a gas tamponade during surgery and to suffer from persistent corneal epithelial erosion and NVG recurrence after surgery. Conclusions: SLRNPA in DR is a severe status of DR. Treatment for DR patients with SLRNPA is difficult, and the prognosis is poor, so clinicians must thus pay more attention to SLRNPA in DR.

Intraocular myofibroblastoma tumour of the ciliary body: a case report and literature review.

BACKGROUND: Inflammatory Myofibroblastoma Tumors (IMTs) are extremely tumour rare in the intraocular. CASE PRESENTATION: A ciliary body tumor was found under slit lamp biomicroscopy in a 55-year-old male first diagnosed with cataract. Then this patient underwent trans-sclera resection via partial lamellar sclerouvectomy and par plans vitrectomy to remove the mass. Hematoxylin and eosin (HE) staining and immunohistochemistry findings showed that the characteristics of the tumor were consistent with IMT. CONCLUSIONS: We reported a rare case of intraocular IMT, which is confirmed by H&E staining, and IHC positive staining for Vimentin, Desmin and ALK, while negative staining for SMA, S-100, ki-67, CK, CD68, and calponin.

Acute exudative paraneoplastic polymorphous vitelliform maculopathy in a patient with thymoma, myasthenia gravis, and polymyositis.

IMPORTANCE: This is the first reported case of acute exudative paraneoplastic polymorphous vitelliform maculopathy (AEPPVM) in a patient with thymoma, accompanied by myasthenia gravis (MG) and polymyositis. OBJECTIVE: To examine the pathogenesis of ocular disease in a patient with yolk-like fundus lesions and thymoma, MG, and polymyositis throughout the body based on clinical manifestations, diagnosis, differential diagnosis, and genetic testing to determine the appropriate treatment course. DESIGN, SETTING, AND PARTICIPANTS: We describe a 63-year-old woman who presented to our tertiary medical center with a 3-month history of reduced visual acuity in both eyes. Concurrent fundoscopy revealed a 2.0 × 1.7-mm, unifocal, yellow, round vitelliform lesion in the macular region, surrounded by multifocal, shallow, yellow-white pockets of subretinal fluid. The patient's medical history included thymoma with thymectomy treatment, combined with pericardiectomy and postoperative radiotherapy (20 years prior), followed by a diagnosis of MG with suspect thymic association (15 years prior). Three years prior, the patient had been diagnosed with polymyositis related to paraneoplastic syndrome; 1 year prior, she had been examined for pleural thickening due to suspected metastatic tumor. RESULTS: On her most recent follow-up visit at 3 months after initial diagnosis, the patient was stable with no clinically significant progression in ocular or systemic conditions.

Bilateral Diffuse Uveal Melanocytic Proliferation Secondary to Rectal Adenocarcinoma: A Case Report and Literature Review.

Background: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular syndrome that causes progressive visual loss in patients, and is associated with an underlying malignancy. Recently, the incidence of BDUMP has increased with the prolonged life expectancy of oncology patients. Case Presentation: We report a case of a 68-year-old man with significant visual loss in both eyes. The patient presented with a diffusely thickened choroid and ciliary body, extremely shallow anterior chamber, increased intraocular pressure, and cataract formation, accompanied by exudative retinal detachment in both eyes. He underwent a pars plana vitrectomy and choroidal biopsy, which revealed benign proliferation of melanocytes. A small amount of subretinal fluid persisted, and uveal thickness persisted in the early postoperative period. During the 1-year follow-up assessment, he underwent rectal tumor resection, and was pathologically diagnosed with rectal adenocarcinoma. Six months after the rectal tumor resection, the subretinal fluid was completely absorbed and the retina had reattached. The thickness of both the ciliary body and choroid had significantly decreased. Conclusion: This case report describes a rare paraneoplastic intraocular syndrome, BDUMP, which was associated with rectal adenocarcinoma. Treatment for the primary malignancy gradually improved the visual symptoms and signs.

Quantitative assessment of the retinal microvasculature and choriocapillaris in myopic patients using swept-source optical coherence tomography angiography.

PURPOSE: To study the retinal capillary microvasculature and the choriocapillaris (CC) in myopic eyes using swept-source optical coherence tomography angiography (SS-OCTA). METHODS: Patients with high myopia (≥ - 6D; axial length ≥ 26.5 mm), moderate myopia (≥ - 3D, < - 6D), and age-matched healthy subjects presenting to the Shanghai General Hospital and Doheny-UCLA Eye Centers were enrolled in this prospective, multicenter study. Any subjects with evidence of macular abnormalities suggestive of pathologic myopia were excluded. SS-OCTA at both sites was performed using a Zeiss PLEX Elite instrument with a 6 × 6 mm scan pattern centered on the fovea. Two repeated volume scans were acquired for image averaging. The instrument pre-defined en face slab of the superficial and deep retinal capillary microvasculature was used to isolate and display the superficial and deep retinal capillaries. A slab spanning from 21 to 31 µm deep to the RPE fit line was used to isolate and display the CC. The OCTA images were exported for averaging using Image J. Littmann's method and the Bennett formula were applied to adjust for the impact of magnification in the high and moderate myopia groups. The resultant images were then binarized. Though projection artifact removal software was used, regions below the large superficial retinal vessels were excluded for quantitative analyses of the deep retinal capillary plexus and the CC. Vessel density (VD) and vessel length density (VLD) of the superficial and deep retinal capillary plexus (SCP, DCP) and CC flow deficit (FD) were analyzed, quantified, and compared between different groups. RESULTS: Twenty-five eyes of 25 patients with high myopia, 25 eyes of 25 patients with moderate myopia, and 25 eyes of 25 normal age-matched controls were included in this study. The VD of the SCP was lower in the high myopia group compared with the emmetropic control groups (p < 0.05), but the VD of the DCP demonstrated no significant difference among the three groups (p > 0.05). The VLDs of the SCP were lower in the high and moderate myopia groups compared with the control group (p < 0.05), while the VLD of the DCP was lower in the high myopia group compared with the moderate myopia and emmetropic control group (p < 0.05). The CC FD% in the high myopia group was significantly greater than both the control and moderate myopia subjects (p < 0.05). Of note, the severity of the CC flow deficit was not correlated with choroidal thickness (p > 0.05). CONCLUSION: The retinal microvasculature may demonstrate alterations in highly myopia eyes. The CC in macular regions shows greater impairment in eyes with high myopia compared with eyes with lesser degrees of myopia, and these deficits are already present in the absence of features of pathologic or degenerative myopia. The threshold of CC FD leading to myopic maculopathy remains to be defined.

Involvement of microRNA-34a in Age-Related Susceptibility to Oxidative Stress in ARPE-19 Cells by Targeting the Silent Mating Type Information Regulation 2 Homolog 1/p66shc Pathway: Implications for Age-Related Macular Degeneration.

The aging retinal pigment epithelium and oxidative stress, mediated by reactive oxygen species (ROS) accumulation, have been implicated in the mechanisms of age-related macular degeneration (AMD). The expression level of the adapter protein p66shc, a key protein that regulates cellular oxidative stress, is relatively low under normal conditions because of the effects of silent mating type information regulation 2 homolog 1 (SIRT1) on the binding of fully deacetylated histone H3' to the p66shc promoter region, thus inhibiting p66shc transcription and expression. The equilibrium between SIRT1 and p66shc is disrupted in the presence of various stresses, including AMD. As a major target gene, SIRT1 is regulated by microRNA-34a (miR-34a), and overexpression of miR-34a results in significant inhibition of post-transcriptional expression of SIRT1. Furthermore, our recent studies demonstrated that miR-34a is significantly upregulated, accompanied by reduced tolerance to oxidative stress in hydrogen peroxide-induced prematurely senescent ARPE-19 cells. Moreover, the expression of SIRT1 is decreased, whereas that of p66shc is increased in these cells. Accordingly, miR-34a may play a key role in age-related susceptibility to oxidative stress in ARPE-19 cells by targeting the SIRT1/p66shc pathway, leading to AMD. In this review article, we discuss the functions of miR-34a in modulating the SIRT1/p66shc pathway in age-related conditions, including AMD.

Anatomic Outcomes and Prognostic Factors of Vitrectomy in Patients with Primary Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment.

PURPOSE: This study was undertaken to assess the associations between the anatomic outcomes of patients who underwent vitrectomy for rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) and their preoperative variables. METHODS: A total of 175 patients with RRDCD who underwent vitrectomy in one eye were included in the analysis. The primary outcome measured was the retinal status after primary vitrectomy and at the end of follow-up. RESULTS: The retinal reattachment rate was 72.57% after primary surgery, and the final total reattachment rate was 89.14% after follow-up. Binary logistic regression analysis identified that the retinal reattachment rate after primary vitrectomy was significantly associated with older age (odds ratio = 1.03, p = 0.02), mild proliferative vitreoretinopathy (PVR) (PVR grade C vs. PVR grades A-B: odds ratio = 0.31, p = 0.04; PVR grade D vs. PVR grades A-B: odds ratio = 0.03, p < 0.01), and intravitreal steroid treatment (odds ratio = 4.60, p = 0.02), and that the final retinal reattachment rate was independently associated with older age (odds ratio = 1.05; p = 0.01). CONCLUSIONS: Vitrectomy is a good surgical option for RRDCD. Older age, mild preoperative PVR, and perioperative intravitreal triamcinolone acetonide injections increase the primary reattachment rates after one operation. Older age was the only independent prognostic factor for the final retinal reattachment in patients with RRDCD.

Retrospective Analyses of Potential Risk Factors for Posterior Capsule Opacification after Cataract Surgery.

PURPOSE: To evaluate the potential risk factors of posterior capsule opacification (PCO) after cataract surgery. METHODS: Data on PCO patients diagnosed from September 2015 to May 2017 were obtained from the Department of Ophthalmology at Qingdao Municipal Hospital, Qingdao, China. The factors associated with PCO were assessed using Pearson's χ2 test for univariate analyses and logistic regression for multivariate analyses. RESULTS: Eyes (652) from 550 patients were enrolled in this study. All patients were diagnosed with PCO/non-PCO and had <3 years of follow-up after surgery. The numbers of PCO and non-PCO were 108 eyes and 544 eyes, respectively. Statistically significant associations with PCO were found for age at the time of surgery (χ2 = 78.504; p < 0.001), diabetes (χ2 = 4.829; p=0.028), immune diseases (χ2 = 4.234; p=0.004), high myopia (χ2 = 5.753; p=0.016), lens nucleus hardness (χ2 = 11.046; p=0.026), surgery type (χ2 = 11.354; p=0.001), a history of vitrectomy (χ2 = 4.212; p=0.004), ocular inflammation (χ2 = 6.01; p=0.009), and the intraocular lens (IOL) type (χ2 = 8.696; p=0.003). Multivariable data analyses using logistic regression analyses of the variables showed that age at the time of surgery <60 years, diabetes, lens nucleus hardness of III-V, extracapsular cataract extraction (ECCE), postvitrectomy, and hydrophilic IOLs were significant independent risk factors associated with PCO. CONCLUSIONS: Age <60 years, diabetes, lens nucleus hardness of III-V, ECCE, postvitrectomy, and a hydrophilic IOL were significantly associated with the formation of PCO. Estimation of the incidence of and risk factors for PCO should help in patients counseling and in the design of treatment protocols to reduce or prevent its development.

Pigment dispersion syndrome and pigmentary glaucoma after secondary sulcus transscleral fixation of single-piece foldable posterior chamber intraocular lenses in Chinese aphakic patients.

PURPOSE: To describe secondary pigment dispersion syndrome (PDS) and pigmentary glaucoma after secondary sulcus transscleral fixation of 1-piece hydrophobic acrylic foldable posterior chamber intraocular lenses (PC IOLs) in aphakic patients in a Chinese population. SETTING: Department of Ophthalmology, Qingdao Municipal Hospital, Qingdao, China. DESIGN: Retrospective case series. METHODS: This chart review included eyes that had secondary sulcus transscleral fixation of a 1-piece hydrophobic acrylic foldable PC IOL (Tecnis ZCB00) between March 2011 and March 2014. The patients' demographic data, clinical data, postoperative complications, intervals between initial surgery and the onset of PDS, pigmentary glaucoma occurrences, and findings on slitlamp biomicroscopy, gonioscopy, and ultrasound biomicroscopy (UBM) were recorded. RESULTS: The study comprised 23 consecutive eyes of 21 patients. Seventeen eyes of 16 patients were diagnosed with PDS, and 7 eyes of 6 patients were diagnosed with pigmentary glaucoma. The slitlamp examination and UBM showed that the location between the IOL optic and the posterior surface of the iris was very close. Slitlamp examination of the anterior chamber angle using a gonioscope showed dense pigment deposition on the IOL surfaces. A reverse pupillary block was found in 10 eyes of 9 patients. Other postoperative complications included intraocular hemorrhage, pupillary capture of the IOL optic, IOL tilt, IOL decentration, IOL dislocation, and suture erosion. CONCLUSION: The 1-piece hydrophobic acrylic foldable PC IOL was not suitable for sulcus transscleral fixation because of a high incidence of PDS and pigmentary glaucoma after surgery in a Chinese population.

Subretinal heterotopic respiratory epithelium: a case report and literature review.

A 51-year-old female underwent vitrectomy surgery to remove a group of spherical subretinal tumors beneath the detached retina. Hematoxylin and eosin staining and immunohistochemical findings showed that the characteristics of the tumor were consistent with a subretinal heterotopic respiratory epithelium. This is the first report of a respiratory epithelial heterotopia located in the subretinal space.

Diosmin alleviates retinal edema by protecting the blood-retinal barrier and reducing retinal vascular permeability during ischemia/reperfusion injury.

BACKGROUND AND PURPOSE: Retinal swelling, leading to irreversible visual impairment, is an important early complication in retinal ischemia/reperfusion (I/R) injury. Diosmin, a naturally occurring flavonoid glycoside, has been shown to have antioxidative and anti-inflammatory effects against I/R injury. The present study was performed to evaluate the retinal microvascular protective effect of diosmin in a model of I/R injury. METHODS: Unilateral retinal I/R was induced by increasing intraocular pressure to 110 mm Hg for 60 min followed by reperfusion. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. Rats were evaluated for retinal functional injury by electroretinogram (ERG) just before sacrifice. Retinas were harvested for HE staining, immunohistochemistry assay, ELISA, and western blotting analysis. Evans blue (EB) extravasation was determined to assess blood-retinal barrier (BRB) disruption and the structure of tight junctions (TJ) was examined by transmission electron microscopy. RESULTS: Diosmin significantly ameliorated the reduction of b-wave, a-wave, and b/a ratio in ERG, alleviated retinal edema, protected the TJ structure, and reduced EB extravasation. All of these effects of diosmin were associated with increased zonular occluden-1 (ZO-1) and occludin protein expression and decreased VEGF/PEDF ratio. CONCLUSIONS: Maintenance of TJ integrity and reduced permeability of capillaries as well as improvements in retinal edema were observed with diosmin treatment, which may contribute to preservation of retinal function. This protective effect of diosmin may be at least partly attributed to its ability to regulate the VEGF/PEDF ratio.

Inverse relationship between macular pigment optical density and axial length in Chinese subjects with myopia.

BACKGROUND: Macular pigment (MP) has been the focus of much attention in recent years, due to its protective effect against macular degenerations. In this study, we investigated the association between macular pigment optical density (MPOD) and axial length (AL) in Chinese subjects with myopia. METHODS: In total, 173 myopes (mean spherical equivalent [MSE] ≤-1.00D) were recruited for this prospective observational study. MPOD was measured in both eyes of each subject using a macular metrics densitometer. AL was measured in eyes using an IOL-Master. A raw coefficient of correlation analysis and a partial correlation analysis were used to investigate the relationship between MPOD and AL. RESULTS: The age of the subjects ranged from 18 to 67 years. The overall mean MPOD for the cohort was 0.412 ± 0.119 (range, 0.105-0.812). The mean AL was 25.18 ± 1.08 mm (range, 23.14-28.19 mm). Using a raw coefficient of correlation, a significant inverse correlation was found between MPOD and AL (r= -0.134, p=0.012). When using a partial correlation analysis to eliminate the impact of covariant, a significant inverse correlation was also found between MPOD and AL (r= -0.142, p=0.008). Furthermore, when AL was divided into two groups: AL>26 mm and AL ≤ 26 mm, a significant inverse correlation was observed between MPOD and AL in the former (r= -0.253, p=0.029), but no significant relationship was observed between these in the latter (r=0.104, p=0.067). CONCLUSIONS: MPOD correlated inversely with AL in this sample of Chinese subjects with myopia.

Diosmin protects rat retina from ischemia/reperfusion injury.

OBJECTIVE: Diosmin, a natural flavone glycoside, possesses antioxidant activity and has been used to alleviate ischemia/reperfusion (I/R) injury. The aim of this study was to clarify whether the administration of diosmin has a protective effect against I/R injury induced using the high intraocular pressure (IOP) model in rat retina, and to determine the possible antioxidant mechanisms involved. METHODS: Retinal I/R injury was induced in the rats by elevating the IOP to 110 mmHg for 60 min. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. The levels of malondialdehyde (MDA) and the activities of total-superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in the retinal tissues were determined 24 h after I/R injury. At 7 days post-I/R injury, electroretinograms (ERGs) were recorded, and the density of surviving retinal ganglion cells (RGCs) was estimated by counting retrograde tracer-labeled cells in whole-mounted retinas. Retinal histological changes were also examined and quantified using light microscopy. RESULTS: Diosmin significantly decreased the MDA levels and increased the activities of T-SOD, GSH-Px, and CAT in the retina of rats compared with the ischemia group (P<0.05), and suppressed the I/R-induced reduction in the a- and b-wave amplitudes of the ERG (P<0.05). The thickness of the entire retina, inner nuclear layer, inner plexiform layer, and outer retinal layer and the number of cells in the ganglion cell layer were significantly less after I/R injury (P<0.05), and diosmin remarkably ameliorated these changes on retinal morphology. Diosmin also attenuated the I/R-induced loss of RGCs of the rat retina (P<0.05). CONCLUSION: Diosmin protected the retina from I/R injury, possibly via a mechanism involving the regulation of oxidative parameters.

Valproic acid regulates antioxidant enzymes and prevents ischemia/reperfusion injury in the rat retina.

PURPOSES: To investigate whether valproic acid (VPA) has a neuroprotective effect against ischemia/reperfusion (I/R) injury in the rat retina, and to elucidate the potential antioxidant mechanisms involved. METHODS: Adult male Wistar rats were randomly divided into four groups: sham (group A), sham plus VPA (group B), I/R plus vehicle (group C), and I/R plus VPA (group D). Retinal I/R injury was produced by inducing an exceedingly high intraocular pressure (IOP). Prior to insult, VPA was administered subcutaneously (300 mg/kg twice daily) for 7 days, after which the animal was sacrificed. Levels of retinal malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were determined. Protein expressions of retinal poly(ADP-ribose) (PAR) and nitrotyrosine (NT) were analyzed by Western blotting 24 h after injury. Apoptosis of retinal cells was evaluated 24 h after I/R injury by immunofluorescence of activated caspase-3 in histological sections of retina. Seven days after reperfusion, electroretinography (ERG) was performed, and retinal histological changes were examined by light microscopy. RESULTS: Following ischemia, the thickness of the entire retina, including the inner nuclear layer (INL) and inner plexiform layer (IPL), as well as the number of cells in the ganglion cell layer (GCL) were significantly greater in group D than in group C (p < 0.05). VPA suppressed I/R-induced reductions in ERG a- and b-wave amplitudes (p < 0.05). VPA attenuated I/R-induced activation of caspase-3 in ganglion cells and INL cells (p < 0.001). VPA significantly decreased MDA levels and increased activities of SOD, GSH-Px, and CAT in group D (p < 0.05). VPA attenuated activation of PAR and accumulation of NT in the retina after I/R (p < 0.01). CONCLUSIONS: VPA protects the retina from I/R injury by enhancing anti-oxidative effects and inhibiting apoptosis of retinal cells.

Valproic acid-mediated neuroprotection in retinal ischemia injury via histone deacetylase inhibition and transcriptional activation.

Retinal ischemia plays a central role in several retinal diseases. The pathogenesis of retinal ischemia involves changes in gene expression. Valproic acid (VPA), a broad-spectrum histone deacetylase inhibitor, is an anticonvulsant and mood-stabilizing drug with neuroprotective effects. Here, we investigated whether VPA protects the retina and optic nerve axon from ischemic damage in a rat model and determined a possible protective mechanism. Adult male Wistar rats were randomized into sham, ischemia/reperfusion (I/R)-plus-vehicle, and I/R-plus-VPA groups. Rats received subcutaneous injections of 300 mg/kg VPA or phosphate-buffered saline twice a day after retinal ischemia induced by acute high intraocular pressure. Twenty-four hours after I/R, retinal neuron apoptosis was evaluated using the TUNEL assay. The expression of heat-shock protein 70 (Hsp70), activated-caspase-3, and apoptotic-protease-activating factor-1 (apaf-1), acetylation levels of histone H3, release of cytochrome c, and interaction between Hsp70 and apaf-1 were analyzed by immunoblotting analysis in all groups; the transcriptional activation of the Hsp70 gene and interaction between the Hsp70 promoter with p300 or HDAC1 were analyzed using chromatin immunoprecipitation assay. Seven days after I/R, the histological changes in the retina were evaluated using hematoxylin and eosin staining, and optic nerve axon damage was evaluated using toluidine blue staining and transmission electron microscopy. The density of retinal ganglion cells (RGCs) was analyzed using Fluoro-Gold retrograde labeling at 7, 14, 21 days after I/R. VPA markedly attenuated I/R-induced retinal neuron apoptosis, damage to RGCs, and morphological injury to the retina and optic nerve axons. VPA resulted in the upregulation of Hsp70 and hyperacetylation of histone H3, accompanied by Hsp70 promoter hyperacetylation, which may result from increased p300 recruitment to the Hsp70 promoter. Furthermore, VPA increased the binding between Hsp70 and apaf-1 to block apoptosome formation and reduced the release of cytochrome c and activation of caspase-3 in the retina after I/R. Therefore, VPA-mediated neuroprotection against I/R injury in the retina may involve cytoprotective Hsp70 induction via transcriptional activation and inhibition of the mitochondria-mediated apoptosis pathway.