Retinal Ischemia-reperfusion Model Research Articles

Deletion of myeloid HDAC3 promotes efferocytosis to ameliorate retinal ischemic injury

Ischemia-induced retinopathy is a hallmark finding of common visual disorders including diabetic retinopathy (DR) and central retinal artery and vein occlusions. Treatments for ischemic retinopathies fail to improve clinical outcomes and the design of new therapies will depend on understanding the underlying disease mechanisms. Histone deacetylases (HDACs) are an enzyme class that removes acetyl groups from histone and non-histone proteins, thereby regulating gene expression and protein function. HDACs have been implicated in retinal neurovascular injury in preclinical studies in which nonspecific HDAC inhibitors mitigated retinal injury. Histone deacetylase 3 (HDAC3) is a class I histone deacetylase isoform that plays a central role in the macrophage inflammatory response. We recently reported that myeloid cells upregulate HDAC3 in a mouse model of retinal ischemia-reperfusion (IR) injury. However, whether this cellular event is an essential contributor to retinal IR injury is unknown. In this study, we explored the role of myeloid HDAC3 in ischemia-induced retinal neurovascular injury by subjecting myeloid-specific HDAC3 knockout (M-HDAC3 KO) and floxed control mice to retinal IR. The M-HDAC3 KO mice were protected from retinal IR injury as shown by the preservation of inner retinal neurons, vascular integrity, and retinal thickness. Electroretinography confirmed that this neurovascular protection translated to improved retinal function. The retinas of M-HDAC3 KO mice also showed less proliferation and infiltration of myeloid cells after injury. Interestingly, myeloid cells lacking HDAC3 more avidly engulfed apoptotic cells in vitro and after retinal IR injury in vivo compared to wild-type myeloid cells, suggesting that HDAC3 hinders the reparative phagocytosis of dead cells, a process known as efferocytosis. Further mechanistic studies indicated that although HDAC3 KO macrophages upregulate the reparative enzyme arginase 1 (A1) that enhances efferocytosis, the inhibitory effect of HDAC3 on efferocytosis is not solely dependent on A1. Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult.

A novel function and mechanism of ischemia-induced retinal astrocyte-derived exosomes for RGC apoptosis of ischemic retinopathy

Retinal ischemia is a common clinical event leading to retinal ganglion cell (RGC) death, resulting in irreversible vision loss. In the retina, glia-neuron communication is crucial for multiple functions and homeostasis. Extracellular vesicles, notably exosomes, play a critical role. The functions and mechanisms of retinal astrocyte-secreted exosomes remain unclear. Here, we isolated astrocyte-derived exosomes under hypoxia or normoxia and explored their role in an in vivo retinal ischemia-reperfusion (RIR) model. We found that hypoxia triggered astrocytes to produce a significantly increased number of exosomes, which could be internalized by RGCs in vivo or in vitro. Also, in the RIR model, the hypoxia-induced exosomes ameliorated the RIR injury and suppressed the RGC apoptosis. Furthermore, microRNA sequencing of retinal astrocyte-secreted exosomes revealed different patterns of exosomal miRNAs under hypoxia, particularly enriched with miR-329-5p. We verified that miR-329-5p was specifically bound to MAPK8 mRNA, and subsequent JNK-pathway molecules were downregulated. We anticipated that the miR-329-5p/JNK pathway is a key to suppressing RGC apoptosis and preventing RIR injury. Such findings provided insights into the therapeutic potential of hypoxia-induced astrocyte-secreted exosomes and the miR-329-5p for treating retina ischemic diseases.

N-acetylserotonin alleviates retinal ischemia-reperfusion injury via HMGB1/RAGE/NF-κB pathway in rats.

To observe the effects of N-acetylserotonin (NAS) administration on retinal ischemia-reperfusion (RIR) injury in rats and explore the underlying mechanisms involving the high mobility group box 1 (HMGB1)/receptor for advanced glycation end-products (RAGE)/nuclear factor-kappa B (NF-κB) signaling pathway. A rat model of RIR was developed by increasing the pressure of the anterior chamber of the eye. Eighty male Sprague Dawley were randomly divided into five groups: sham group (n=8), RIR group (n=28), RIR+NAS group (n=28), RIR+FPS-ZM1 group (n=8) and RIR+NAS+ FPS-ZM1 group (n=8). The therapeutic effects of NAS were examined by hematoxylin-eosin (H&E) staining, and retinal ganglion cells (RGCs) counting. The expression of interleukin 1 beta (IL-1β), HMGB1, RAGE, and nod-like receptor 3 (NLRP3) proteins and the phosphorylation of nuclear factor-kappa B (p-NF-κB) were analyzed by immunohistochemistry staining and Western blot analysis. The expression of HMGB1 protein was also detected by enzyme-linked immunosorbent assay (ELISA). H&E staining results showed that NAS significantly reduced retinal edema and increased the number of RGCs in RIR rats. With NAS therapy, the HMGB1 and RAGE expression decreased significantly, and the activation of the NF-κB/NLRP3 pathway was antagonized along with the inhibition of p-NF-κB and NLRP3 protein expression. Additionally, NAS exhibited an anti-inflammatory effect by reducing IL-1β expression. The inhibitory of RAGE binding to HMGB1 by RAGE inhibitor FPS-ZM1 led to a significant decrease of p-NF-κB and NLRP3 expression, so as to the IL-1β expression and retinal edema, accompanied by an increase of RGCs in RIR rats. NAS may exhibit a neuroprotective effect against RIR via the HMGB1/RAGE/NF-κB signaling pathway, which may be a useful therapeutic target for retinal disease.

Retinal ischemia-reperfusion injury induces intense lipid synthesis and remodeling

The retina is a high-metabolism tissue composed of various cell types with complex functions that relies heavily on the blood supply to maintain homeostasis. Retinal ischemia-reperfusion injury is a critical pathogenic mechanism in glaucoma, and changes in lipid molecules may lead to retinal tissue damage. However, retinal lipid profile alterations caused by this mechanism remain unclear. Thus, this study employed a retinal ischemia-reperfusion model to analyze changes in the lipid profile between sham-operated and ischemia-reperfusion groups. We discovered that ischemia-reperfusion injury-induced alterations in 338 lipid molecules, which potentially caused lipid droplet formation and mitochondrial damage. Notably, we identified characteristic changes in various lipids, including cholesterol esters, cardiolipin, and ceramide, which may serve as potential biomarkers for assessing the severity of retinal injury and therapeutic interventions. The ischemia-reperfusion-specific features identified in this study provide a more comprehensive understanding of the pathophysiological mechanisms underlying this condition.

PDGFRB upregulation contributes to retinal damages in the rat model of retinal ischemia-reperfusion

Retinal ischemic disease is a major type of retinal diseases causing vision loss. Identifying the molecular mechanisms mediating the retinal ischemia-reperfusion (RIR) is the key to targeted intervention. In this study, we performed RNA-seq analysis of the retinal tissues of a retinal ischemia-reperfusion model of Sprague-Dawley (SD) rats, followed by differential gene expression analysis, gene ontology (GO) enrichment analysis, and protein-protein interaction (PPI) analysis. After studying we found that: The major biological processes affected after RIR was the regulation of vascular development. PPI analysis unveiled a regulatory module in which Platelet Derived Growth Factor Receptor Beta (PDGFRB) was upregulated. In the RIR cell model of human retinal microvascular endothelial cells (HRCEC) induced by oxygen-glucose deprivation/reperfusion (OGD/R), silencing PDGFRB at least partially rescued the detrimental effect on cell proliferation and in vitro angiogenic ability. In the rat model of RIR, the administration of PDGFR inhibitor alleviated the damages in the retinal microvascular system. Besides, we further demonstrated the protective effect of procyanidin against RIR induced damages in both the cell and animal model by dampening the overexpression of PDGFRB. Together, our data indicate that the upregulation of PDGFRB contributes to RIR-induced damages in retinal microvascular system, which provides a targetable strategy for therapeutic intervention.

Prothymosin α Plays Role as a Brain Guardian through Ecto-F1 ATPase-P2Y12 Complex and TLR4/MD2.

Prothymosin alpha (ProTα) was discovered to be a necrosis inhibitor from the conditioned medium of a primary culture of rat cortical neurons under starved conditions. This protein carries out a neuronal cell-death-mode switch from necrosis to apoptosis, which is, in turn, suppressed by a variety of neurotrophic factors (NTFs). This type of NTF-assisted survival action of ProTα is reproduced in cerebral and retinal ischemia-reperfusion models. Further studies that used a retinal ischemia-reperfusion model revealed that ProTα protects retinal cells via ecto-F1 ATPase coupled with the Gi-coupled P2Y12 receptor and Toll-like receptor 4 (TLR4)/MD2 coupled with a Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). In cerebral ischemia-reperfusion models, ProTα has additional survival mechanisms via an inhibition of matrix metalloproteases in microglia and vascular endothelial cells. Heterozygous or conditional ProTα knockout mice show phenotypes of anxiety, memory learning impairment, and a loss of neurogenesis. There are many reports that ProTα has multiple intracellular functions for cell survival and proliferation through a variety of protein-protein interactions. Overall, it is suggested that ProTα plays a key role as a brain guardian against ischemia stress through a cell-death-mode switch assisted by NTFs and a role of neurogenesis.

Single-cell RNA sequencing reveals a landscape and targeted treatment of ferroptosis in retinal ischemia/reperfusion injury

BackgroundThe aim of this study was to establish a complete retinal cell atlas of ischemia–reperfusion injury by single-cell RNA sequencing, and to explore the underlying mechanism of retinal ischemia–reperfusion injury in mice.MethodsSingle-cell RNA sequencing was used to evaluate changes in the mouse retinal ischemia reperfusion model. In vivo and in vitro experiments were performed to verify the protective effect of inhibiting ferroptosis in retinal ischemia–reperfusion injury.ResultsAfter ischemia–reperfusion injury, retinal cells were significantly reduced, accompanied by the activation of myeloid and a large amount of blood-derived immune cell infiltration. The IFNG, MAPK and NFKB signaling pathways in retinal neuronal cells, together with the TNF signaling pathway in myeloid give rise to a strong inflammatory response in the I/R state. Besides, the expression of genes implicating iron metabolism, oxidative stress and multiple programed cell death pathways have changed in cell subtypes described above. Especially the ferroptosis-related genes and blocking this process could apparently alleviate the inflammatory immune responses and enhance retinal ganglion cells survival.ConclusionsWe established a comprehensive landscape of mouse retinal ischemia–reperfusion injury at the single-cell level, revealing the important role of ferroptosis during this injury, and targeted inhibition of ferroptosis can effectively protect retinal structure and function.

Houttuynia cordata Thunb rescues retinal ganglion cells through inhibiting microglia activation in a rat model of retinal ischemia-reperfusion.

To determine whether Houttuynia cordata Thunb (HCT) can increase the survival of the retinal ganglion cells (RGCs) and inhibit microglia activation following retinal ischemia-reperfusion (RIR) injury. Rat model of RIR was induced by transient elevation of the intraocular pressure (IOP). HCT was orally administered for 2d before the performance of retinal RIR model and once a day for the next 14d. After 14d of RIR injury, the rats were sacrificed for further analysis. Survival RGCs were stained with haematoxylin and eosin (H&E). Apoptosis of RGCs was detected by TUNEL staining. Retinal function was examined by flash-electroretinography (F-ERG). Retinal microglia were labeled using Iba-1, one specific marker for microglia. The mRNA expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) were assessed by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR). Systemic HCT treatment significantly reduced RGCs death by H&E staining and exhibited an anti-apoptotic effect as assessed by TUNEL staining at day 14 after RIR injury. HCT greatly improved the retinal function as examined by F-ERG. The number of activated microglia significantly increased after RIR injury, which was significantly attenuated by HCT treatment. Besides, RIR injury induced a strong upregulation of pro-inflammatory genes TNF-α, iNOS and IL-1β mRNAs at day 14 post injury, which was suppressed by HCT. Neuroprotective effects of HCT encourage the survival of RGCs through inhibiting microglia activation due to RIR injury. Together these results support the use of HCT as promising therapy for the ischemic events of the retina diseases.

BDNF improves axon transportation and rescues visual function in a rodent model of acute elevation of intraocular pressure.

Optic neuropathies lead to blindness; the common pathology is the degeneration of axons of the retinal ganglion cells. In this study, we used a rat model of retinal ischemia-reperfusion and a one-time intravitreal brain-derived neurotrophic factor (BDNF) injection; then we examined axon transportation function, continuity, physical presence of axons in different part of the optic nerve, and the expression level of proteins involved in axon transportation. We found that in the disease model, axon transportation was the most severely affected, followed by axon continuity, then the number of axons in the distal and proximal optic nerve. BDNF treatment relieved all reductions and significantly restored function. The molecular changes were more minor, probably due to massive gliosis of the optic nerve, so interpretation of protein expression data should be done with some caution. The process in this acute model resembles a fast-forward of changes in the chronic model of glaucoma. Therefore, impairment in axon transportation appears to be a common early process underlying different optic neuropathies. This research on effective intervention can be used to develop interventions for all optic neuropathies targeting axon transportation.

Retinoprotective Effect of 2-Ethyl-3-hydroxy-6-methylpyridine Nicotinate

An important task of pharmacology is to find effective agents to improve retinal microcirculation and resistance to ischemia. The purpose of the study is to pharmacologically evaluate the retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate in a rat model of retinal ischemia–reperfusion. A retinal ischemia–reperfusion model was used, in which an increase in intraocular pressure (IOP) to 110 mmHg was carried out within 30 min. The retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate at a dose of 3.8 mg/kg, in comparison with nicotinic acid at a dose of 2 mg/kg and emoxipine at a dose of 2 mg/kg, was estimated by the changes in the eye fundus during ophthalmoscopy, the retinal microcirculation level with laser Doppler flowmetry (LDF), and electroretinography (ERG) after 72 h of reperfusion. The use of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate prevented the development of ischemic injuries in the fundus and led to an increase in the retinal microcirculation level to 747 (median) (lower and upper quartiles: 693;760) perfusion units (p = 0.0002) in comparison with the group that underwent no treatment. In the group with the studied substance, the b-wave amplitude increased significantly (p = 0.0022), and the b/a coefficient increased reliably (p = 0.0002) in comparison with the group with no treatment. Thus, 2-ethyl-3-hydroxy-6-methylpyridine nicotinate has established itself as a potential retinoprotector.

Correction of retinal ischemic injuries by using non-selective imidazoline receptor agonists in the experiment

Introduction: Retinoprotective effects of non-selective imidazoline receptor agonists: potassium salt of С7070; sodium salt of С7070; С7070 processed with CO2 – were investigated in comparison with C7070 on the retinal ischemia-reperfusion model in rats.
 Materials and methods: The protective effects of the substances were evaluated by using ophthalmoscopy, laser Doppler flowmetry, electroretinography, histological and morphometric studies of retinal layers.
 Results and discussion: The most pronounced retinoprotective effect was observed in potassium salt of C7070 at a dose of 10 mg/kg, which expresses in approaching the normal eye fundus image, achieving the target values of the retinal blood flow, b/a coefficient, and reaching the norm values of morphometric indicators. A less pronounced protective effect was found in sodium salt of C7070 at a dose of 10 mg/kg, which expresses in a 71% decrease (p < 0.05) in semi-quantitative assessment of the eye fundus changes, an increase in the retinal blood flow level by 70.4% (p < 0.05), in b/a by 94% (p < 0.05) in comparison with the group without correction, and reaching the norm of the morphometric indicators. A retinoprotective effect of the substance C7070 processed with CO2 at a dose of 10 mg/kg is inferior to that of the sodium salt of C7070.
 Conclusion: The retinoprotective activity of the substances is expressed in descending order: potassium salt of С7070 (10 mg/kg) ≈ С7070 (50 mg/kg) > sodium salt of С7070 (10 mg/kg) > С7070 processed with CO2 (10 mg/kg) ≈ С7070 (10 mg/kg). Injections of glibenclamide leveled the neuroretinoprotective effects of the substances to varying degrees, which confirmed the participation of ATP-dependent potassium channels in the implementation of these effects.

Inhibition of the Keap1-Nrf2 protein-protein interaction protects retinal cells and ameliorates retinal ischemia-reperfusion injury

The Nrf2-Keap1 pathway regulates transcription of a wide array of antioxidant and cytoprotective genes and offers critical protection against oxidative stress. This pathway has demonstrated benefit for a variety of retinal conditions. Retinal ischemia plays a pivotal role in many vision threatening diseases. Retinal vascular endothelial cells are an important participant in ischemic injury. In this setting, Nrf2 provides a protective pathway via amelioration of oxidative stress and inflammation. In this study, we investigated a potent small molecule inhibitor of the Nrf2-Keap1 protein-protein interaction (PPI), CPUY192018, for its therapeutic potential in retinal cells and retinal ischemia-reperfusion injury. In human retinal endothelial cells (HREC), treatment with CPUY192018 increased Nrf2 protein levels and nuclear translocation, stimulated Nrf2-ARE-induced transcriptional capacity, and induced Nrf2 target gene expression. Furthermore, CPUY192018 protected HREC against oxidative stress and inflammatory activation. CPUY192018 also activated Nrf2 and suppressed inflammatory response in macrophages. In the retinal ischemia-reperfusion (I/R) model, administration of CPUY192018 induced Nrf2 target gene activation in the retina. Both systemic and topical treatment with CPUY192018 rescued visual function after ischemia-reperfusion injury. Taken together, these findings indicate that small molecule Keap1-Nrf2 PPI inhibitors can activate the Nrf2 pathway in the retina and provide protection against retinal ischemic and inflammatory injury, suggesting Keap1-Nrf2 PPI inhibition in the treatment of retinal conditions.

HDAC2 Regulates Glial Cell Activation in Ischemic Mouse Retina.

The current study was undertaken to investigate whether histone deacetylases (HDACs) can modulate the viability of retinal ganglion cells (RGCs) and the activity of glial cells in a mouse model of retinal ischemia-reperfusion (IR) injury. C57BL/6J mice were subjected to constant elevation of intraocular pressure for 60 min to induce retinal IR injury. Expression of macroglial and microglial cell markers (GFAP and Iba1), hypoxia inducing factor (HIF)-1α, and histone acetylation was analyzed after IR injury. To investigate the role of HDACs in the activation of glial cells, overexpression of HDAC1 and HDAC2 isoforms was performed. To determine the effect of HDAC inhibition on RGC survival, trichostatin-A (TSA, 2.5 mg/kg) was injected intraperitoneally. After IR injury, retinal GFAP, Iba1, and HIF-1α were upregulated. Conversely, retinal histone acetylation was downregulated. Notably, adenoviral-induced overexpression of HDAC2 enhanced glial activation following IR injury, whereas overexpression of HDAC1 did not significantly affect glial activation. TSA treatment significantly increased RGC survival after IR injury. Our results suggest that increased activity of HDAC2 is closely related to glial activation in a mouse model of retinal IR injury and inhibition of HDACs by TSA showed neuroprotective potential in retinas with IR injuries.

HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model.

PurposeThe therapeutic approach for retinal ganglion cell (RGC) degeneration has not been fully established. Recently, it has been reported that hypoxia-inducible factor (HIF) may be involved with retinal neurodegeneration. In this study, we investigated neuroprotective effects of a HIF inhibitor against RGC degeneration induced in a murine model of retinal ischemia-reperfusion (I/R).MethodsEight-weeks-old male C57/BL6J mice were treated with intraperitoneal injection of a HIF inhibitor topotecan (1.25 mg/kg) for 14 days followed by a retinal I/R procedure. Seven days after the I/R injury, the therapeutic effect was evaluated histologically and electrophysiologically.ResultsThe increase of HIF-1α expression and the decrease of retinal thickness and RGC number in I/R were significantly suppressed by administration of topotecan. Impaired visual function in I/R was improved by topotecan evaluated with electroretinogram and visual evoked potentials.ConclusionsTopotecan administration suppressed HIF-1a expression and improved RGC survival resulting in a functional protection against retinal I/R. These data indicated that the HIF inhibitor topotecan may have therapeutic potentials for RGC degeneration induced with retinal ischemia or high intraocular pressure.

The effects of endothelium-specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model.

Glaucoma is a leading cause of irreversible blindness worldwide. Vascular factors play a substantial role in the pathogenesis of glaucoma. Expressed in the vascular endothelium, cytochrome P450 (CYP) 2J2 is one of the CYP epoxygenases that metabolize arachidonic acid to produce epoxyeicosatrienoic acids and exert pleiotropic protective effects on the vasculature. In the present study, we investigated whether endothelium-specific overexpression of CYP2J2 (tie2-CYP2J2-Tr) protects against retinal ganglion cell (RGC) loss induced by glaucoma and in what way retinal vessels are involved in this process. We used a glaucoma model of retinal ischemia-reperfusion (I/R) injury in rats and found that endothelium-specific overexpression of CYP2J2 attenuated RGC loss induced by retinal I/R. Moreover, retinal I/R triggered retinal vascular senescence, indicated by up-regulated senescence-related proteins p53, p16, and β-galactosidase activity. The senescent endothelial cells resulted in pericyte loss and increased endothelial secretion of matrix metallopeptidase 9, which further contributed to RGC loss. CYP2J2 overexpression alleviated vascular senescence, pericyte loss, and matrix metallopeptidase 9 secretion. CYP2J2 suppressed endothelial senescence by down-regulating senescence-associated proteins p53 and p16. These 2 proteins were positively regulated by microRNA-128-3p, which was inhibited by CYP2J2. These results suggest that CYP2J2 protects against endothelial senescence and RGC loss in glaucoma, a discovery that may lead to the development of a potential treatment strategy for glaucoma.-Huang, J., Zhao, Q., Li, M., Duan, Q., Zhao, Y., Zhang, H. The effects of endothelium-specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model.

A Novel HIF Inhibitor Halofuginone Prevents Neurodegeneration in a Murine Model of Retinal Ischemia-Reperfusion.

Neurodegeneration caused with retinal ischemia or high intraocular pressure is irreversible in general. We have focused on the role of hypoxia-inducible factor (HIF) in retinal homeostasis and revealed that HIF inhibition may be effective against retinal neovascular and neurodegeneration. In this study, we performed in vitro screening of natural products and found halofuginone, which is a derivative of febrifugine extracted from hydrangea, as a novel HIF inhibitor. Administration of halofuginone showed a significant neuroprotective effect by inhibiting HIF-1α expression in a murine retinal ischemia-reperfusion model histologically and functionally. These results indicate that halofuginone can be a neuroprotective agent in ischemic retinal degenerative diseases.

Neuroprotective Effects of HSF1 in Retinal Ischemia-Reperfusion Injury.

PurposeRetinal ischemia, a common cause of several vision-threatening diseases, contributes to the death of retinal neurons, particularly retinal ganglion cells (RGCs). Heat shock transcription factor 1 (HSF1), a stress-responsive protein, has been shown to be important in response to cellular stress stimuli, including ischemia. This study is to investigate whether HSF1 has a role in retinal neuronal injury in a mouse model of retinal ischemia-reperfusion (IR).MethodsIR was induced by inserting an infusion needle into the anterior chamber of the right eye and elevating a saline reservoir connected to the needle to raise the intraocular pressure to 110 mm Hg for 45 minutes. HSF1, Hsp70, molecules in the endoplasmic reticulum (ER) stress branches, tau phosphorylation, inflammatory molecules, and RGC injury were determined by immunohistochemistry, Western blot, or quantitative PCR.ResultsHSF1 expression was significantly increased in the retina 6 hours after IR. Using our novel transgenic mice carrying full-length human HSF gene, we demonstrated that IR-induced retinal neuronal apoptosis and necroptosis were abrogated 12 hours after IR. RGCs and their function were preserved in the HSF1 transgenic mice 7 days after IR. Mechanistically, the beneficial effects of HSF1 may be mediated by its induction of chaperone protein Hsp70 and alleviation of ER stress, leading to decreased tau phosphorylation and attenuated inflammatory response 12 to 24 hours after IR.ConclusionsThese data provide compelling evidence that HSF1 is neuroprotective against retinal IR injury, and boosting HSF1 expression may be a beneficial strategy to limit neuronal degeneration in retinal diseases.

Correction of Experimental Retinal Ischemia by l-Isomer of Ethylmethylhydroxypyridine Malate.

An important task of pharmacology and ophtalmology is to find specific and highly effective agents for correcting retinal ischemia. The objective of this study is to increase the effectiveness of pharmacological correction of retinal ischemia by using new 3-hydroxypyridine derivative–l-isomer of ethylmethylhydroxypyridine malate. A modification to the retinal ischemia-reperfusion model was used, in which an increase in intraocular pressure is carried out by mechanical pressure (110 mmHg) to the front chamber of the eye for 30 min. The protective effects of l-isomer of ethylmethylhydroxypyridine malate in comparison with Emoxipine as pretreatment, with parabulbar injection, based on the model of retinal ischemia-reperfusion, were estimated by the changes in the ratio of the amplitudes of the a- and b-waves of electroretinography (the b/a coefficient) and ophthalmoscopy. The use of l-isomer of ethylmethylhydroxypyridine malate improves the retinal electrophysiological state after 72 h of reperfusion; in the group of rats treated with l-isomer of ethylmethylhydroxypyridine malate, the coefficient b/a was reliably increased by 9.5%, p < 0.05, in comparison with animals treated with Emoxipine, and by 91.7%, p < 0.05, in comparison with the group with no treatment. Furthermore, it prevents the development of ischemic changes in the retina observed in ophthalmoscopy to a greater extent than Emoxipine.

Synergistic neuroprotective effect of rasagiline and idebenone against retinal ischemia-reperfusion injury via the Lin28-let-7-Dicer pathway.

Retinal ischemia-reperfusion (RIR) injury causes neuronal degeneration and initiates various optic nerve diseases. This study aimed to investigate the synergistic neuroprotective effect of rasagiline and idebenone against RIR injury. A combination of rasagiline and idebenone was administered intraperitoneally immediately after establishment of the RIR model. Treatment with the combination of the two drugs resulted in a significant restoration of retinal thickness and retinal ganglion cells. Apoptosis of cells in ganglion cell layers was also ameliorated, suggesting that the effect of the two drugs was synergistic and the expression of brain-derived neurotrophic factor increased. Furthermore, idebenone and rasagiline induced the expression of Lin28A and Lin28B, respectively, which resulted in a reduced expression of microRNAs in the let-7 family and an increased protein output of Dicer. The data obtained from gene overexpression and knockdown experiments indicated that let-7 and Dicer were necessary for the synergistic neuroprotective effect of the two drugs. Our findings suggested that combination therapy with rasagiline and idebenone produced a synergistic effect that ameliorated RIR injury and restored visual function. In addition, the combined treatment provided neuroprotection via enhancement of the selective regulation of let-7 by Lin28A/B. These findings implied that a treatment with the combination of rasagiline and idebenone is a feasible treatment option for optic nerve diseases.

Pharmacological correction of retinal ischemia/reperfusion by minoxidil

Introduction/Objective. The objective of this paper was to increase the effectiveness of pharmacological correction of retinal ischemia-reperfusion by using minoxidil. Methods. The research was carried out on 180 Wistar rats. A modification of the retinal ischemia-reperfusion model was used, in which an increase in intraocular pressure is carried out by mechanical pressure (110 mmHg) to the front chamber of the eye for 30 minutes. Protective effects of minoxidil at a dose 0.5 mg/kg on the model of retinal ischemia-reperfusion were estimated by the changes in the level of retinal microcirculation (laser Doppler flowmetry), electroretinogram amplitude, morphometry of retinal layers after 1 hour and 72 hours of reperfusion. Results. Minoxidil at a dose 0.5 mg/kg of rat mass improves retinal microcirculation, its electrophysiological state after 1 hour and 72 hours of reperfusion, and prevents the development of degenerative changes in the retina caused by ischemic damage to a greater extent than recombinant erythropoietin at a dose of 50 IU/kg and sildenafil at a dose of 0.5 mg/kg in monotherapy. The protective effects of minoxidil were eliminated by the preliminary administration of glibenclamide at a dose of 5 mg/kg, which indicates the presence of the preconditioning effect of minoxidil, realized through adenosine triphosphate-dependent potassium channels. Conclusion. Minoxidil at a dose of 0.5 mg/kg of rat mass protects the retina from ischemic-reperfusion injury. Protective effects of minoxidil are carried out by a preconditioning action, as evidenced by the lack of positive effects with the administration of glibenclamide.