Visual Disfunction due to the Selective Effect of Glutamate Agonists on Retinal Cells

One of the causes of nervous system degeneration is an excess of glutamate released upon several diseases. Glutamate analogs, like N-methyl-DL-aspartate (NMDA) and kainic acid (KA), have been shown to induce experimental retinal neurotoxicity. Previous results have shown that NMDA/KA neurotoxicity induces significant changes in the full field electroretinogram response, a thinning on the inner retinal layers, and retinal ganglion cell death. However, not all types of retinal neurons experience the same degree of injury in response to the excitotoxic stimulus. The goal of the present work is to address the effect of intraocular injection of different doses of NMDA/KA on the structure and function of several types of retinal cells and their functionality. To globally analyze the effect of glutamate receptor activation in the retina after the intraocular injection of excitotoxic agents, a combination of histological, electrophysiological, and functional tools has been employed to assess the changes in the retinal structure and function. Retinal excitotoxicity caused by the intraocular injection of a mixture of NMDA/KA causes a harmful effect characterized by a great loss of bipolar, amacrine, and retinal ganglion cells, as well as the degeneration of the inner retina. This process leads to a loss of retinal cell functionality characterized by an impairment of light sensitivity and visual acuity, with a strong effect on the retinal OFF pathway. The structural and functional injury suffered by the retina suggests the importance of the glutamate receptors expressed by different types of retinal cells. The effect of glutamate agonists on the OFF pathway represents one of the main findings of the study, as the evaluation of the retinal lesions caused by excitotoxicity could be specifically explored using tests that evaluate the OFF pathway.

Comparison of three regional anaesthetic techniques for infraorbital or maxillary nerve block in cats: a cadaveric study

Objectives The maxillary nerve courses very close to the globe, rendering cats – with their large eyes – at risk of globe penetration during infraorbital or maxillary nerve blocks. Therefore, the goals of the study were to compare the distribution and potential complications of three infraorbital or maxillary regional injection techniques. Methods Twenty-three bilateral maxillae of cat cadavers were used in a randomised blinded trial. Each maxilla was injected with a 0.2 ml 1:1 mixture of lidocaine 2% and a contrast medium by one of three injection techniques: infraorbital foramen (IOF; n = 14); infraorbital canal (IOC; n = 16); or maxillary foramen (MF; transpalpebral approach; n = 16) using a 25 G 1.6 cm needle. CT imaging of each cadaver head was performed before and after injections. A radiologist scored injectate distribution (none [0], mild [1], moderate [2], large [3]) in four locations: rostral, central and caudal IOC, and at the MF, for which the distribution side was also determined. Comparisons were performed with ordinal logistic mixed effects ( P <0.05). Results The median (range) total distribution score of the IOC and MF technique were significantly higher compared with the IOF technique (6.5 [4–12], 4 [2–8] and 0 [0–10], respectively). The total IOC score was also significantly higher compared with the MF technique. Injectate distribution at the MF was significantly more central following IOC injection compared with MF injection, which distributed centrolaterally. None of the techniques resulted in intraocular injection. Conclusions and relevance The IOC and MF techniques produced a satisfactory spread of the mixture that could result in effective maxillary anaesthesia in cats. Further studies are required to determine the effectiveness and safety of these techniques.

Intraocular Injection of Stivant® (A Biosimilar to Bevacizumab): A Case Series

Purpose: To report the results of intravitreal injection of a bevacizumab biosimilar called Stivant®. Methods: This prospective interventional case series was conducted on eyes with neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), and diabetic macular edema (DME). Stivant® was injected in three consecutive months and changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were measured at baseline and monthly up to one month after the third injection. Results: Three hundred and eighty-five eyes with DME (234 eyes, 61%), nAMD (87 eyes, 22%), and macular edema secondary to RVO (64 eyes, 17%) were enrolled. The mean ± standard deviation age of the patients was 61.7 ± 7.20 years. The mean BCVA and CMT changed from 0.63 ± 0.3 to 0.51 ± 0.3 LogMAR (P = 0.12 ) and from 420.4 ± 47.3μm at baseline to 316.7 ± 50.6 μm (P < 0.001) in the DME group; from 0.79 ± 0.3 to 0.68 ± 0.3 LogMAR (P = 0.19) and from 376.1 ± 31.7 μm to 303 ± 31.3 μm (P = 0.019) in the nAMD group; and from 0.81 ± 0.4 to 0.63 ± 0.4 LogMAR (P = 0.05) and from 424.21 ± 18 μm to 303.4 ± 18.8 μm (P < 0.001) in the RVO group, respectively. Conclusion: Our limited experience showed that the intravitreal injection of Stivant® was well tolerated. Although the results of this case series showed relative improvement in CMT one month after the last injection of Stivant®, BCVA improvement was statistically significant only in the RVO group. This would be essential to design a randomized clinical trial to evaluate the non-inferiority of Stivant® in comparison to bevacizumab.

Recombinant adenovirus causes prolonged mobilization of macrophages in the anterior chamber of mice

Purpose: Ocular tissues of mice have been studied in many ways using replication deficient species C type 5 adenoviruses (Ad5) as tools for manipulating gene expression. While refinements to injection protocols and tropism have led to several advances in targeting cells of interest, there remains a relative lack of information concerning how Ad5 may influence other ocular cell types capable of confounding experimental interpretation. Here, a slit-lamp is used to thoroughly photodocument the sequalae of intraocular Ad5 injections over time in mice, with attention to potentially confounding indices of inflammation. Methods: A cohort of C57BL/6J mice were randomly split into 3 groups (Virus, receiving unilateral intraocular injection with 5x107 pfu of a cargo-less Ad5 construct; Saline, receiving unilateral balanced salt solution injection; and Naïve, receiving no injections). A total of 52 eyes from 26 mice were photodocumented via slit-lamp at 4 timepoints (baseline, 1, 3, and 10 weeks following initiation of the experiment) by an observer masked to treatments and other parameters of the experimental design. Following the last in vivo exam, tissues were collected. Based on the slit-lamp data, tissues were studied via immunostaining with the macrophage marker F4/80. Results: The masked investigator was able to use the sequential images from each mouse to assign each mouse into its correct treatment group with near perfect fidelity. Virus injected eyes were characterized by corneal damage indicative of intraocular injection and a prolonged mobilization of clump cells on the surface of the iris. Saline injected eyes had only transient corneal opacities indicative of intraocular injections, and Naïve eyes remained normal. Immunostaining with F4/80 was consistent with ascribing the clump cells visualized via slit-lamp imaging as a type of macrophage.

Intraocular injection of KH902 alleviates retinal hypoxia in a mouse model of oxygen-induced retinopathy

Inhibition of vascular endothelial growth factor (VEGF) has been widely applied in antineovascularization therapies. As a novel anti-VEGF agent, KH902 (conbercept) is designed to restrain pathological angiogenesis. However, the effects of KH902 on retinal hypoxia have not been well studied. In a mouse model of oxygen-induced retinopathy (OIR), we assessed retinal hypoxia at postnatal days 14 (P14) and P17, as well as retinal neovascularization (RNV) at P17. In addition, we evaluated the protein level of VEGF and galectin-1 (Gal-1). Changes of the neuroretinal structure were also examined. Our results indicated that KH902 could remit retinal hypoxia in OIR at P14 and P17, which was an exciting novel finding for KH902 function. Additionally, we confirmed that KH902 markedly reduces RNV. Our results indicated that administration of KH902 downregulated VEGF expression, as well as Gal-1. Damage of neuroretinal structure after KH902 injection was not observed, which was also an encouraging result. Our study suggests that KH902 plays a role in alleviating retinal hypoxia and that it could be used for the treatment of other neovascular ocular diseases.

Retinal and Corneal Toxicity and Pharmacokinetic Analysis of Intraocular Injection of Ganciclovir in Rabbit Eyes

Purpose. To evaluate the safety and pharmacokinetic changes of ganciclovir (GCV) intraocular injection. Methods. GCV (2 mg/0.1 mL) was injected into rabbit eyes. Aqueous GCV concentration was detected by high-performance liquid chromatography. Potential toxicity was assessed by slit-lamp examination, optical coherence tomography, fundus examination, confocal microscopy, and histology. Results. Aqueous GCV concentrations were 24.83 ± 6.41 μg/mL, 0.65 ± 0.52 μg/mL, and undetected on the 1st, 3rd, and 7th day after intravitreal injection. GCV could not be detected on the first day after intracameral injection. No corneal abnormality was found after intravitreal injection, but retinal edema was observed on the first day which receded later. Corneal edema was obvious with endothelial cytoarchitecture damaged after intracameral injection; fluid retention also existed in retina. Conclusions. GCV intravitreal injection offers effective, sustained drug concentration in the anterior chamber, and its damage to retina receded over time. Intracameral injection results in rapid drug elimination and severe damage to endothelium and thus is not recommended.

Cytokines and the Pathogenesis of Macular Edema in Branch Retinal Vein Occlusion

Branch retinal vein occlusion (BRVO) is a very common retinal vascular problem in patients with lifestyle-related diseases, such as hypertension and arteriosclerosis. In patients with BRVO, development of macular edema is the main cause of visual impairment. BRVO is still a controversial condition in many respects. Over the years, various methods such as laser photocoagulation have been tried to treat macular edema associated with BRVO, but the results were not satisfactory. After vascular endothelial growth factor (VEGF) was found to have an important role in the pathogenesis of macular edema in BRVO patients, treatment of this condition was revolutionized by development of anti-VEGF therapy. Although macular edema improves dramatically following intraocular injection of anti-VEGF agents, repeated recurrence and resistance of edema is a major problem in some BRVO patients. This suggests that factors or cytokines other than VEGF may be associated with inflammation and retinal hypoxia in BRVO and that the pathogenesis of macular edema is complicated. The present review assesses the role of various factors and cytokines in the pathogenesis of macular edema associated with BRVO. We present a mechanism that is not only plausible but should also be useful for developing new therapeutic strategies.