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Glaucoma is an irreversible sight-threatening disorder primarily due to elevated intraocular pressure (IOP), leading to retinal ganglion cell (RGC) death by apoptosis with subsequent loss of optic nerve fibers. A considerable amount of empirical evidence has shown the significant association between tumor necrosis factor cytokine (TNF; TNFα) and glaucoma; however, the exact role of TNF in glaucoma progression remains unclear. Total inhibition of TNF against its receptors can cause side effects, although this is not the case when using selective inhibitors. In addition, TNF exerts its antithetic roles via stimulation of two receptors, TNF receptor I (TNFR1) and TNF receptor II (TNFR2). The pro-inflammatory responses and proapoptotic signaling pathways predominantly mediated through TNFR1, while neuroprotective and anti-apoptotic signals induced by TNFR2. In this review, we attempt to discuss the involvement of TNF receptors (TNFRs) and their signaling pathway in ocular tissues with focus on RGC and glial cells in glaucoma. This review also outlines the potential application TNFRs agonist and/or antagonists as neuroprotective strategy from a therapeutic standpoint. Taken together, a better understanding of the function of TNFRs may lead to the development of a treatment for glaucoma.

Oxidative stress plays an important role in retinal neurodegeneration and angiogenesis associated with diabetes. In this study, we investigated the effect of the tocotrienol-rich fraction (TRF), a potent antioxidant, against diabetes-induced changes in retinal layer thickness (RLT), retinal cell count (RCC), retinal cell apoptosis, and retinal expression of vascular endothelial growth factor (VEGF) in rats. Additionally, the efficacy of TRF after administration by two different routes was compared. The diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin. Subsequently, diabetic rats received either oral or topical treatment with vehicle or TRF. Additionally, a group of non-diabetic rats was included with either oral or topical treatment with a vehicle. After 12 weeks of the treatment period, rats were euthanized, and retinas were collected for measurement of RLT, RCC, retinal cell apoptosis, and VEGF expression. RLT and RCC in the ganglion cell layer were reduced in all diabetic groups compared to control groups (p < 0.01). However, at the end of the experimental period, oral TRF-treated rats showed a significantly greater RLT compared to topical TRF-treated rats. A similar observation was made for retinal cell apoptosis and VEGF expression. In conclusion, oral TRF supplementation protects against retinal degenerative changes and an increase in VEGF expression in rats with streptozotocin-induced diabetic retinopathy. Similar effects were not observed after topical administration of TRF.

Background Diabetic retinopathy (DR) is the second commonest microvascular complication of diabetes mellitus. It is characterized by chronic inflammation and angiogenesis. Palm oil-derived tocotrienol-rich fraction (TRF), a substance with anti-inflammatory and anti-angiogenic properties, may provide protection against DR development. Therefore, in this study, we investigated the effect of TRF on retinal vascular and morphological changes in diabetic rats. The effects of TRF on the retinal expression of inflammatory and angiogenic markers were also studied in the streptozotocin (STZ)-induced diabetic rats. Methods Male Sprague Dawley rats weighing 200–250 g were grouped into normal rats (N) and diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg body weight) whereas N similarly received citrate buffer. STZ-injected rats with blood glucose of more than 20 mmol/L were considered diabetic and were divided into vehicle-treated (DV) and TRF-treated (DT) groups. N and DV received vehicle, whereas DT received TRF (100 mg/kg body weight) via oral gavage once daily for 12 weeks. Fundus images were captured at week 0 (baseline), week 6 and week 12 post-STZ induction to estimate vascular diameters. At the end of experimental period, rats were euthanized, and retinal tissues were collected for morphometric analysis and measurement of NFκB, phospho-NFκB (Ser536), HIF-1α using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Retinal inflammatory and angiogenic cytokines expression were measured by ELISA and real-time quantitative PCR. Results TRF preserved the retinal layer thickness (GCL, IPL, INL and OR; p < 0.05) and retinal venous diameter (p < 0.001). TRF also lowered the retinal NFκB activation (p < 0.05) as well as expressions of IL-1β, IL-6, TNF-α, IFN-γ, iNOS and MCP-1 (p < 0.05) compared to vehicle-treated diabetic rats. Moreover, TRF also reduced retinal expression of VEGF (p < 0.001), IGF-1 (p < 0.001) and HIF-1α (p < 0.05) compared to vehicle-treated rats with diabetes. Conclusion Oral TRF provided protection against retinal inflammation and angiogenesis in rats with STZ-induced diabetes by suppressing the expression of the markers of retinal inflammation and angiogenesis.

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The purpose of this study was to evaluate the use of Fiji Image J application for digital fundus image analysis of retinal vessel diameter in diabetic retinopathy rat model. Male Sprague-Dawley rats, weighing 200-250 grams, were divided into two groups: normal and diabetic. The diabetes was induced by intraperitoneal (IP) injection of streptozotocin (STZ, 55 mg/kg body weight). Normal rats received IP citrate buffer. Fundus images were captured at week 0, 6 and 12 post-induction to observe changes in retinal veins and arteries. Images obtained were then analyzed using Fiji Image J software. Retinal venous diameter was increased in both groups at week 6 and 12 compared to baseline (p<0.05). However, no significant differences were seen in the retinal venous diameter at week 12 compared to week 6 in both groups. When comparing between the groups, retinal venous diameter in diabetic group was significantly greater compared to normal group at week 6 and 12 by 1.37- and 1.35-folds (p<0.001), respectively. For the retinal arterial diameter in diabetic group, an increase was observed at week 6 and 12 compared to baseline by 1.17- and 1.2-folds (p<0.05) respectively, however, similar changes were not observed in normal group. There was also no significant difference between the retinal arterial diameter of normal and diabetic group at week 6 and 12.  In conclusion, retinal vessels diameter analysis of fundus images using Fiji Image J can be utilized to determine quantitative changes between normal and rats with STZ-induced diabetic retinopathy.

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Recently, a considerable amount of literature has emerged around the theme of neuroinflammation linked to neurodegeneration. Glaucoma is a neurodegenerative disease characterized by visual impairment. Understanding the complex neuroinflammatory processes underlying retinal ganglion cell loss has the potential to improve conventional therapeutic approaches in glaucoma. Due to the presence of multiple barriers that a systemically administered drug has to cross to reach the intraocular space, ocular drug delivery has always been a challenge. Nowadays, studies are focused on improving the current therapies for glaucoma by utilizing nanoparticles as the modes of drug transport across the ocular anatomical and physiological barriers. This review offers some important insights on the therapeutic advancements made in this direction, focusing on the use of nanoparticles loaded with anti-inflammatory and neuroprotective agents in the treatment of glaucoma. The prospect of these novel therapies is discussed in relation to the current therapies to alleviate inflammation in glaucoma, which are being reviewed as well, along with the detailed molecular and cellular mechanisms governing the onset and the progression of the disease.