Rupali Vohra

The Role of Inflammation in the Pathogenesis of Glaucoma

Glaucoma is an ocular disorder characterized by the progressive loss of retinal ganglion cells (RGC) and their axons. There are various hypotheses concerning the cause of RGC death. Previously, glaucoma was defined by high intraocular pressure (IOP); during the past decade, however, glaucoma specialists have acknowledged that elevated IOP is the most important risk factor for glaucoma, but does not define the disease. Other factors such as genetics, blood flow, and excitotoxicity are suggested as potential causal factors for progressive RGC death observed in glaucoma. We review recent studies elucidating a possible role of low-grade inflammation as a causal factor in the pathogenesis of glaucoma.

Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease

In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.

Mitochondrial dysfunction underlying outer retinal diseases

Dysfunction of photoreceptors, retinal pigment epithelium (RPE) or both contribute to the initiation and progression of several outer retinal disorders. Disrupted Müller glia function might additionally subsidize to these diseases. Mitochondrial malfunctioning is importantly associated with outer retina pathologies, which can be classified as primary and secondary mitochondrial disorders. This review highlights the importance of oxidative stress and mitochondrial DNA damage, underlying outer retinal disorders. Indeed, the metabolically active photoreceptors/RPE are highly prone to these hallmarks of mitochondrial dysfunction, indicating that mitochondria represent a weak link in the antioxidant defenses of outer retinal cells.

Interaction between VEGF and Calcium-Independent Phospholipase A2 in Proliferation and Migration of Retinal Pigment Epithelium

Purpose: Inhibition of VEGF in the eye is an important treatment modality for reducing proliferation and migration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD). Additionally, previous studies suggest calcium-independent phospholipase A2 group VIA (iPLA2-VIA) to be a potential regulator of cell proliferation and migration, and evidence show abundant expression of iPLA2-VIA in RPE cells. The aim of the present study was to evaluate the potential role of iPLA2-VIA in VEGF-induced proliferation and migration of RPE cells. Materials and methods: The human RPE cell line, ARPE-19, was used in all assays. To explore the role of iPLA2-VIA in VEGF-induced RPE proliferation and migration, iPLA2-VIA inhibition by the iPLA2-VIA specific inhibitor, bromoenol lactone, was done. RPE cell proliferation and migration were evaluated by measurements of incorporated radioactive thymidine in DNA and by a Boyden chamber technique, respectively. A luciferase assay monitored the VEGF-induced iPLA2-VIA transcriptional activity. Western blot analysis and an activity assay were used to detect the protein levels and activity of iPLA2-VIA respectively after treatment with VEGF. Results: RPE cells treated with VEGF showed significant increased proliferation and migration. Furthermore, inhibition of iPLA2-VIA significantly reduced the spontaneous proliferation and migration as well as the VEGF-induced proliferation and migration. Finally, inhibition of iPLA2-VIA reduced the VEGF-induced iPLA2-VIA-activity, -protein level, and -promoter activity. Conclusions: A significant interaction between VEGF and iPLA2-VIA in the regulation of RPE cells appears to be relevant in elucidating the exact mechanisms of action in the proliferative and migratory phenotype of RPE cells in AMD.

Disturbed mitochondrial function restricts glutamate uptake in the human Müller glia cell line, MIO-M1

Using the human Müller cell line, MIO-M1, the aim was to study the impact of mitochondrial inhibition in Müller glia through antimycin A treatment. MIO-M1 cell survival, levels of released lactate, mitochondrial function, and glutamate uptake were studied in response to mitochondrial inhibition and glucose restriction. Lactate release decreased in response to glucose restriction. Combined glucose restriction and blocked mitochondrial activity decreased survival and caused collapse of the respiratory chain measured by oxygen consumption rate and extracellular acidification rate. Mitochondrial inhibition caused impaired glutamate uptake and decreased mRNA expression of the glutamate transporter, EAAT1. Over all, we show important roles of mitochondrial activity in MIO-M1 cell function and survival.

Neuroprotection of the inner retina: Müller cells and lactate

Müller cells: The neglected neighbor: Müller cells constitute the majority of retinal glial cells and offer more alternating functions than any other cell of the retina. Uniquely, Müller cells cover the complete thickness of the retina, and their roles therefore differ correspondingly to the retinal segment in which they are located. In the inner retina, Müller cells are crucial in taking up toxic molecules, such as excessive glutamate from the synapses between bipolar cells and retinal ganglion cells (RGCs), thereby preventing glutamate-induced excitoxic RGC death (Bringmann et al., 2009; Skytt et al., 2016; Toft-Kehler et al., 2016; Vohra et al., 2017) (Figure 1). Additionally, Müller cells are crucial in maintaining ion balances and have also been suggested to secrete essential neuroprotective factors as well as to buffer energy sources to the neighboring cells (Bringmann et al., 2006, 2009). Despite being over looked for decades Müller cells have now been proven essential in overall retinal maintenance, and increasing attention and acknowledgement has been attributed to their mere presence and function. In general, Müller cells contain elevated amounts of mitochondria and are known to be extremely resistant to various forms of pathogenic conditions, such as hypoxia, hypoglycemia and oxidative stress (Toft-Kehler et al., 2016; Vohra et al., 2017), indicating that the Müller cells’ defense towards toxic stress might be defined by their energy metabolism and increased adenosine triphosphate (ATP) turnover. However, in the case of excessive stress or multiple toxic factors, the defense mechanisms may diminish and result in dysfunctional Müller cells (Toft-Kehler et al., 2016; Vohra et al., 2017). As a compensatory self defensive mechanism, the Müller cells might take up alternate energy substrates, such as glutamate, to accommodate the need for a greater energy consumption (Skytt et al., 2016; Toft-Kehler et al., 2016, 2017) (Figure 1). Recently, Müller cells were proposed to take up lactate from the outer retina and merely transfer lactate to inner retinal neurons as an alternate energy substrate (Hurley et al., 2015). However, we challenge this assumption by arguing that Müller cells may in fact metabolize lactate (Vohra et al., 2018), which during compromised glucose availability may be essential in upholding their protection of inner retinal neurons. Although human peripheral blood lactate levels lie between 1–2 mM, physiological levels of retinal lactate extend up to 5–50 mM depending on the species. Certainly, these high levels of lactate must play a role in maintaining retinal function and survival (Kolko et al., 2016). In line with this, our previous studies have shown increased uptake of radioactively marked glutamate by the human Müller cell line, MIO-M1 in response to 10 mM of extracellular L-lactate (Vohra et al., 2018), thus verifying a boosted Müller cell function in the presence of lactate. Moreover, our recent paper highlighted numerous novel features of lactate uptake in Müller cells such as sustained glycogen storage and increased survival, indicating a shift in scientific reasoning towards lactate being more than merely a metabolic waste product. The present perspective article aims to highlight the importance of Müller cell energy metabolism with special attention to lactate-linked neuroprotection in the inner retina.

Potential link between sporadic cerebral amyloid angiopathy and vision loss: A case report

out antiglaucoma medications and without additional glaucoma surgery needed (Table 1). The mean postoperative follow-up was 30.1 months. Surgical success rate was 86.9% at 1 year. Similar success rates were found for those patients under (n = 10) and above (n = 46) 30 years of age (84% versus 87%, at 1 year after surgery). The IOP was reduced from a preoperative mean of 37.4 11.6 mmHg to a postoperative mean of 11.5 3.9 mmHg (1 year). At final follow-up, the mean IOP was 12.4 5.2 mmHg. At last follow-up, 50 (82%) patients had a BCVA that was either unchanged, improved or within 1 line of preoperative levels. There were no intraoperative complications in this series. There were also no cases of endophthalmitis, loss of light perception or tube-related complications. Multivariate regression analyses showed that none of the preoperative characteristics, including type of uveitis, uveitis activity before and after surgery and ethnicity, were associated with a higher risk of surgical failure. We found a high percentage of success for the Baerveldt GDI in uveitic glaucoma (86.9% at 1 year), which is comparable to the 91.7% success rate in the only other report published about the very same subject (Ceballos et al. 2002). Our outcomes compared favourably with previous studies using other GDI in uveitic glaucoma, reporting success rates of 79% at 1 year using Molteno GDIs and 77% using Ahmed GDIs (Hill et al. 1993; Papadaki et al. 2007). Chawla et al. (2013) demonstrated good long-term survival rates of 5FU-enhanced trabeculectomy in patients with uveitic glaucoma, comparable with results for primary openangle glaucoma. However, they reported that patients under 30 years of age were at a higher risk for failure and 50% in this age group went on to require GDI surgery. For the Baerveldt GDI in this study, we found similar success rates for those patients under and above 30 years of age. When we look at the result of the previous studies and combine these results with our findings, we could advise a primary Baerveldt GDI for uveitic glaucoma in patients under 30 years of age. In older patients, a trabeculectomy would be a reasonable first surgical option in the management of uncontrolled uveitic glaucoma. Subsequently, a Baerveldt GDI can still be used in the future if needed.