Glaucoma is one of the most common sight-threatening eye disorders and one of the main causes of irreversible blindness worldwide. The current therapies focusing on reducing intraocular pressure (IOP) are often insufficient to prevent the progression of the disease, so the therapeutic management of glaucoma remains a challenge. The aim of this study was to evaluate the neuroprotective, IOP-lowering independent effects of a nutritional supplement containing forskolin, homotaurine, spearmint extract and vitamins of the B group in a model of acute glaucoma developed in mice. Glaucoma was induced in adult wild-type C57BL/6J mice by transient elevation of IOP. The dietary supplement, branded as Gangliomix® (125 mg/kg/day), was administered by oral gavage for 17 days and ocular hypertension was induced on the 10th day of treatment. A histological analysis of the retinas was performed and RGC survival was evaluated with fluorogold labeling and Brn3a immunostaining on wholemount and retinal sections. Expression of alpha-spectrin, caspase-3, PARP-1 and GFAP was studied with western blotting or immunofluorescence. A significant increase in RGC survival was reported in the retina of mice treated with the dietary supplement as compared to vehicle-treated animals. The observed neuroprotection was associated with a calpain activity decrease, reduction in caspase-3 and PARP-1 activation, and prevention of GFAP upregulation. These effects were independent from the hypotensive effects of the supplement. Altogether, our data suggest that the dietary supplementation with forskolin, homotaurine, spearmint extract and vitamins of the B group supports RGC survival and may offer beneficial effects in glaucoma patients in combination with the currently used IOP-lowering therapy.
Purpose: Diabetic retinopathy (DR) is one of the most serious complications of diabetes mellitus and a leading cause of vision loss among working‐age population in industrialized countries (1, 2). DR has long been considered a microvascular disease (3). However, more recently, neurodegeneration and neuroinflammation emerged as important determinants in the pathogenesis and evolution of the pathology (4). Autophagy, the main catabolic pathway involved in the degradation and recycling of damaged organelles and macromolecules, plays an important role in the pathophysiology of retina neurodegenerative diseases (5). Here we studied the changes occurring in ex‐vivo cultured retinas under normal and high glucose conditions and focused on the autophagy pathway. Methods: Organotypic retinal culture from C57BL/6J mice were exposed to normal (15 mM) (NG) or high (50 mM) glucose (HG) for 7 days. Neuronal survival and glial activation were studied by immunofluorescence with cell subtype specific antibodies. Protein or mRNA levels of autophagy‐related proteins (LC3, p62, Atg5‐12) and inflammatory markers (GFAP, IL‐1β and IL‐6) were studied by western blotting or quantitative PCR. Results: Loss of the neuronal components and reduction of glial reactivity were observed in the retina maintained in NG for 7 days. These cellular changes were only slightly affected by exposure to HG. However, under these conditions an upregulation of inflammatory related proteins and significant changes in the autophagic flux were reported. Conclusions: Our preliminary data suggest that autophagy is modulated in organotypic retinal cultures exposed to HG although further experiments are needed to define its pathological role. References. 1. Seewoodhary M. Nurs Stand(2021; 30 36: 71–76. 2. Prokofyeva E and Zrenner E. Ophthalmic Res 2012; 7 47: 171–188. 3. Cheung CY et al. Diabetologia 2017; 60: 1770–1781. 4. Kadłubowska J et al. Curr Neuropharmacol 2016; 14: 831–839. 5. Adornetto A et al. Front Cell Dev Biol 2020; 4;8: 121. This work is supported by grants from the Italian Ministry of Education, University and Research: PRIN 2017 protocol number “2017TSHBXZ_002.”
Dravet syndrome (DS) is an epileptic encephalopathy caused by mutations in the Scn1a gene encoding the α1 subunit of the Nav1.1 sodium channel, which is associated with recurrent and generalized seizures, even leading to death. In experimental models of DS, histological alterations have been found in the brain; however, the retina is a projection of the brain and there are no studies that analyze the possible histological changes that may occur in the disease. This study analyzes the retinal histological changes in glial cells (microglia and astrocytes), retinal ganglion cells (RGCs) and GABAergic amacrine cells in an experimental model of DS (Syn-Cre/Scn1aWT/A1783V) compared to a control group at postnatal day (PND) 25. Retinal whole-mounts were labeled with anti-GFAP, anti-Iba-1, anti-Brn3a and anti-GAD65/67. Signs of microglial and astroglial activation, and the number of Brn3a+ and GAD65+67+ cells were quantified. We found retinal activation of astroglial and microglial cells but not death of RGCs and GABAergic amacrine cells. These changes are similar to those found at the level of the hippocampus in the same experimental model in PND25, indicating a relationship between brain and retinal changes in DS. This suggests that the retina could serve as a possible biomarker in DS.
Purpose: Metformin, a biguanide used to treat diabetes, reduced neuroinflammation in vitro and in vivo and resulted neuroprotective in experimental Parkinson's disease. Metformin has also recently been shown to promote neurogenesis (1). The study aims to evaluate the putative neuroprotective effect of metformin in glaucomatous diabetic patients. Methods: For this retrospective pilot study, clinical notes of glaucomatous diabetic patients of the ophthalmological department of the University Hospital of Rome Tor Vergata were reviewed. Among all, 15 patients were compliant with the inclusion criteria. Patients were then divided into 2 sub‐groups: the Glaucoma group treated with metformin (n = 16 eyes) and the Glaucoma group treated with insulin (n = 14 eyes). Any glaucoma treatment was accepted with exception of brimonidine, citicoline, and coenzyme Q10. Patients must have performed in their clinical history two 24‐2 visual field examinations carried out 6 months apart. Results: Patients were homogeneous in terms of age (p = 0.09) and gender (p > 0.73). Metformin and Insulin groups were homogeneous in terms of Mean Deviation (MD) and Pattern Standard Deviation (PSD) at baseline (T0) (p = 0.70 and p = 0.73 respectively). After 6 months (T1) MD did not change significantly in the metformin group (p = 0.64). On the contrary, at T1 MD significantly worsened in the Insulin group (p = 0.01). No difference was found in terms of PSD in both groups. The visual field Index did not change in the Metformin group while significantly worsened in the Insulin group (p = 0.03). Conclusions: This study suggests for the first time a possible neuroprotective effect of metformin in glaucomatous diabetic patients. Patients under Metformin did not show a worsening of the visual field test in 6 months. Conversely, patients under Insulin worsened. Other prospective are required to confirm our results. Reference 1. Rotermund C, Machetanz G, Fitzgerald JC. The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front Endocrinol (Lausanne). 2018; 9: 400. doi: 10.3389/fendo.2018.00400. PMID: 30072954; PMCID: PMC6060268.
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