The Role of Diet, Micronutrients and the Gut Microbiota in Age-Related Macular Degeneration: New Perspectives from the Gut\u207bRetina Axis.

Age-related macular degeneration (AMD) is a complex multifactorial disease and the primary cause of legal and irreversible blindness among individuals aged 6565 years in developed countries. Globally, it affects 30\u207b50 million individuals, with an estimated increase of approximately 200 million by 2020 and approximately 300 million by 2040. Currently, the neovascular form may be able to be treated with the use of anti-VEGF drugs, while no effective treatments are available for the dry form. Many studies, such as the randomized controlled trials (RCTs) Age-Related Eye Disease Study (AREDS) and AREDS 2, have shown a potential role of micronutrient supplementation in lowering the risk of progression of the early stages of AMD. Recently, low-grade inflammation, sustained by dysbiosis and a leaky gut, has been shown to contribute to the development of AMD. Given the ascertained influence of the gut microbiota in systemic low-grade inflammation and its potential modulation by macro- and micro-nutrients, a potential role of diet in AMD has been proposed. This review discusses the role of the gut microbiota in the development of AMD. Using PubMed, Web of Science and Scopus, we searched for recent scientific evidence discussing the impact of dietary habits (high-fat and high-glucose or -fructose diets), micronutrients (vitamins C, E, and D, zinc, beta-carotene, lutein and zeaxanthin) and omega-3 fatty acids on the modulation of the gut microbiota and their relationship with AMD risk and progression

Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death

Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are coupled to neuronal NOX2 activation is not well understood. Here, we identify a signaling pathway coupling NMDA receptor activation to NOX2 activation in primary neuron cultures. Calcium influx through the NR2B subunit of NMDA receptors leads to the activation of phosphoinositide 3-kinase (PI3K). Formation of phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) by PI3K activates the atypical protein kinase C, PKC zeta (PKCχf), which in turn phosphorylates the p47phox organizing subunit of neuronal NOX2. Calcium influx through NR2B-containing NMDA receptors triggered mitochondrial depolarization, NOX2 activation, superoxide formation, and cell death. However, equivalent magnitude calcium elevations induced by ionomycin did not induce NOX2 activation or neuronal death, despite causing mitochondrial depolarization. The PI3K inhibitor wortmannin prevented NMDA-induced NOX2 activation and cell death, without preventing cell swelling, calcium elevation, or mitochondrial depolarization. The effects of wortmannin were circumvented by exogenous supply of the PI3K product, PI(3,4,5)P3, and by transfection with protein kinase M, a constitutively active form of PKCχ. These findings demonstrate that superoxide formation and excitotoxic neuronal death can be dissociated from mitochondrial depolarization, and identify a novel role for PI3K in this cell death pathway. Perturbations in this pathway may either increase or decrease superoxide production in response to NMDA receptor activation, and may thereby impact neurological disorders, in which excitotoxicity is a contributing factor. © 2013 Macmillan Publishers Limited All rights reserved

Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death.

Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are coupled to neuronal NOX2 activation is not well understood. Here, we identify a signaling pathway coupling NMDA receptor activation to NOX2 activation in primary neuron cultures. Calcium influx through the NR2B subunit of NMDA receptors leads to the activation of phosphoinositide 3-kinase (PI3K). Formation of phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) by PI3K activates the atypical protein kinase C, PKC zeta (PKCζ), which in turn phosphorylates the p47(phox) organizing subunit of neuronal NOX2. Calcium influx through NR2B-containing NMDA receptors triggered mitochondrial depolarization, NOX2 activation, superoxide formation, and cell death. However, equivalent magnitude calcium elevations induced by ionomycin did not induce NOX2 activation or neuronal death, despite causing mitochondrial depolarization. The PI3K inhibitor wortmannin prevented NMDA-induced NOX2 activation and cell death, without preventing cell swelling, calcium elevation, or mitochondrial depolarization. The effects of wortmannin were circumvented by exogenous supply of the PI3K product, PI(3,4,5)P3, and by transfection with protein kinase M, a constitutively active form of PKCζ. These findings demonstrate that superoxide formation and excitotoxic neuronal death can be dissociated from mitochondrial depolarization, and identify a novel role for PI3K in this cell death pathway. Perturbations in this pathway may either increase or decrease superoxide production in response to NMDA receptor activation, and may thereby impact neurological disorders, in which excitotoxicity is a contributing factor

Tat-NR2B9c prevents excitotoxic neuronal superoxide production

The Tat-NR2B9c peptide has shown clinical efficacy as a neuroprotective agent in acute stroke. Tat-NR2B9c is designed to prevent nitric oxide (NO) production by preventing postsynaptic density protein 95 (PSD-95) binding to N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase; however, PSD-95 is a scaffolding protein that also couples NMDA receptors to other downstream effects. Here, using neuronal cultures, we show that Tat-NR2B9c also prevents NMDA-induced activation of neuronal NADPH oxidase, thereby blocking superoxide production. Given that both superoxide and NO are required for excitotoxic injury, the neuroprotective effect of Tat-NR2B9c may alternatively be attributable to uncoupling neuronal NADPH oxidase from NMDA receptor activation