[Iron and age-related macular degeneration: a new track].

Iron has a fundamental role for cell physiology and especially in retina as a cofactor of many pathways of the visual transduction. A tightly regulated homeostasis avoids the accumulation of prooxidant and proinflammatory free iron. A dysfunction of iron retinal homeostasis is associated with many genetic or age-related degenerative diseases such as age-related macular degeneration (AMD).

From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology.

Iron is essential for cell survival and function. It is a transition metal, that could change its oxidation state from Fe to Fe involving an electron transfer, the key of vital functions but also organ dysfunctions. The goal of this review is to illustrate the primordial role of iron and local iron homeostasis in retinal physiology and vision, as well as the pathological consequences of iron excess in animal models of retinal degeneration and in human retinal diseases.

Targeting iron-mediated retinal degeneration by local delivery of transferrin.

Iron is essential for retinal function but contributes to oxidative stress-mediated degeneration. Iron retinal homeostasis is highly regulated and transferrin (Tf), a potent iron chelator, is endogenously secreted by retinal cells. In this study, therapeutic potential of a local Tf delivery was evaluated in animal models of retinal degeneration.

[Iron and regulatory proteins in the normal and pathological retina].

Iron is necessary for cell metabolism, but excess iron can be toxic Iron can generate oxygen free radicals through the Fenton reaction. Iron accumulation has been observed in the retina of patients with age-related macular degeneration (AMD). We have shown its accumulation in photoreceptor segments in two animal models of genetic retinal degeneration (RCS rats and Rd10 mice).

Developmental iron uptake and axonal transport in the retina of the rat.

We examined differently aged postnatal (P) rats for the distribution and uptake of iron in the eye with the main emphasis on iron uptake in the retina. The concentration of iron in the eye was 48 μg/g in rats aged one postnatal day (P1). Then concentration fell to approximately 12 μg/g at P30 and rose to 35 μg/g at P70.

Overexpressed or intraperitoneally injected human transferrin prevents photoreceptor degeneration in rd10 mice.

Purpose: Retinal degeneration has been associated with iron accumulation in age-related macular degeneration (AMD), and in several rodent models that had one or several iron regulating protein impairments. We investigated the iron concentration and the protective role of human transferrin (hTf) in rd10 mice, a model of retinal degeneration.

Methods: The proton-induced X-ray emission (PIXE) method was used to quantify iron in rd10 mice 2, 3, and 4 weeks after birth.

Light-induced retinal degeneration correlates with changes in iron metabolism gene expression, ferritin level, and aging.

Purpose: Retinal degeneration is associated with iron accumulation in several rodent models in which iron-regulating proteins are impaired. Oxidative stress is catalyzed by unbound iron.

Methods: The role of the heavy chain of ferritin, which sequesters iron, in regulating the thickness of the photoreceptor nuclear layer in the 4- and 16-month-old wild-type H ferritin (HFt(+/+)) and heterozygous H ferritin (HFt(+/-)) mice was investigated, before and 12 days after exposure to 13,000-lux light for 24 hours.

FGF1 nuclear translocation is required for both its neurotrophic activity and its p53-dependent apoptosis protection.

Fibroblast growth factor 1 (FGF1) is a differentiation and survival factor for neuronal cells both in vitro and in vivo. FGF1 activities can be mediated not only by paracrine and autocrine pathways involving FGF receptors but also by an intracrine pathway, which is an underestimated mode of action. Indeed, FGF1 lacks a secretion signal peptide and contains a nuclear localization sequence (NLS), which is consistent with its usual intracellular and nuclear localization.

[Distribution of transferrin and transferrin receptor of the type 1 in the process of formation of the rat eye retina in early postnatal ontogenesis].

By the method of indirect immunohistochemistry, distribution of transferrin and of transferrin receptor of the type (TFR1) was studied in the formed rat eye retina at the period of early postnatal ontogenesis (from birth to opening of eyelids). It has been established that the character of distribution of these proteins and intensity of specific staining change dependent on the retina formation stage. Retina of the newborn rat is characterized by diffuse transferrin distribution in nuclear retina layers (in the neuroblast layer--NBL) and in the ganglionic cell layer (GCL) as well as in the eye pigment epithelium (PE); relative immunoreactivity to transferrin is not high.

The protective role of transferrin in Müller glial cells after iron-induced toxicity.

Purpose: Transferrin (Tf) expression is enhanced by aging and inflammation in humans. We investigated the role of transferrin in glial protection.

Methods: We generated transgenic mice (Tg) carrying the complete human transferrin gene on a C57Bl/6J genetic background.

PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular barrier. A model for retinal edema.

VEGF is considered as an important factor in the pathogenesis of macular edema. VEGF induces the rupture of the blood retinal barrier and may also influence the retinal pigment epithelial (RPE) outer retinal barrier. The aim of this work was to analyze the influence of the VEGF receptor pathways in the modulation of the RPE barrier breakdown in vitro and in vivo.

Single-stranded oligonucleotide-mediated in vivo gene repair in the rd1 retina.

Purpose: The aim of this study was to test whether oligonucleotide-targeted gene repair can correct the point mutation in genomic DNA of PDE6b(rd1) (rd1) mouse retinas in vivo.

Methods: Oligonucleotides (ODNs) of 25 nucleotide length and complementary to genomic sequence subsuming the rd1 point mutation in the gene encoding the beta-subunit of rod photoreceptor cGMP-phosphodiesterase (beta-PDE), were synthesized with a wild type nucleotide base at the rd1 point mutation position. Control ODNs contained the same nucleotide bases as the wild type ODNs but with varying degrees of sequence mismatch.

[The teaching of the biology of ageing in France 1990-2005: DEA with the course of speciality of Master Seeks].

In 1990, following an idea arising from an Inserm study section on aging, the Diplôme d'études approfondies (DEA) de Biologie du vieillissement was created. Since then, more than 300 students have followed these courses which cover the cellular mechanisms of aging and associated diseases, from basic causes of aging to CNS and sensory organs aging, as well as nutritional aspects, sarcopenia and osteoporosis, vascular and neuroendocrine aging. More than 150 thesis have been defended and more than a quarter of students has been recruited on permanent positions in French universities and research institutions (10 %) and hospitals (16 %).

Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis.

Purpose: The antiangiogenic effect of an antisense oligodeoxynucleotide (ODN) targeting insulin receptor substrate (IRS)-1 was evaluated on rat corneal neovascularization.

Methods: Eyes with neovessels were treated with subconjunctival injections of IRS-1 antisense oligonucleotide (ASODN), IRS-1 sense ODN (SODN), or PBS. At 8 and 24 hours after the first subconjunctival injection, the expression of IRS-1, VEGF, and IL-1beta mRNA was evaluated.

VP22 light controlled delivery of oligonucleotides to ocular cells in vitro and in vivo.

Purpose: To study VP22 light controlled delivery of antisense oligonucleotide (ODN) to ocular cells in vitro and in vivo.

Methods: The C-terminal half of VP22 was expressed in Escherichia coli, purified and mixed with 20 mer phosphorothioate oligonucleotides (ODNs) to form light sensitive complex particles (vectosomes). Uptake of vectosomes and light induced redistribution of ODNs in human choroid melanoma cells (OCM-1) and in human retinal pigment epithelial cells (ARPE-19) were studied by confocal and electron microscopy.

The LEI/L-DNase II pathway is activated in light-induced retinal degeneration in rats.

Retinal death induced by light seems to be a caspase-independent process. In this work we investigate the LEI/L-DNase II pathway, a caspase-independent pathway, in light-induced retinal degeneration in Fischer rats. Measurement of DNase activity in total retinal extracts of light exposed Fischer rats was performed by analysing a plasmid degradation on an agarose gel.

Iontophoresis: from the lab to the bed side.

Pioneer work on iontophoresis undertaken by David Maurice during the 1970s and 1980s laid the initial groundwork for its potential implementation as a promising ocular therapeutic modality. A better understanding of tissue interactions within the eye during electric current application, along with better designs of drug delivery devices have enabled us to pursue David Maurice's original ideas and take them from the bench to the bed side. In the present study we demonstrate the potential application of an iontophoresis device (Eyegate, Optis, France) for the treatment of certain human eye diseases.

Fibroblast growth factor-2 protects endothelial cells from damage after corneal storage at 4 degrees C.

Background: Since the introduction of cold corneoscleral segment storage prior to keratoplasty there have been continuous efforts to ameliorate the preservation media in order to better maintain the quality of the corneal epi- and endothelium. Recent studies have shown that basic fibroblast growth factor (FGF-2) preserves the viability of, for example, retinal ganglion cells and pigment epithelium cells. Therefore, we investigated the effect of different concentrations of FGF-2 added to a modified Optisol storage medium on endothelial damage after corneal storage at 4 degrees C.

Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy.

Background: Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)-2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy.

Methods And Results: We describe here that COX-2 is induced in retinal astrocytes in human diabetic retinopathy, in the murine and rat model of ischemic proliferative retinopathy in vivo, and in hypoxic astrocytes in vitro.

Delivery of antisense oligonucleotide to the cornea by iontophoresis.

We wished to evaluate the potential of iontophoresis to promote the delivery of antisense oligonucleotides (ODN) directed at the vascular endothelial growth factor (VEGF)-R2 receptor (KDR/Flk) to the cornea of the rat eye. Fluorescence (CY5)-labeled ODNs in phosphate-buffered saline (PBS) (20 microM) were locally administered to rat eyes, and their fate within the anterior segment was studied. Thirty-four male, 5-week-old Wistar rats were used for all experiments.

Apoptosis induced by Na+/H+ antiport inhibition activates the LEI/L-DNase II pathway.

L-DNase II is derived from its precursor leucocyte elastase inhibitor (LEI) by post-translational modification. In vitro, the conversion of LEI into L-DNase II can be induced by incubation of LEI at an acidic pH. In this study, we proposed to analyze the effects of intracellular acidification on this transformation.