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| December 2005 | Inside IOVS | Volume 46/12 |
Transscleral-RPE Permeability of PEDF Protein
Current ocular polypeptide delivery approaches are, for the most part, bioengineered DNA viral vectors that use intraocular routes. Amaral et al. (p. 4383) explored direct delivery to the choroid and retina of pigment epithelium-derived factor (PEDF), an antiangiogenic and neurotrophic protein. They demonstrate the permeability properties of the sclera and choroid/RPE to PEDF protein and its structurally-related counterpart ovalbumin. Upon subconjunctival delivery, these relatively large proteins traversed the sclera-choroid-RPE layers to reach the retina. Their conclusions suggest that subconjunctival routes of PEDF protein delivery offer novel, feasible, and minimally invasive means for administration in the clinic.
A New Function for Mitochondria in the Extraocular Muscles
Mitochondria are particularly abundant in the extraocular muscles, supposedly in response to the metabolic demands imposed by the fast and constant activity of these muscles. Andrade et al. (p. 4541) have now demonstrated an additional role for these organelles. By regulating intracellular calcium levels, mitochondria influence moment-to-moment contractile function and increase the dynamic range of the extraocular muscles. This novel function impacts the control of force production by the oculomotor system and may be also important for matching metabolic demand with supply, including the activation of a unique genetic program to sustain mitochondrial content in the extraocular muscles.
Specificity of the Steady-State VEP Vernier Acuity in Amblyopia
Chen et al. (p. 4563) present a visual evoked potential (VEP) measure of vernier acuity suitable for use in pre-verbal patients. The stimulus used contains both vernier offset and motion cues, and there is a potential confounding of motion responses with vernier responses, especially in patients who have asymmetric motion VEPs. The authors show that motion confounds are minimal in a group of patients with large motion asymmetries. They also show, using control stimuli, that motion confounds are minimal in children with untreated amblyopia. The results suggest that the technique may be used as a valid measure of position acuity in non-verbal individuals.
Diurnal Variation of Optic Nerve Head Blood Flow
Sehi et al. (p. 4581) report that in untreated early glaucoma, the mean optic nerve head blood flow is autoregulated in response to diurnal fluctuation of the ocular perfusion pressure. However, they found that the autoregulatory mechanism was not consistent across the nerve head as there were small locations, mostly in the temporal sector, which did not show autoregulation during the day. The blood flow fluctuation in these locations was associated with the change in systolic blood pressure and ocular perfusion pressure. This may suggest that regional susceptibility of the nerve head in specific quadrants precedes glaucomatous optic nerve damage.
Serotonin 5-HT2 Receptor Agonist Enhances Uveoscleral Outflow in Monkey Eyes
Serotonin has been postulated to be involved in modulating aqueous humor dynamics, but until recently its specific role has been elusive. Gabelt et al. (p. 4691) have established that the intraocular pressure lowering activity of R-DOI, a selective serotonin 5-HT2 agonist, is due primarily to an increase in uveoscleral outflow. This linkage has implications for a greater understanding of aqueous humor dynamics and for the management of glaucoma and is reminiscent of the mechanism by which FP prostaglandins lower IOP.
Parapapillary Retina is Protected from Degeneration in ABCA4 Disease
ABCA4-associated retinal degenerations like Stargardt disease or cone-rod dystrophy show a centrifugal gradient of disease severity, with macular photoreceptors and RPE having greater vulnerability than the peripheral retina. Cideciyan et al. (p. 4739) show that the parapapillary retina forms an exception to this gradient. Using autofluorescence imaging, they demonstrate the preserved region to be an annulus, at least 0.6 mm wide, surrounding the optic nerve head. The spared region has important implications in terms of visual function: patients who have lost central vision use the parapapillary retina as the preferred fixation locus. This study suggests that the retina between the fovea and optic nerve head serves as a convenient, accessible and informative region for structural and functional studies to determine natural history or outcome of therapy in ABCA4 disease.
Matrix Metalloproteinase Activation and Retinal Ganglion Cell Death
NMDA receptor overstimulation leads to formation of nitric oxide (NO) via neuronal NO synthase (nNOS) and subsequent cell death. Matrix metalloproteinases (MMPs), representing endopeptidases that remodel tissues, are important in retinal diseases. Manabe et al. (p. 4747) demonstrate that increased MMP-9 activity occurs primarily in retinal ganglion cells (RGCs) after NMDA injection. They also found that MMPs appear to be S-nitrosylated, and MMP activation is reduced in nNOS-deficient mice. MMP inhibitors protect RGCs from excitotoxic insult via NO-activated MMP-9, suggesting that an extracellular proteolytic pathway contributes to RGC death. These results may lead to new treatments of retinal diseases.
Inhibition of EphB4-EphrinB2 Signaling Inhibits Choroidal Neovascularization
The EphB4-EphrinB2 receptor tyrosine kinases play critical roles in development and specification of venous versus arterial endothelial phenotypes; however, little is known about their role in the adult circulation. In this issue, He et al. (p. 4772) show that dominant negative inhibition of EphB4-EphrinB2 signaling using monomeric soluble extracellular domain of EphB4 significantly inhibits the development of experimental choroidal neovascularization . This study demonstrates a role for EphB4-EphrinB2 in adult ocular wound healing and provides a novel target for therapeutic intervention for choroidal neovascularization.
Riluzole Reduces Vasoproliferative Retinopathy in an Animal Model
Riluzole is an FDA-approved drug for amyotrophic lateral sclerosis. Yoo et al. (p. 4780) report that riluzole, at concentrations attainable in humans, significantly inhibits VEGF-triggered PKCb activation and cell proliferation in endothelial cell cultures. Moreover, riluzole reduced the severity of abnormal vessel formation in a rat model of retinopathy of prematurity (ROP). Since riluzole has been already widely used in human patients with a favorable side effect profile, its effects in proliferative retinopathies, including diabetic retinopathy, might be examined. The results highlight the possibility that currently marketed drugs may have potentially beneficial effects in other apparently unrelated diseases.
IGF1-R and c-MET as Prognostic Tools in Uveal Melanoma
Uveal melanoma metastasizes preferentially to the liver. An altered IGF-1R and c-Met expression in uveal melanoma may act to enhance cell growth and tumor progression. Economou et al. (p. 4372) investigated the c-Met and IGF-1R immunoreactivity of 132 cases of paraffin-embedded primary uveal melanomas. Both of these receptors were variably expressed, and a high expression was associated with a decreased survival in this disease. The prognostic value of IGF-1R was stronger than currently used prognostic parameters like tumor cell type and tumor diameter. The strong correlation between IGF-1R expression and melanoma-specific mortality points to the use of IGF-1R as a prognostic tool.
Palisade Endings in Extraocular Muscles are Cholinergic
Palisade endings are nervous end organs unique to the extraocular muscles (EOMs) of mammals and man. So far, palisade endings have been considered to be sensory organs providing important information about the eye position. Konakci et al. (p. 4548) analyzed the molecular characteristics of palisade endings in EOMs of a primate species (monkey). They showed that palisade endings are cholinergic structures indicating an effector function of this EOM specific organ. As palisade endings are also present in human EOMs, these novel data of palisade endings in a primate species may also be of interest for strabismus surgery.
Psychophysical Abnormalities in Carriers of Leber Hereditary Optic Neuropathy
Leber hereditary optic neuropathy (LHON) - a maternally inherited mitochondrial disorder that causes sudden and permanent bilateral loss of central vision in young adults – may be present subclinically in asymptomatic carriers. In a psychophysical study, Ventura et al. (p. 4809) report that asymptomatic carriers of the 11778 mitochondrial DNA mutation show losses of spatial contrast sensitivity to red-green, blue-yellow and achromatic gratings. These losses may reflect ongoing damage to the neurons affected by LHON – the ganglion cells of the papillomacular bundle. Longitudinal studies are necessary to know if they are predictive of the acute phase or are a mild consequence of carrying the mutation.
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