full-circle-cauterization-limbal-vascular-plexus-for-surgically

Full-Circle Cauterization of Limbal Vascular Plexus for Surgically Induced Glaucoma in Rodents

Glaucoma, the second leading cause of blindness worldwide, is a heterogeneous group of ocular disorders characterized by structural damage to the optic ...

Universidade Federal do Rio de Janeiro

Diabetic retinopathy is the leading cause of acquired blindness in working-age individuals. Recent work has revealed that neurodegeneration occurs earlier than vascular insult and that distal optic nerve damage precedes retinal degeneration and vascular insult. Since we have shown that optic nerve degeneration is reduced after optic nerve crush in Galectin-3 knockout (Gal-3 -/-) mice, we decided to investigate whether Gal-3 -/- could relieve inflammation and preserve both neurons and the structure of the retina and optic nerve following 8 weeks of diabetes. Diabetes was induced in 2-month-old male C57/bl6 WT or Gal-3 -/- mice by a single injection of streptozotocin (160 mg/kg). Histomorphometric retinal analyses showed no gross difference, except for a reduced number of retinal ganglion cells in WT diabetic mice, correlated to increased apoptosis. In the optic nerve, Gal-3 -/- mice showed reduced neuroinflammation, suggested by the smaller number of Iba1+ cells, particularly the amoeboid profiles in the distal end. Furthermore, iNOS staining was reduced in the optic nerves of Gal-3 -/- mice, as well as GFAP in the distal segment of the optic nerve. Finally, optic nerve histomorphometric analyses revealed that the number of myelinated fibers was higher in the Gal-3 -/- mice and myelin was more rectilinear compared to WT diabetic mice. Therefore, the present study provided evidence that Gal-3 is a central target that stimulates neuroinflammation and impairs neurological outcomes in visual complications of diabetes. Our findings provide support for the clinical use of Gal-3 inhibitors against diabetic visual complications in the near future.

Lack of Galectin-3 attenuates neuroinflammation and protects the retina and optic nerve of diabetic mice.

Glaucoma is a neurodegenerative disorder characterized by the progressive functional impairment and degeneration of the retinal ganglion cells (RGCs) and their axons, and is the leading cause of irreversible blindness worldwide. Current management of glaucoma is based on reduction of high intraocular pressure (IOP), one of its most consistent risk factors, but the disease proceeds in almost half of the patients despite such treatments. Several experimental models of glaucoma have been developed in rodents, most of which present shortcomings such as high surgical invasiveness, slow learning curves, damage to the transparency of the optic media which prevents adequate functional assessment, and variable results. Here we describe a novel and simple method to induce ocular hypertension in pigmented rats, based on low-temperature cauterization of the whole circumference of the limbal vascular plexus, a major component of aqueous humor drainage and easily accessible for surgical procedures. This simple, low-cost and efficient method produced a reproducible subacute ocular hypertension with full clinical recovery, followed by a steady loss of retinal ganglion cells and optic axons, accompanied by functional changes detected both by electrophysiological and behavioral methods.

A subacute model of glaucoma based on limbal plexus cautery in pigmented rats.

Gangliosides are glycosphingolipids abundantly expressed in the vertebrate nervous system, and are classified into a-, b-, or c-series according to the number of sialic acid residues. The enzyme GD3 synthase converts GM3 (an a-series ganglioside) into GD3, a b-series ganglioside highly expressed in the developing and adult retina. The present study evaluated the visual system of GD3 synthase knockout mice (GD3s ), morphologically and functionally. The absence of b- series gangliosides in the retinas of knockout animals was confirmed by mass spectrometry imaging, which also indicated an accumulation of a-series gangliosides, such as GM3. Retinal ganglion cell (RGC) density was significantly reduced in GD3s mice, with a similar reduction in the number of axons in the optic nerve. Knockout animals also showed a 15% reduction in the number of photoreceptor nuclei, but no difference in the bipolar cells. The area occupied by GFAP-positive glial cells was smaller in GD3s retinas, but the number of microglial cells/macrophages did not change. In addition to the morphological alterations, a 30% reduction in light responsiveness was detected through quantification of pS6-expressing RGC, an indicator of neural activity. Furthermore, electroretinography (ERG) indicated a significant reduction in RGC and photoreceptor electrical activity in GD3s mice, as indicated by scotopic ERG and pattern ERG (PERG) amplitudes. Finally, evaluation of the optomotor response demonstrated that GD3s mice have reduced visual acuity and contrast sensitivity. These results suggest that b-series gangliosides play a critical role in regulating the structure and function of the mouse visual system.

GD3 synthase deletion alters retinal structure and impairs visual function in mice.

Based on our preview evidence that reduced nuclear content of the transcription factor Myc-associated protein X (MAX) is an early event associated with degeneration of retinal ganglion cells (RGCs), in the present study, our purpose was to test whether the overexpression of human MAX had a neuroprotective effect against RGC injury.

Article	Year
Lack of Galectin-3 attenuates neuroinflammation and protects the retina and optic nerve of diabetic mice. Brain research\| PubMed ID: 30016630	2018
A subacute model of glaucoma based on limbal plexus cautery in pigmented rats. Scientific reports\| PubMed ID: 31705136	2019
GD3 synthase deletion alters retinal structure and impairs visual function in mice. Journal of neurochemistry\| PubMed ID: 34081777	2021
Neuroprotective Gene Therapy by Overexpression of the Transcription Factor MAX in Rat Models of Glaucomatous Neurodegeneration. Investigative ophthalmology & visual science\| PubMed ID: 35103748	2022

Carla Andreia Abreu

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