Ischemic Conditioning Protects from Axoglial Alterations of the Optic Pathway Induced by Experimental Diabetes in Rats

Diego C. Fernandez,Ruth E. Rosenstein,Hernán J. Aldana Marcos,Laura A. Pasquini,Damián Dorfman,Tailoi Chan-Ling

doi:10.1371/journal.pone.0051966

Abstract

Diabetic retinopathy is a leading cause of blindness. Visual function disorders have been demonstrated in diabetics even before the onset of retinopathy. At early stages of experimental diabetes, axoglial alterations occur at the distal portion of the optic nerve. Although ischemic conditioning can protect neurons and synaptic terminals against ischemic damage, there is no information on its ability to protect axons. We analyzed the effect of ischemic conditioning on the early axoglial alterations in the distal portion of the optic nerve induced by experimental diabetes. Diabetes was induced in Wistar rats by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mm Hg for 5 min; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. The application of ischemia pulses prevented a deficit in the anterograde transport from the retina to the superior colliculus, as well as an increase in astrocyte reactivity, ultraestructural myelin alterations, and altered morphology of oligodendrocyte lineage in the optic nerve distal portion at early stages of experimental diabetes. Ischemia tolerance prevented a significant decrease of retinal glutamine synthetase activity induced by diabetes. These results suggest that early vision loss in diabetes could be abated by ischemic conditioning which preserved axonal function and structure.

Highlights

Diabetic retinopathy (DR) is one of the most common and feared complications of diabetes
The cholera toxin b-subunit (CTB)-intensity was quantified for each section and a thermal scale was applied for a clear representation of the CTB-staining pattern
The present results indicate that ischemic conditioning, which showed no effect per se, prevented a deficit in the anterograde transport from the retina to the superior colliculus (SC), and the decrease in axon number and myelination, as well as the alterations in astrocytes and OL lineage in the distal portion of the optic nerve (ON) induced by experimental diabetes

Summary

Introduction

Diabetic retinopathy (DR) is one of the most common and feared complications of diabetes This disease is a leading cause of blindness in people of working age in industrialized countries and affects the daily lives of millions of people. DR has been considered to be a microcirculatory disease of the retina, it is becoming increasingly clear that neuronal cells of the retina are affected by diabetes, resulting in dysfunction and even degeneration of some neuronal cells [2]. These neurodegenerative changes include increased apoptosis of retinal ganglion cells (RGCs), glial cell reactivity, microglial activation, and altered glutamate metabolism [3]. We have recently shown a significant loss of ganglion cell layer (GCL) cells and an increase in the number of apoptotic RGCs 15 weeks after diabetes induction by streptozotocin (STZ) injection [7]

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