Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models.

Huilan Zeng,Alina V Dumitrescu,Oliver W Gramlich,Markus H Kuehn,Benjamin W Elwood,David Wadkins

doi:10.3390/biom12020281

Abstract

Neuroinflammation significantly contributes to the pathophysiology of several neurodegenerative diseases. This is also the case in glaucoma and may be a reason why many patients suffer from progressive vision loss despite maximal reduction in intraocular pressure. Pioglitazone is an agonist of the peroxisome proliferator-activated receptor gamma (PPARγ) whose pleiotrophic activities include modulation of cellular energy metabolism and reduction in inflammation. In this study we employed the DBA2/J mouse model of glaucoma with chronically elevated intraocular pressure to investigate whether oral low-dose pioglitazone treatment preserves retinal ganglion cell (RGC) survival. We then used an inducible glaucoma model in C57BL/6J mice to determine visual function, pattern electroretinographs, and tracking of optokinetic reflex. Our findings demonstrate that pioglitazone treatment does significantly protect RGCs and prevents axonal degeneration in the glaucomatous retina. Furthermore, treatment preserves and partially reverses vision loss in spite of continuously elevated intraocular pressure. These data suggest that pioglitazone may provide treatment benefits for those glaucoma patients experiencing continued vision loss.

Highlights

Glaucoma is the leading cause of irreversible blindness in the world
In this study we evaluate the ability of pioglitazone to morphologically protect retinal ganglion cell (RGC) and optic nerve axons and to preserve visual function in two distinct pre-clinical mouse models of glaucoma
In order to determine if pioglitazone provides a protective effect on RGCs, mice (n = 20)

Summary

Introduction

Glaucoma is the leading cause of irreversible blindness in the world. The disease is characterized by optic nerve head changes, narrowing of the visual field and decreased vision caused by dysfunction and death of retinal ganglion cells (RGCs) [1,2]. Reducing the intraocular pressure (IOP) in patients by medical or surgical means is currently the only approved treatment and while this approach does reduce the rate of disease progression, vision continues to be lost in many patients [3]. These individuals would benefit from neuroprotective regimens that directly target RGCs, but despite considerable research efforts such therapies are not currently available. The difficulty in developing effective neuroprotective treatments in glaucoma is due, at least in part, to the multifactorial etiology of the disease. Factors including disturbances in ocular blood flow, immune-mediated processes, oxidative stress, metabolic vulnerability, and genetic predisposition have all been implicated in causing the disease [4–9]

Methods

Results

Discussion

Conclusion