A Neurobehavioral Analysis of the Prevention of Visual Impairment in the DBA/2J Mouse Model of Glaucoma

Abstract

PURPOSE. Timoptic-XE treatment was used to examine the relationship between age-related changes in intraocular pressure (IOP), retinal cell loss, visual ability, and neuronal labeling in the superior colliculus in the DBA/2J mouse model of pigmentary glaucoma.METHODS. Mice were administered Timoptic-XE (0.0%, 0.25%, or 0.50%) daily from 9 weeks to 12 months of age. Visual ability and IOP were evaluated at 3, 6, 9, and 12 months of age. Mice from each group were then given intraocular injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), and estimates of the number of cells in the ganglion cell layer of the retina, WGA-HRP transneural labeling of cells, cell count, and cross-sectional area of Nissl-stained cells in the superior colliculus were obtained. RESULTS.Mice treated with 0.50% and 0.25% Timoptic-XE maintained a high level of performance in behavioral vision tasks, while 12-month-old untreated mice (0.0% Timoptic-XE) exhibited impaired visual performance. Timoptic-XE therapy reduced IOP and cell loss in the ganglion cell layer of the retina and prevented somal shrinkage and the decrease in WGA-HRP transneural labeling in the superior colliculus that occurred in untreated mice at 12 months of age.CONCLUSIONS. This study provides a comprehensive assessment of the efficacy of Timoptic-XE in DBA/2J mice by correlating age-related visual system changes in the retina and brain with changes in IOP and visual ability. These results showed that reducing IOP not only rescued retinal ganglion cell atrophy but also restored visual function and altered patterns of neurodegeneration that occur with blindness. (Invest Ophthalmol Vis Sci. 2012;53:5956-5966) DOI:10.1167/iovs.12-10020 G laucoma is the second leading cause of blindness after cataracts.1 Clinically, glaucoma is characterized by ''cupping'' of the optic nerve head and visual deterioration due to the progressive loss of retinal ganglion cells and axons. 2,3 Pigmentary glaucoma is caused by the liberation of melanin pigment through the mechanical disruption of the posterior iris by the lens zonules. When pigment accumulates within the anterior segment structures and the trabecular meshwork, it blocks aqueous outflow, resulting in an increase in intraocular pressure (IOP) and subsequent damage to the optic nerve and retinal ganglion cell death. 4,5 High IOP (>21 mm Hg) is the strongest and most consistent risk factor for glaucoma; and although not all patients exhibit ocular hypertension, the probability of retinal ganglion cell loss and optic nerve damage increases exponentially with higher IOP, thus all current glaucoma treatments involve the reduction of IOP.2,6 Timolol maleate, a nonselective b 1 and b 2 adrenergic receptor antagonist, applied topically to the eye, decreases IOP by reducing aqueous humor production by blocking of breceptors on the ciliary epithelium. Timolol maleate (Timoptic) has been viewed as the gold standard therapy for glaucoma 7 and is used as the clinical benchmark in ocular hypotensive medication-registr...

The contribution of the sclera and lamina cribrosa to the pathogenesis of glaucoma

“…Mammalian eyes subjected to weeks to months of IOP elevation undergo neuronal, glial, and connective tissue alterations that are phenotypically similar to humans (Morrison et al, 1990(Morrison et al, , 1997Soto et al, 2011). In addition, IOP lowering slows RGC loss in animal model eyes (Wong and Brown, 2012) as it does in humans. A monkey model of elevated IOP (Gaasterland and Kupfer, 1974; has been extensively used to study glaucoma changes in the retina, ONH (Morrison et al, 1990), and brain (Weinreb et al, 1994).…”

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

“…In D2 mice, high IOP causes RGC loss that can be prevented by IOP-lowering interventions (28)(29)(30)(31). Importantly, glaucoma in D2 mice is an axonopathy, as evidenced by substantial RGC protection in the presence of the Wallerian degeneration slow allele (D2.Wld s ) (20).…”

Effect of Antiglaucoma Medicine on Intraocular Pressure in DBA/2J Mice

“…However, we did not note any adverse effects to drugs during our investigation [21]. Previous reports about DBA/2J mice evaluated the effects of clinically used antiglaucoma medicine [21,27]. Schuettauf et al [21] reported that daily administration of timolol eye drops could prevent retinal ganglion cell loss.…”

“…However, they did not refer to IOP changes during their experiments. Another report showed that daily administration of Timoptic XE eye drops for 12 months resulted in retinal ganglion cell survival with IOP reduction [27]. Surprisingly, there is no report describing the short-term IOP-lowering effects of antiglaucoma medicines specifically concerning DBA/2J.…”