Citicoline ameliorates the effect of elevated intraocular pressure on functional connectivity in the visual pathway

Abstract

Purpose : Currently, lowering intraocular pressure (IOP) is the only clinically proven way to treat glaucoma. However, glaucomatous neurodegeneration may still continue after IOP is reduced. Recent studies suggest that citicoline may improve visual outcomes in glaucoma patients, yet its underlying mechanisms remain poorly understood. Here we examined the effects of IOP elevation on visuomotor response and brain functional connectivity (FC) with and without citicoline treatment.

Methods : Eighty-two Long Evans rats were divided into 6 groups and received acute or chronic IOP elevation to the right eye. Acute IOP elevation was induced by anterior chamber perfusion for 60min at 15mmHg (sham, n=10), 40mmHg (mild, n=12) or 130mmHg (severe, n=12). Chronic IOP elevation was induced by intracameral injection of an optically clear crosslinking hydrogel. A subset of animals (treated, n=19) received daily oral citicoline treatment (500mg/kg) for 7 days prior to, and every 48 hours for 14 days after gel injection, while another 19 rats were not treated orally (untreated). Ten rats received intracameral injection of buffer solution as sham control. IOP and visual acuity (VA) were measured by tonometry and optokinetics, respectively, for 5 weeks. Resting-state FC MRI was acquired at 9.4 Tesla covering the visual brain nuclei at 5 weeks after IOP elevation induction.

Results : Hydrogel injection significantly increased IOP for 5 weeks, with no difference between citicoline-treated (25.8±0.4mmHg) and untreated (26.4±0.5mmHg) groups (p>0.05). Severe acute IOP elevation resulted in lower VA [0.21±0.03cycles/degree (c/d)] than mild acute IOP elevation (0.38±0.03c/d) at week 5 (p<0.05), whereas VA of the citicoline-treated chronic group (0.31±0.01c/d) was higher than the untreated group (0.26±0.01c/d) (p<0.05). Larger magnitude of acute IOP elevation caused larger FC differences in subcortical visual nuclei (Fig. 1). In the chronic IOP elevation groups, untreated animals showed significantly decreased cortico-collicular, cortico-geniculate and subcortical FC, while citicoline treatment appeared to preserve or improve such FC (Fig. 2).

Conclusions : Increasing magnitude and duration of IOP elevation caused differential effects on visuomotor behavior and functional brain integrity, whereas citicoline ameliorated the effects. These findings merit further investigation into treating glaucoma beyond lowering IOP.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.