Preliminary evaluation of an optomotry system for safety pharmacology applications: effect of sodium iodate on visual acuity in albino and pigmented rats

Sharon Storey, Karen Tse, Qasim Hussain, Jenny McKay, Alison Bigley, Rob Knowles, Dan Heathcote, Jean-Pierre Valentin & Will S. Redfern, Safety Assessment UK, AstraZeneca R&D Alderley Park, Cheshire SK10 4TG, UK.

Numerous drugs affect retinal function in clinical use and may cause toxic damage to one or more cell types (Constable & Pirmohamed, 2004). However, preclinical methods for detecting such effects are cumbersome. Recently, a semi-automated method of assessing the optomotor response in rodents was devised ( Douglaset al., 2005). We have undertaken a preliminary evaluation of its suitability in safety pharmacology applications, and of its ability to detect the retinotoxic effects of sodium iodate in both pigmented (Long Evans) and albino (Han Wistar) rats. Sodium iodate impairs visual acuity in humans, and a dose of 50 mg/kg i.v. has been reported to decrease the amplitude of the electroretinogram in albino rats (Sugimoto et al., 1994).

Male rats (Han Wistar and Long Evans; age range 9-11 weeks; weight range 258-385 g) were tested in an OptoMotry apparatus (CerebralMechanics, Lethbridge, Canada). This is a chamber formed by 4 computer monitors displaying a vertical sine wave grating as a ‘virtual cylinder’, with the rat’s viewpoint at its centre. The grating was rotated at
2 rpm to elicit head tracking movements. Grating frequency was increased until there were no observable head-tracking movements; the highest visible frequency was taken as the threshold of visual acuity, in cycles per degree (c/d). On the following day, rats received an intravenous infusion of either sodium iodate (50 mg/kg; n = 8 per strain) or 0.9% w/v NaCl (aq) (n = 2 per strain). The rats were tested in the OptoMotry apparatus 2 h later, then re-tested daily for a further 3 days. At 7 days post-dose the rats were euthanased and retinae prepared for both light and electron microscopy.

Baseline visual acuities for Han Wistar and Long Evans rats were 0.355 ± 0.007 and 0.530 ± 0.004 c/d, respectively. In Han Wistar rats there was a dramatic loss of visual acuity 2 h after infusion of sodium iodate (0.021 ± 0.021 c/d; P < 0.001 vs. pre-dose), which remained at this level for a further 24 h. There was partial recovery of visual acuity during the subsequent 2 days of testing. In Long Evans rats the reduction in visual acuity was only partial, and developed slowly, reaching a maximal effect at
48 h post dose (0.290 ± 0.017 c/d; P < 0.01 vs. pre-dose), with partial recovery at 72 h. Histopathological analysis revealed diffuse, moderate degeneration of the retinal pigmented epithelial cell layer and degeneration of the outer segments of the photoreceptor layer in both strains of rat.

In conclusion, the OptoMotry system was capable of detecting and quantifying deficits in visual acuity caused by a known retinal toxicant in two strains of rats with different baseline levels of visual acuity. The system enabled repeated measurements over several days, during which partial recovery of function was evident. It therefore offers promise as a potentially useful tool to detect adverse effects of candidate drugs on visual function in rodents, prior to human exposure. Further work is required to assess its sensitivity, specificity and throughput.

Constable S, Pirmohamed M (2004) Exp Opin Drug Saf 3: 249-59.
Douglas RM et al. (2005) Visual Neurosci 22: 677-84.
Sugimoto S et al. (1994) J Toxicol Sci 19: 531-42.