Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage

Abstract

Our purpose was to find a method to create a large animal model of inducible photoreceptor damage. To this end, we tested in domestic swine the efficacy of two chemical toxins, known to create photoreceptor damage in other species: Iodoacetic Acid (IAA) and Sodium Iodate (NaIO3). Intravenous (IV) administration of NaIO3 up to 90 mg/kg had no effect on retinal function and 110 mg/kg was lethal. IV administration of IAA (5 – 20 mg/kg) produced concentration dependent changes in visual function as measured by full field and multi-focal electroretinograms (ffERG and mfERG), and 30 mg/kg IAA was lethal. The IAA-induced effects measured at two weeks were stable through eight weeks post-injection, the last time point investigated. IAA at 7.5, 10, and 12 mg/kg produce a concentration-dependent reduction in both ffERG b-wave and mfERG N1 – P1 amplitudes compared to baseline at all post-injection times. Comparisons of dark- and light-adapted ffERG b-wave amplitudes show a more significant loss of rod relative to cone function. The fundus of swine treated with ≥10 mg/kg IAA was abnormal with thinner retinal vessels and pale optic discs, and we found no evidence of bone spicule formation. Histological evaluations show concentration-dependent outer retinal damage that correlates with functional changes. We conclude that NaIO3, is not an effective toxin in swine. In contrast, IAA can be used to create a rapidly inducible, selective, stable and concentration-dependent model of photoreceptor damage in swine retina. Because of these attributes this large animal model of controlled photoreceptor damage should be useful in the investigation of treatments to replace damaged photoreceptors.

Functional evaluation of iodoacetic acid induced photoreceptor degeneration in the cat

“…The IAA has been extensively used as an effective tool to selectively eliminate retinal photoreceptors in a variety of species for the last 60 years [1,3,4,10,11,14,22]. As observed in other species, the toxic effects of IAA treatment are dose dependent.…”

“…However, this method is technically challenging and the dosage of IAA for complete rods and cones removal remains to be determined. It was reported that, after a swine received a single injection of IAA via ear vein (20 mg kg 1 ), at two weeks post-IAA there was no rod-or cone-driven ERG response [11]. Thus, it is plausible that ear vein injection is more effective than limb vessel delivery.…”

“…However, at the same time the inner retina and central visual system are well preserved, which is a similar case that could be found in retinitis pigmentosa (RP) and age related macular degenerations (AMD) of human. By intravenous delivery of IAA via ear vein, it has been demonstrated that IAA could quickly produce a massive photoreceptor depletion in large mammals such as swine and results in severe visual impairment whereas retinal ganglion cells are spared [10,11].…”

Genetically Engineered Pig Models for Human Diseases

“…In many cases, wild-type pigs are being used as models already. Wild-type pigs are particularly useful for studying cardiovascular disease (2), atherosclerosis (3), cutaneous pharmacology (4), wound repair (5), cancer (6), diabetes (7), and ophthalmology (8). In many cases, they are the species of choice for translational medicine (9, 10).…”

1H NMR Spectroscopy Characterization of Porcine Vitreous Humor in Physiological and Photoreceptor Degeneration Conditions

“…22 To date, several porcine models of photoreceptor degeneration have been proposed, 23,24 including the transgenic miniature swine, for example, the TgP23H model of retinitis pigmentosa, 24 or induced by an intravenous injection of iodoacetic acid (IAA). 21,25,26 The latter chemical compound causes an inhibition of anaerobic glycolysis through the reaction with the glyceraldehyde-3-phosphate dehydrogenase. 27 Photoreceptors are affected by IAA injection in a dosedependent manner (assessed between 7.5 and 12 mg/kg), with a decrease in production of energy and eventually death.…”