Five week old Sprague Dawley BR outbred albino rats and young mature purebred Beagle dogs, male and female

SIGNALMENT:
Five week old Sprague Dawley BR outbred albino rats and young mature purebred Beagle dogs, male and female

HISTORY:
Representative sections of retina in the rat and dog (with corresponding electron micrograph from one of the dogs) given an ATP-sensitive potassium channel activator once daily by gavage in the highest dose group for 9 months and 8 months respectively. One dog in the high dose group developed visual impairment. High dose dogs developed emesis, loose stools and increased their food consumption and water intake. In the high dose rats, 11 males and two females were found dead or sacrificed in moribund condition.

OPHTHALMOSCOPIC & GROSS PATHOLOGY RESULTS:
In the rat, there was dose-related yellow discoloration of the retina. In the dog, ophthalmologic examination results included yellow or pale discoloration of the fundus, discoloration of the sclera, lack of clarity or cloudiness in the vitreous body, lack of clarity in the retina, and discoloration of the optic nerve. Cells/crystals were evident in the vitreous body; there was a decrease in the size of retinal vessels as well as abnormal responses to the pupillary light, menace, and visual placement tests.

Other gross findings in the dog included discoloration of the mucous membranes, skin and/or toenails, dull, coarse faded haircoat, and a thin appearance.

LABORATORY RESULTS:
Test article-related laboratory findings in the dog included increased serum TSH, increases in T3 and T4, minimal decreases in erythrocyte count, yellow serum, increases in alkaline phosphatase, minimal decreases in serum total protein, albumin and creatinine and dark yellow urine.

Electrocardiographic findings in the dog included changes in T waves (increased amplitude, altered polarity, and spiked or dome-dart appearance), increased amplitude of the Q and R waves and increased amplitude of the S waves.

MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:

  1. Murine retina: Mild multifocal outer retinal (photoreceptors and outer nuclear layer) degeneration (light microscopy)
  2. Nontapetal canine retina: Marked focally extensive retinal degeneration and atrophy with focally extensive retinal detachment and hypertrophy of retinal pigmented epithelium (light microscopy, transmission electron microscopy) Canine retinal pigmented epithelium: Intracytoplasmic membranous inclusions (transmission electron microscopy)

CONTRIBUTOR:
Bristol-Myers Squibb, New Brunswick and Hopewell, NJ, and Mt. Vernon, IN, USA

CONTRIBUTOR'S COMMENTS:

The lesions in the rat and the dog are consistent with degeneration of the outer layers of retina. The different stages of lesions (acute in rat, chronic in dog) can be explained with species variation in pharmacokinetics. The high energy requirements and rapid turnover of the photoreceptors in the outer retina make them susceptible to injury via toxins, light, etc. (Stone et al., 1999, Wilcock, 1993). In the developed mammalian retina, the ability to switch energy sources from aerobic to anaerobic metabolism makes the retina resistent to changes in energy supply (Stone et al., 1999).

Research indicates that ATP-sensitive potassium channels are protective during an ischemic episode (Ettaiche et al., 2001), making it unlikely that the degenerative changes are mechanistically associated with the given compound.

In these studies, the main drug-related change in the retina is thought to be degeneration of photoreceptors. Increased photoreceptor turnover was supported by the membranous inclusions evident in retinal pigmented epithelium (RPE) using transmission electron microscopy in the dog. The combination of photoreceptor degeneration and increased demand on the phagocytic capacity of the RPE may have resulted in focal areas of retinal detachment, hypertrophy of the RPE and further atrophy and disorganization of the outer layers of the retina.

The cause of fundic discoloration evident during the ophthalmoscopic examination was undetermined; one consideration was the accumulation of a drug metabolite which may have resulted in damage to photoreceptors. Tissue distribution studies indicated that compound concentrations in several tissues, including eye, were substantially higher than in plasma for up to 24 hours after administration.

REFERENCES:

  1. Ettaiche M, Heurteaux C, Blondeau N, Borsotto M, Tinel N, Lazdunski M. ATP-sensitive potassium channels (KATP) in retina: a key role for delayed ischemic tolerance. Brain Res 890 (1): 118-129, 2001.
  2. Stone J, Maslim J, Valter-Kocsi K, Mervin K, Bowers F, Chu Y, Barnett N, Provis J, Lewis G, Fisher SK Bisti S, Gargini C, Cervetto L, Merin S, Pe’er J. Mechanisms of Photoreceptor Death and Survival in Mammalian Retina. Prog Ret Eye Res 18 (6): 689-735, 1999.
  3. Wilcock, BP. The Eye and the Ear. In: Pathology of Domestic Animals, Jubb KVF, Kennedy PC, and Palmer N, editors: San Diego: Academic Press, Inc., 502-505, 1993.

 

 

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40X H&E. Treated rat with focal degeneration of outer retina. 

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40X H&E. Control canine nontapetal retina 

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40X H&E.  Treated dog with diffuse marked retinal atrophy and hypertrophy of retinal pigmented epithelium in nontapetal retina.  

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Transmission electron micrograph, 3,600x, Control canine outer tapetal retina

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Transmission electron micrograph, 3,600x. Treated dog with marked degeneration of photoreceptors, outer nuclear layer, and hypertrophy of retinal pigmented epithelium in nontapetal retina.

 

1 Comment
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Retinal Degeneration/Atrophy

November 27, 2019 11:04 AM by Pritpal Singh Malhi, BVSc, MVSc, PhD, DAVCP

and Retinal detachment with RPE hypertrophy (in dog)

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