Pathogenesis and reversibility of retinopathy induced by 1,4-bis (4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in pigmented rats

Abstract

Pigmented male rats were administered a suspension of 0, 25, or 100 mg/kg 2-phenyl-APB-144 in corn oil by gavage. The rats were killed at 4 and 12 h, and at 1, 2, 4, 7, 14, 28, 57, or 84 days after a single oral administration. The primary site of retinopathy appeared to be the retinal pigment epithelial (RPE) cells. The RPE cells showed necrosis within 12 h post-exposure (PE) at 25 mg/kg and within 4 h PE at 100 mg/kg. Subsequently, photoreceptor outer segments (POS) were disrupted with a hyperplastic RPE cell response within 2 days PE. Intact photoreceptor inner segments (PIS) and RPE cells apposing closely with distal POS were important determinants for reversibility of the damaged POS. The damaged RPE cells were regenerated prior to restoration of normal POS. At 25 mg/kg, both the RPE cells and POS were damaged, but PIS were intact. The damaged POS were regenerated from intact PIS with closely apposing RPE cells. By 14 days PE, the damaged POS had partially regenerated and attained approximately one third to one half of their normal length. By 57 and 84 days PE, the damaged retina had regained an essentially normal structure. In contrast, at 100 mg/kg, the POS and PIS were extensively disrupted, with marked RPE cell hyperplasia after 7 days PE resulting in the formation of multiple retinal arcades (foldings), and rosettes by 14 days PE. Subsequently, retinal arcades and rosettes gradually disappeared as the result of extensive loss of PIS and POS with progressive migration of photoreceptor nuclei toward the Bruch's membrane after 28 days PE. Focal regeneration of POS was observed by 57 days PE where intact PIS and a single layer of regenerated RPE cells were apposed closely with distal POS. The POS regeneration did not occur where the RPE cells were denuded or hyperplastic RPE cells were present. The hyperplastic RPE cells were devoid of slender apical processes, closely enclosing the distal POS. Approximately 20-30% of the retina had partially regained a normal structure by 84 days PE.

Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs

“…Therefore, endogenous Hsp90 plays an indispensable role in homeostasis of the retina. Several reports showed that photoreceptors are the primary components of phototransduction (Bonting et al, 1961;Fox et al, 1997), and that structural disorder of photoreceptor cells was irreversible (Lee and Valentine, 1991). Therefore, inhibition of Hsp90 might lead to irreversible retinal damage.…”

Apoptosis of photoreceptor cells in ornithine-induced retinopathy

“…Various pharmacological agents are known to affect the RPE cells primarily [10,17] or to affect the neurosensory retina and damage the RPE secondarily [2,7,16]. When the physiological functions of the RPE are altered, the overlying retina is also affected and results in decrease of visual function.…”

Morphologic characteristics of retinal degeneration induced by sodium iodate in mice

“…In contrast, with 1,4-bis (4-amynophenoxy)-2phenylbenzene (2-phenyl-APB-144), RPE necrosis is the primary site of toxicity with subsequent photoreceptor outer segment disruption. 10 Although the final event in all cases is the photoreceptor cell degeneration, the primary target differs with each model.…”