Retinotoxicity of 1,4,-bis(4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in albino and pigmented rats

Abstract

Albino and pigmented strains of rats were administered 0, 5, 25, 100 or 500 mg/kg 2-phenyl-APB-144 by gavage and were killed 14 days later. Although no ocular lesions were found in rats dosed at 5 mg/kg, similar dose-related retinopathy was found at 25, 100, or 500 mg/kg in both albino and pigmented rats. The primary target site appeared to be retinal pigment epithelial (RPE) cells and photoreceptor outer segments (POS). At 25 mg/kg or greater, multifocal retinal detachment with disrupted POS occurred where the RPE cells showed necrotic changes and contact loss with POS due to fragmentation of apical processes in the RPE cells. Also, RPE cells showed hyperplasia, migration, and phagocytic activity toward disrupted POS. The photoreceptor nuclei (outer nuclear cells) were displaced into the areas occupied by disrupted POS. At 100 or 500 mg/kg, multifocal or diffuse disruption of POS and photoreceptor inner segments (PIS) was observed with markedly proliferating RPE cells. The photoreceptor nuclei were disorganized, less numerous, and necrotic. Some photoreceptor nuclei directly apposed the RPE cells or Bruch's membrane due to the absence of both POS and PIS. The cytoplasm of RPE cells was loaded with phagosomes, disrupted lamellar discs, myelin bodies, and lysosomal residual bodies. The morphological changes appeared to be related to lysosomal dysfunction of the RPE cells. The presence of melanin pigment in the RPE cells did not appear to be the primary factor in the development of the retinopathy.

Phototoxic Lesions Induced by Quinolone Antibacterial Agents in Auricular Skin and Retina of Albino Mice

“…Changes progressed thereafter to degeneration and thinning of the retina, including the photoreceptor segments, ONL and outer plexiform layer. POS destruction and accumulation of inclusion bodies in RPE cells have been described in the retinopathies induced by a variety of chemical agents: 2-aminooxy propionic acid derivatives, hexachlorophene, gentamicin, aminoglycoside antibiotics, netilmicin, cytosine arabinoside, phenothiazine derivatives, chloroquine, lead, laser, 2-phenyl-APB-144 (24), vitamin E deficiency (2), and 4,4'-methylenedianiline (25).…”

“…diated with UVA (FL20SBLB Black Light, Toshiba, Japan) for 4 hr (20 joule/cm2). The animals from the SPFX groups were sacrificed by bleeding under ether anesthesia 2 (during irradiation), 4 (immediately after irradiation), 8,12,24,48, and 96 hr after administration, whereas those from the ENX and LVFX groups and from the nontreatment and UVA irradiation groups were sacrificed at 96 hr. The auricles and eyes were removed, fixed in 10% buffered formalin and Davidson's solution, respectively, embedded in parrafin wax, sectioned, stained with hematoxylin and eosin, and examined histologically.…”

Fibulin 2, a Tyrosine O-Sulfated Protein, Is Up-regulated Following Retinal Detachment

“…Retinal detachment can lead to the exposure of the quiescent RPE cells (72) to multiple cytokines, which may modulate their behavior and cause them to dissociate from the Bruch membrane (73), undergo major morphological changes on the apical surface (74), or change their morphology from flat cuboid to columnar in appearance and enlarge in size (75). RPE proliferation and migration after retinal detachment has been observed in many species (49,50,76,77). An extreme condition that results due to retinal detachment occurs during proliferative vitreoretinopathy, where RPE cells trans-differentiate into myofibroblasts and proliferate into the vitreous humor to form sub-retinal membranes (78,79).…”

2-Phenyl-APB-144-Induced Retinal Pigment Epithelium Degeneration and Its Underlying Mechanisms

“…1) as provided in a previous report. 18 Salubrinal 20 was from Calbiochem (La Jolla, CA), N-acetyl cysteine (NAC) and bafilomycin A1 (bafilomycin) were from Sigma-Aldrich (St. Louis, MO), 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was from Alexis (Farmingdale, NY), z-VAD-fmk was from the Peptide Institute, Inc. (Osaka, Japan), and Acridine Orange was from Life Technologies (Carlsbad, CA).…”

“…16,17 Unexpected side effects were observed in rats, demonstrating that APB specifically damaged the RPE and promoted its degeneration within 7 days. 18,19 However, availability of an animal model, and the underlying mechanisms of the compound, were not investigated until recently. To our knowledge, there are no reports showing the effects of APB on the organelle pH and autophagic machinery or on the underlying molecular mechanisms of pathology in the RPE.…”