Morphological and functional changes due to drug-induced lysosomal storage of sulphated glycosaminoglycans in the rat retina

Bredehorn, T; Clausen, Matthias; Duncker, G.; Lüllmann‐Rauch, Renate

doi:10.1007/s004170100361

Cited by 7 publications

(5 citation statements)

References 19 publications

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“…Further studies by immunoelectron microscopy revealed that the materials in some vacuoles were immunoreactive for G M2 ganglioside. Although we have found no papers addressing the involvement of RPE cells in human G M2 gangliosidoses, the findings of the present study using a mouse model imply that ganglioside stores in RPE cells appear in the shape of 'vacuolated inclusions', as seen in inherited (mucopolysaccharidoses) [22,23] and drug-induced [24] lysosomal storage of glycosaminoglycans. Lysosomal ␤ -hexosaminidase isozymes (HexA, HexB, and HexS) play a role in the degradation of G M2 ganglioside and related glycolipids [1] , glycosaminoglycans [25] , and N-linked oligosaccharides [26,27] .…”

Section: Discussioncontrasting

confidence: 58%

Involvement of Retinal Neurons and Pigment Epithelial Cells in a Murine Model of Sandhoff Disease

et al. 2008

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Background/Aims: To investigate the effects of deficient degradation of glycolipids on the morphological appearance of all retinal cells in a murine model of G_M2 gangliosidosis (Sandhoff disease). Methods: The morphological appearance of the retina in Sandhoff mice at symptomatic stages (3 and 4 months of age) was examined by immunohistochemistry, lectin histochemistry and electron microscopy. Results: Under a light microscope, intense immunoreactivity for G_M2 ganglioside was observed in the ganglion cell, inner plexiform, and inner nuclear layers in the Sandhoff mice. The ganglion cell layers and retinal pigment epithelium in the Sandhoff mice were stained intensely withconcanavalin A agglutinin and succinylated wheat germ agglutinin. Ultrastructural studies revealed numerous inclusions in the cytoplasm of retinal ganglion cells and other neuronal cells (particularly amacrine cells), whereas we failed to detect apparent involvement of photoreceptor cells. In addition to the cytoplasmic inclusions in the retinal neurons, vacuolation was evident in the retinal pigment epithelium. Conclusion: These findings suggest that neuronal cells and pigment epithelial cells are more vulnerable to the deficient ganglioside degradation than other retinal cells in Sandhoff mice.

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Section: Discussioncontrasting

confidence: 58%

Involvement of Retinal Neurons and Pigment Epithelial Cells in a Murine Model of Sandhoff Disease

et al. 2008

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“…Amiodarone, chloroamitriptyline, chlorphentermine, clomipramine, imipramine, iprindole, various aminoglycosides, and other cationic amphophilic compounds interfere with the enzymatic degradation of phospholipids. Consequently, their systemic administration results in accumulation of phospholipids in various retinal cells, including the pigment epithelium (retinal lipidosis), which is reminiscent of glycosaminoglycan storage observed in some inherited mucopolysaccharidoses (Bredehorn et al, 2001). The phospholipids are stored in abnormal cytoplasmic inclusions with crystalloid substructure and are partially reversible upon discontinuation of treatment (Lullmann-Rauch, 1976; Bockhardt et al, 1978; Drenckhahn and Lullmann-Rauch, 1978; Bockhardt and Lullmann-Rauch, 1980; Lullmann-Rauch, 1981; D’Amico et al, 1985; Tabatabay et al, 1987; Duncker and Bredehorn, 1994; Bredehorn et al, 2001).…”

Section: Toxic Effects On the Pigment Epitheliummentioning

confidence: 99%

An Overview on the Toxic Morphological Changes in the Retinal Pigment Epithelium after Systemic Compound Administration

Mecklenburg

Schraermeyer

2007

Toxicol Pathol

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Many medications that are administered systemically for nonocular conditions may evoke ocular toxicological complications. Therefore, the eye is routinely investigated histopathologically in preclinical in vivo toxicity studies. The retinal pigment epithelium is a likely target for systemically administered compounds, since the underlying choroid is highly vascularized. The specialized pigment epithelium has numerous functions that all maintain the integrity and function of photoreceptors. Consequently, toxic effects on the pigment epithelium will eventually affect the neural retina. The potential of pigment epithelial cells to respond to toxic injury is limited, but a standardized terminology to describe its morphological changes does not exist in the scientific literature. Detailed morphologic analysis, however, might allow early detection of retinotoxicity and may provide evidence on the underlying pathomechanism. We here review toxic effects on the pigment epithelium focusing in particular on the morphology of toxic cell injury. Morphological changes comprise hypertrophy, intracytoplasmic accumulation of cellular components, loss of cell polarity, degeneration, metaplasia, and formation of subretinal membranes. Some of these changes are reversible whereas others are permanent, leading to impaired function of the pigment epithelium and eventually to photoreceptor loss and retinal atrophy.

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“…Despite extensive PLD, laboratory animals generally seem to be well. However, effects on cell function are possible 92 , 93 and include impairment of cell metabolism or of pino/endocytosis. Some drugs such as propranolol and verapamil were reported to lead to lactate dehydrogenase (LDH) release from hepatocytes, while other drugs, such as chloroquine and amiodarone, may be associated with myopathy.…”

Section: Examples Of Addressing Apfsmentioning

confidence: 99%

Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples

Ettlin¹,

Kuroda

Plassmann³

et al. 2010

J Toxicol Pathol

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To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions.

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Morphological and functional changes due to drug-induced lysosomal storage of sulphated glycosaminoglycans in the rat retina

Cited by 7 publications

References 19 publications

Involvement of Retinal Neurons and Pigment Epithelial Cells in a Murine Model of Sandhoff Disease

Involvement of Retinal Neurons and Pigment Epithelial Cells in a Murine Model of Sandhoff Disease

An Overview on the Toxic Morphological Changes in the Retinal Pigment Epithelium after Systemic Compound Administration

Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples

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