Induction of mucopolysaccharidosis in rats by treatment with immunostimulatory acridine derivatives

Grave, S.; Lüllmann, Heinz; Lüllmann-Rauch, R; Osterkamp, G.; Prokopek, M.

doi:10.1016/0041-008x(92)90071-y

Cited by 15 publications

(8 citation statements)

References 23 publications

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“…While the present study did not include the quantitation of GAGs, results from other organs may be quoted. In the liver and spleen of rats treated with the same acridine derivatives as the present animals, the GAGs were increased by factors of approximately 50 and 20, respectively [9]. The drug-induced GAG storage was not evenly distributed throughout the retina.…”

Section: Discussionmentioning

confidence: 91%

“…On electroretinography, the chloroquine and tilorone retinopathies are characterised by decreasing b-wave and awave amplitudes [4,7,13]. Two other cationic amphiphilic agents, the antiviral and immunomodulatory acridine derivatives, compounds CL-90.100 (3,6-bis[2-(diethylamino) ethoxyl]acridine) and CL-246.738, have been reported to interfere with the lysosmal degradation of sulphated glycosaminoglycans (GAGs), thus inducing mucopolysaccharidosis in visceral organs of rats [2,8,9,11].…”

Section: Introductionmentioning

confidence: 99%

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

Bredehorn

Clausen

Duncker

et al. 2001

Graefe's Arch Clin Exp Ophthalmol

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the glycosaminoglycan storage in pigment epithelium is reminiscent of that seen in some inherited mucopolysaccharidoses of humans. When a given cell type shows lysosomal accumulation of glycosaminoglycans as a consequence of impaired degradation, it can be assumed to be engaged in the turnover of glycosaminoglycans under normal conditions. Thus the present results suggest that not only the retinal pigment epithelium but also Müller cells, photoreceptor cells, and, to variable degree, retinal neurons are normally involved in the catabolism of sulphated glycosaminoglycans. We believe that the lysosomal storage of glycosaminoglycans caused secondary cellular disturbance responsible for the functional changes shown by electroretinography.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Bredehorn

Clausen

Duncker

et al. 2001

Graefe's Arch Clin Exp Ophthalmol

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“…3B). The clearer vacuoles present in animals given ELA were more typical for those described with intracellular accumulation (Ruben, 1987) or drug-induced mucopolysaccharidosis (Grave et al, 1992).…”

Section: Electron Microscopymentioning

confidence: 98%

“…Transmission electron microscopy is the most sensitive and specific method for detecting and identifying phospholipidosis which manifests ultrastructurally as cytoplasmic, membrane-bound lamellar whorls (Jolly and Walkley, 1997). Visualization of the ultrastructural morphology and biochemical quantification of phospholipids are useful techniques for differentiating phospholipid accumulation from other potential causes of light microscopic microvesicular cytoplasmic vacuolation such as neutral lipidosis, mucopolysaccharidosis and clear cytoplasmic vacuoles of intracellular drug accumulation (Grave et al, 1992;Hein and Lullmann-Rauch, 1989;Ruben, 1987).…”

Section: Introductionmentioning

confidence: 99%

A clinical flow cytometric biomarker strategy: validation of peripheral leukocyte phospholipidosis using Nile red

et al. 2006

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Phospholipidosis, or intracellular accumulation of phospholipids, is caused by specific classes of xenobiotics. This phenomenon represents a challenge for risk assessment that could benefit from the use of biomarkers in the clinical development of new drug candidates. Flow cytometry, coupled with the lipophilic fluoroprobe Nile red, was correlated to histopathology, electron microscopy and inorganic phosphorus detection to validate the utility of this method for monitoring phospholipidosis in peripheral blood leukocytes. Replicate studies with model test compounds were conducted in which F344 rats were given 4 or 7 doses of either maprotiline hydrochloride, imipramine hydrochloride, tilorone dihydrochloride, amikacin hydrate or vehicle control. Transmission electron and light microscopy were used to examine peripheral blood smears and tissue samples for the presence of cytoplasmic vacuoles. Unstained and Nile red stained lysed peripheral blood samples were acquired for analysis using a FACScan flow cytometer. Inorganic phosphorus concentration in the liver was determined from extracted phospholipids and compared with flow cytometry and histological data. It was demonstrated that flow cytometric analysis of Nile red stained lysed whole blood can be used to detect drug-induced phospholipid accumulation in circulating peripheral leukocytes. Furthermore, clinically detectable leukocyte phospholipidosis may be a useful surrogate for coincident or premonitory detection of target organ phospholipidosis.

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“…Dicationic amphiphilic compounds such as tilorone ( Figure 1a) and congeners are accumulated in lysosomes, interfere with the lysosomal degradation of sulphated glycosaminoglycans (GAGs) and cause lysosomal storage of GAGs, predominantly dermatan sulphate [1][2][3][4]. Drug-induced GAG storage has been described in rats and cultured cells of rat, ox and man [1][2][3][4][5][6][7]. Its occurrence in of a lysosomal enzyme (β-hexosaminidase, EC 3.2.1.52), the ability of MT to cause storage of [$&S]GAGs was significantly lower than that of tilorone.…”

Section: Introductionmentioning

confidence: 99%

Tilorone-induced lysosomal lesions: the bisbasic character of the drug is essential for its high potency to cause storage of sulphated glycosaminoglycans

Fischer

Hein

Lüllmann‐Rauch

et al. 1996

Biochemical Journal

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The immunomodulatory agent tilorone -2,7-bis-[2-(diethyl-amino)ethoxy]fluoren-9-one- and congeners are potent inducers of lysosomal storage of sulphated glycosaminoglycans (GAGs) in animals and cultured fibroblasts of animals and man. All potent inducers of GAG storage hitherto described are bisbasic polycyclic aromatic compounds. They are accumulated in lysosomes and disturb the degradation of GAGs, mainly dermatan sulphate. It has been proposed that the drugs cross-link the polyanionic GAG chains giving rise to undergradable drug-GAG complexes. This hypothesis implies that the bisbasic character of the drug molecules is essential for the side effect in question. In the present study, this was tested by comparing tilorone and its monobasic derivative (MT) with respect to (i) induction of GAG storage in cultured bovine corneal fibroblasts and (ii) physicochemical interactions with GAGs in vitro. The intralysosomal concentration of MT achieved after 1-3 days was of the same order of magnitude as previously shown for tilorone. Nevertheless, under conditions that did not enhance the secretion of a lysosomal enzyme (beta-hexosaminidase, EC 3.2.1.52), the ability of MT to cause storage of [35S]GAGs was significantly lower than that of tilorone. Morphological observations showed that MT was much more potent in causing lysosomal storage of polar lipids than of GAGs. CD spectroscopy with tilorone revealed that the presence of GAGs caused the primarily achiral drug molecules to display CD. This suggested a helical orientation of the tilorone molecules within GAG-drug complexes, and short intermolecular distances which allowed electronic coupling of the aromatic ring systems of adjacent drug molecules. In contrast, MT failed to display any induced optical activity, indicating the absence of highly ordered GAG-drug complexes. In conclusion, the present results show that the substitution of the planar aromatic ring system with two basic side chains is essential for the high potency of tilorone in inducing lysosomal GAG storage. This is paralleled by, and presumably causally related to, strong physicochemical interactions with GAGs.

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Induction of mucopolysaccharidosis in rats by treatment with immunostimulatory acridine derivatives

Cited by 15 publications

References 23 publications

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

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

A clinical flow cytometric biomarker strategy: validation of peripheral leukocyte phospholipidosis using Nile red

Tilorone-induced lysosomal lesions: the bisbasic character of the drug is essential for its high potency to cause storage of sulphated glycosaminoglycans

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