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Mucopolysaccharidosis (MPS) in ocular tissues as induced by amphiphilic di-cationic drugs
1Department of Anatomy, University of Kiel, Germany.
Abstract:
The immunostimulatory drug tilorone (2,7-bis(2- (diethylamino)ethoxy)-9H-fluorene-9-one) has previously been described to induce keratopathy in patients and in rats; in the latter, lysosomal storage of sulfated glycosaminoglycans (mucopolysaccharidosis, MPS) was found to be the reason for corneal clouding. In the present histochemical and ultrastructural study, several ocular tissues of rats were examined after chronic treatment with tilorone and two other immunostimulatory agents (3,6-bis(2-(dipiperidyl)ethoxy)-acridine and the diethylamino analogue). The acridine derivatives hardly affected the cornea and sclera. Tilorone as well as the acridine derivatives induced significant MPS in ciliary body, iris, and choroid. While the functional consequences of drug-induced MPS in ocular tissues are not known yet, except for the cornea, this adverse drug action should be taken into account when new compounds are designed that share certain physicochemical features with tilorone. One molecular feature essential for the MPS-inducing potency of a drug appears to be the dicationic amphiphilic character.
Insights
Tilorone and similar immunostimulatory drugs cause mucopolysaccharidosis (MPS) in rat eye tissues, leading to corneal clouding. This adverse drug action is linked to the drug's dicationic amphiphilic molecular structure.
Area of Science:
- Ophthalmology
- Pharmacology
- Histochemistry
Background:
- Tilorone, an immunostimulatory drug, is known to cause keratopathy.
- In rats, tilorone-induced keratopathy is linked to lysosomal storage of sulfated glycosaminoglycans (mucopolysaccharidosis, MPS).
Purpose of the Study:
- To investigate the ocular effects of chronic tilorone and related immunostimulatory agents in rats.
- To examine the induction of MPS in various ocular tissues.
Main Methods:
- Histochemical and ultrastructural examination of rat ocular tissues.
- Chronic administration of tilorone and two acridine derivatives.
Main Results:
- Tilorone and acridine derivatives induced significant MPS in the ciliary body, iris, and choroid.
- Acridine derivatives had minimal effect on the cornea and sclera.
- Tilorone-induced MPS was previously identified as the cause of corneal clouding.
Conclusions:
- Immunostimulatory drugs, including tilorone and acridine derivatives, can induce MPS in multiple ocular tissues.
- The dicationic amphiphilic molecular feature appears essential for MPS-inducing drug potency.
- Potential adverse drug actions on ocular tissues should be considered during the design of new compounds with similar physicochemical properties.