Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1995-08-05
1998-01-13
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
424459, 424422, A61K 9127, A61K 31535
Patent
active
057076499
DESCRIPTION:
BRIEF SUMMARY
(TECHNICAL FIELD)
This invention relates to an agent for curing neuronal diseases, which comprises a substance for accelerating biosynthesis of glycosphingolipids as an effective ingredient.
(BACKGROUND)
It has been known that glycosphingolipids (hereinafter referred to as GSL) exist as a constitutional component of cell surface membranes of mammal cells and they are closely related to a cellular function such as generation, growth, differentiation, transformation, immunoreaction, etc. through a receptor function of a physiologically active substance, an intercellular mutual recognition function, intercellular interaction, etc.
Among them, ganglioside is GSL containing sialic acid, and it is said that it has activity to recoveries from injury of peripheral nerves and a disorder of central nerves, i.e., acceleration of regeneration of nerves and a process of neurotransmission. Heretofore, effectiveness of exogenous ganglioside to various neurotic disease models has been investigated. A medicine named Cronassial.sup.R has already been put on the market in Italy as a medicine utilizing this, and a patent application pertinent thereto was filed (Japanese Provisional Patent Publication No. 34912/1977). However, there have been observed clinical cases that an anti-ganglioside antibody is generated because of administration of this medicine, i.e., the exogenous ganglioside, whereby various neurotic symptoms are caused. For example, there have been reported amyotrophic lateral sclerosis in which an anti-GM2 antibody is generated (Lancet, 337, 1109-1110, 1991) and Guillain-Barre syndrome (Lancet, 338, 757, 1991).
At present, a means for searching a function of ganglioside which has been used most frequently is a means of a type in which ganglioside is added to an experiment system from outside. In that case, a relation to endogenous ganglioside becomes a problem. That is, it is considered that a result obtained by further adding ganglioside to a system in which endogenous ganglioside existing in cell membrane has already formed a complex with various cell surface receptors, etc. does not always reflect actual cytophysiological significance of endogenous ganglioside. Thus, in order to know an inherent role of ganglioside in cytophysiology, a method of specifically changing biosynthesis of endogenous GSL is required. The present inventors have previously synthesized 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) which is an analogue of ceramide and proved that D-threo-PDMP specifically inhibits a glucosylceramide biosynthesizing enzyme and extremely decreases an intracellular content of all GSL using glucosyl-ceramide as a starting substance (J. Lipid. Res., vol. 28, 565-571, 1987). Further, it has been reported that a GSL content is lowered by D-threo-PDMP, whereby extension of neurites is suppressed (J. Biochem., 110, 96-103, 1991).
On the other hand, we have found that L-threo PDMP which is an optical enantiomer of D-threo PDMP has possibility of accelerating biosynthesis of GSL (J. Cell. Physiol., 141, 573-583 (1989)). However, whether or not L-threo-PDMP increases an endogenous ganglioside level in neurocytes and whether or not increase of endogenous ganglioside activates a function of neurocytes are unknown issues and have not been investigated.
An object of the present invention is to provide an agent for curing various diseases caused by disorders of central nervous system and peripheral nervous system, using a medicine which accelerates biosynthesis of endogenous GSL in neurocytes, particularly ganglioside.
(DISCLOSURE OF THE INVENTION)
The present inventors have studied variously in order to develop an agent for curing neuronal diseases based on a new mechanism and consequently found that a specific 2-acylaminopropanol derivative accelerates biosynthesis of GSL and significantly accelerates neurite extension and synapse formation, to accomplish the present invention.
That is, the present invention is an agent for curing neuronal diseases caused by disorders of peripheral nervous system or ce
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Inokuchi Jin-ichi
Usuki Seigou
Page Thurman K.
Seikagaku Corporation
Sikha Murthy
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