Use of nervonic acid and long chain fatty acids for the treatmen

Details Use of nervonic acid and long chain fatty acids for the treatmen Use of nervonic acid and long chain fatty acids for the treatmen

1991-08-06

1993-03-16

Rollins, John W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

514930, A61K 3120

Patent

active

051944480

DESCRIPTION:

BRIEF SUMMARY
This invention is concerned with pharmaceutical compositions containing long chain fatty acids such as nervonic acid, or derivatives thereof, for the treatment of demyelinating diseases such as multiple sclerosis.
Multiple sclerosis (MS) is a disease affecting the mature central nervous system (CNS). The disease is characterised by successive periods of CNS demyelination followed by periods of remission. Although the aetiology of MS is not fully understood a number of factors appear to be important including a genetic predisposition, viral infection and an auto immune response to some antigen resulting in demyelination of the CNS particularly brain, optic nerve and spinal cord.
Regardless of the causes of MS, the pattern of demyelination and remyelination (remission) involves both loss of and reassimilation of myelin components. Since myelin comprises about 60% of its dry weight as lipid, the important lipid components, the fatty acids, have received considerable attention over the years, in particular the long chain fatty acids, since they are the most abundant of fatty acids in many important complex lipids. Long chain fatty acids in the context of this invention are defined as those mono-carboxylic acids having a carbon chain length greater than C22. The complex lipids in the context of this invention include gangliosides (particularly Ganglioside G.sub.7 or G.sub.M4), cerebrosides, sulphatides and sphingomyelin. These lipids contain significant amounts of long chain fatty acids (particularly nervonic acid-cis-tetracos-15-enoic acid) in their structures. Typical compositions of normal myelin are tabulated below:


TABLE 1 ______________________________________ Long Chain Fatty Acids in Myelin Lipids Fatty Ganglioside Cere- Acid* G.sub.7 (G.sub.M4)** broside** Sulphatide** Sphingomyelin*** ______________________________________ C24:1 24.1 45.7 48.0 35.0 C24:0 11.1 15.8 14.3 -- C25:1 5.0 7.8 10.2 2.3 C25:0 1.8 2.3 3.4 -- C26:1 4.1 4.5 9.1 1.0 C26:0 0.8 0.3 1.1 -- ______________________________________ *The total number of carbon atoms: number of double bonds **Derived from human purified myelin (see Ledeen. R. W., et al J. Neurochem., 21 829-839, 1973). ***Derived from human white brain matter (see Gerstl, B., et al Z. Neurol., 202 104-120, 1972).
Destruction of myelin during active MS results in significant loss of these myelin components. Additionally, their replacement requires the availability of their specific component fatty acids. This can arise by two distinct routes, namely in-vivo synthesis (the more important route) and exogenously from the diet. Long chain fatty acids are rare trace components in most modern diets and in-vivo synthesis is not efficient and may be impaired in MS. Several workers have shown that there is a significant depletion of total lipid in MS tissue (brain, spinal cord). More significantly, perhaps, is the absence of specific gangliosides (Ganglioside G.sub.7 or G.sub.M4) in MS white brain matter and demyelinated plaque (see Yu, R. K. et al, J. Neurochem., 23 169-174, 1974).
Myelin destruction not only depletes CNS tissue of vital lipids but also releases myelin basic protein (MBP). MBP is known to be antigenic to myelin and also induces experimental allergic encephalomyelitis (EAE) when injected into laboratory animals. EAE has some neuropathological features in common with MS and is widely used as an animal model for the diseases. However, when MBP is incubated with Ganglioside G.sub.7 (G.sub.M4) prior to injection it significantly reduces the encephalogenic potential of the MBP in guinea pig. (See Mullin, B. R., et al Brain Research, 296 174-176, 1984).
We have now realised that the provision of a pharmacologically acceptable source of long chain fatty acids in MS patients would provide a pool of material vital to the assembly of myelin components for reassembly of the myelin sheath. Moreover the ready availability of these long chain fatty acids would enable the biosynthesis of important gangliosides, particularly Ganglioside G

REFERENCES:
patent: 4505933 (1985-03-01), Horrmann
Holm et al., PNAS 1989, 86:4720-4724.
B Gerstl, et al., Z. NBeurol. 202:104-120 1972.

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