Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing alpha or beta amino acid or substituted amino acid...
Patent
1997-07-03
1999-10-12
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing alpha or beta amino acid or substituted amino acid...
435116, 435199, 558169, 558172, C12P 1304, C12P 1306, C12P 764, A61K 3800
Patent
active
059654139
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a method for producing phosphatidylserines having a side chain derived from a long chain unsaturated fatty acid, more specifically, to a process for producing compounds effective for the prophylaxis and treatment of Parkinson's disease and dementia such as Alzheimer's disease, as well as effective for improving cerebration such as improved resistance against brain stress and improved learning effect.
BACKGROUND ART
A. Bruni, et al., report that the brain glucose level in mice injected via the caudal vein with phosphatidylserine extracted from bovine brain is increased by about 4 fold the level in the control group (A. Bruni et al., Nature, Vol. 260, pp. 331, 1976).
A. Zanotti et al., also report that the oral administration of phosphatidylserine extracted from bovine brain to aged rats with memory deficits for 12 weeks improved the performance of the aged rats (A. Zanotti et al., Psychopharmacology Berl., Vol. 99, pp. 316, 1989).
Furthermore it is confirmed at a double-blind placebo-controlled clinical trial for humans the efficacy of phosphatidylserine extracted from bovine brain in improving the memory impairment in Alzheimer's disease and during the aging stage (P. J. Delwaide et al., Acta Neurol. Scand., Vol. 73, pp. 136, 1986; R. R. Engel et al., Eur. Neuropsychopharmacol., Vol. 2, pp. 149, 1992; T. Cenacci et al., Aging Clin. Exp. Res., Vol. 5, pp. 123, 1993).
As has been described above, bovine brain-derived phosphatidylserine having the effect of increasing brain glucose level has an effect of improving the cerebration in rats and humans. Therefore, it is indicated that the degree of the increase in brain glucose level is an important indicator for selecting a substance with the action of improving cerebration.
However, it is believed that in general unsaturated fatty acid is bound to the beta position of phospholipid, and in natural phosphatidylserine, such as that derived from animal brain, more than ninety-two (92) percent of the fatty acid at beta position contains oleic acid (B. F. Szuhaj & G. R. List, "Lecithins", Am. Oil Chem. Soc., U.S.A., pp. 145, 1985).
In phosphatidylserines produced through a transphosphatidylation reaction with phospholipase-D (PLD), a known method of industrially producing phospholipids, most of fatty acid at beta position thereof was the same as that of the starting material, for example, linoleic acid and linolenic acid when using soybean lecithin, or oleic acid and linoleic acid when using yolk lecithin.
Recently, there have been conducted a variety of studies on n-3 and n-6 groups of long chain unsaturated fatty acids, and there have been conducted many laboratory animal experimentations on the physiologic activities of n-3 group long chain unsaturated fatty acids, including the improvement of learning performance. From these background, it may be possible that, if material combining above noted long chain unsaturated fatty acid and phosphatidylserine, such as phosphatidylserine comprising long chain unsaturated fatty acid in its molecule was produced, summation or synergistic effect of both phosphatidylserine and long chain unsaturated fatty acid will be effective and better cerebration improver may be obtained.
However, there is not known among currently available phosphatidylserine one which may be industrially produced with lower cost and comprises a long chain unsaturated fatty acid of n-3 or n-6 (except linoleic acid) group at beta position.
For example, it has been proposed that a phosphatidylserine derivative having a specific fatty acid at beta position of glycerol structure, which may activate proteinkinase-C (PKC) is a material which is a composition of long chain unsaturated fatty acid and phosphatidylserine for the estimation of the summation or synergistic effect as stated above (Japanese Patent-Laid Open No. 6-279311). In this Japanese patent, it is described that the experiment has been conducted in the condition that the phosphatidylserine derived from bovine brain which is effective for
REFERENCES:
patent: 5117034 (1992-05-01), Ono et al.
patent: 5540935 (1996-07-01), Miyazaki et al.
patent: 5700668 (1997-12-01), DeFarra et al.
P.J. Delwaide et al, "Double-blind randomized controlled study of phosphatidylserine in senile demented patients", Acta Neurol Scand., vol. 73, 1986, pp. 136-140.
R.R. Engel et al, "Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type", European Neuropsychopharmacology, vol. 2, 1992, pp. 149-155.
T. Cenacci et al, "Cognitive decline in the elderly: A double-blind, placebo-contolled multicenter study on efficacy of phosphatidylserine administration", Aging Clin. Exp. Res., vol. 5, No. 2, pp. 123-133, 1993.
B. F. Szuhaj & G.R. List, "Lecithins", American Oil Chemists' Society, U.S.A., 1985, pp. 145-149.
A. Bruni et al., "Pharmacological effects of phosphatidylserine liposomes", Nature, vol. 260, Mar. 1976, pp. 331-333.
A. Zanotti et al, "Chronic phosphatidylserine treatment improves spatial memory and passive avoidance in aged rats", Psychopharmacology Berl., vol. 99, 1989, pp. 316-321.
Kudo Satoshi
Sakai Masashi
Yamatoya Hideyuki
Kabushiki Kaisha Yakul't Honsha
Lilling Herbert J.
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