JP4974031B2 - Medicament for treating Alzheimer's disease and method for producing the same - Google Patents

Description

The present invention relates to a medicament for treating Alzheimer's disease and a method for producing the same. In particular, it is a medicine for treating Alzheimer's disease with monacolins, anti-inflammatory substances, and antioxidants in red yeast rice, and it is applied to the tablet, capsule, powder, beverage, etc. for Alzheimer's disease to be used by consumers. The present invention relates to a medicine for treatment and a method for producing the same.

  Alzheimer's disease (abbreviated as AD) is a persistent neurological dysfunction called senile dementia. When Alzheimer's disease develops, people gradually lose their memory, develop language and emotional disturbances, and gradually lose their wisdom, called dementia. As this disease progresses, patients will need assistance from others in every aspect of their lives, such as bathing, eating, and excretion. In other words, because Alzheimer's patients require 24-hour care, the lives of those around them are often greatly affected.

  On the other hand, loss of memory is most common in Alzheimer's disease and is a common medical condition. In particular, it is often difficult to remember information that has just occurred a short time ago or information that has just been obtained recently, but it is difficult to notice because the initial symptoms appear minute and little by little. Moreover, symptoms such as getting lost in a well-known place, forgetting whether you have done something, taking the past over and over, or not being able to absorb new knowledge, also appear in other dementias, Not specific to Alzheimer's disease.

When the illness worsens, the patient cannot find the appropriate language in the conversation or cannot make a critical decision.
Furthermore, the hardest thing about Alzheimer's disease is that patients may not be able to recognize close people. In addition, his personality is unusually timid, suspicious, and hates interacting with people. As symptoms progress, patients become jealous and even get lost and can't go home.

  Recent studies show that the brains of patients with Alzheimer's disease may have damaged areas that process visual and spatial information. This is enough to explain why the patient is not sure where he is or where his direction is. Also, the patient loses concentration and cannot take care of the various needs of his daily body.

  In the brains of Alzheimer's disease patients, other areas that are very important for memory, such as the basal forebrain and hippocampus, are also affected. Many people suffering from Alzheimer's disease will die from other causes such as pneumonia, but from the date of diagnosis, Alzheimer's disease patients generally survive 6-8 years, but surviving over 20 years. There are many examples.

  Currently, about five drugs for the treatment of Alzheimer's disease are approved by the US Food and Drug Administration (abbreviated as FDA). These drugs are cholinesterase inhibitors (non-brand names are tacrine and donepezil, respectively). Cholinesterase is a key enzyme during acetylcholine degradation reaction, and these drugs act as cholinesterase. Inhibits the degradation of acetylcholine by inhibiting it.

Two of the drugs can increase the content of acetylcholine in the brain, two can delay memory loss, and help the patient perform the actions that they need in daily life .
However, it cannot be forgotten that these drugs are not able to treat Alzheimer's disease but only reduce the symptoms of Alzheimer's disease.

  In addition, since these drugs cause some side effects such as discomfort, headache, diarrhea, insomnia, pain, hallucinations or dizziness for patients, they are not practical therapeutic agents for Alzheimer's disease.

  Therefore, the development of a drug that can effectively treat Alzheimer's disease patients without any clear adverse side effects is awaited.

The main problem to be solved by the present invention is to provide a medicine having a function and effect for reliably treating Alzheimer's disease and a method for producing the same, and the next problem to be solved by the present invention is to provide Alzheimer's disease. simultaneously when treated, it is to provide pharmaceutical and manufacturing method thereof for definite defect side effects to treat all occurring without Alzheimer's disease.

In order to solve the above problems, the present invention provides the following medicament for treating Alzheimer's disease.
And monacolin (monacolins), and anti-inflammatory agent comprises a medicament and antioxidants, tablets, capsules, powders, can be subjected applied to taking consumer beverages such method, materials of the three compounds is formed Alzheimer's disease can be treated using medicine .
In this example, the drug for treating Alzheimer's disease is red yeast rice, the effective minimum content of monacolins is at least 100 μg per 1 g of red yeast rice, and the effective minimum content of antioxidants is The minimum effective content of anti-inflammatory substances is at least 10 μg per 1 g of red yeast rice , and the optimal weight ratio of monacolins, anti-inflammatory substances, and antioxidants is 40: 2 : Can be implemented in a manner that is 1, and can reliably achieve the function and effect without treatment and no obvious adverse side effects.
Furthermore, the present invention further provides a medicament for treating Alzheimer's disease comprising monacolins and an anti-inflammatory substance. The drug for treating Alzheimer's disease is red yeast rice, the effective minimum content of monacolins is at least 200μg per 1g of red yeast rice, and the effective minimum content of anti-inflammatory substances is 1g of red yeast rice It requires at least 60μg or more and the optimal weight ratio of Monacolins to anti-inflammatory substance is 10: 1. This medicine can reliably treat Alzheimer's disease and does not cause any clear adverse side effects. The effect can be achieved.
Furthermore, the steps of the method for producing a medicament for treating Alzheimer's disease disclosed in the present invention are as follows.
First, the rice is washed and sterilized in a high-pressure and high-temperature environment.Subsequently, the red yeast strain is planted in the inoculum culture medium, and the first specific temperature / humidity environment, the specific vibration environment, and the first specific time limit are in contact, After completion of inoculation, the inoculum culture medium is agitated in the first specified temperature environment, and a specific ratio of water is continuously provided within the second specified time limit, and within the third specified time limit and in the first specified temperature environment. After a suitable agitation at regular intervals to achieve afterripening, take out the fermented red yeast rice after the completion of fermentation, hold it at the second specified temperature within the fourth specified period, and dry it.麹 Fermented product is ground and powdered, and the effective weight ratio of monacolins, anti-inflammatory substances and antioxidants contained in the medicine ranges from 10: 4: 1 to 90: 2: 1 Analyze whether the component ratio condition If consistent in medicaments for treating Alzheimer's disease of the present invention, prepared powder該紅fermented koji was completed treatable added to Alzheimer's disease in edible beverage at the predetermined ratio of Monascus beverage Manufacturing. Moreover, the powder of the fermented red yeast rice product that has been prepared can be filled into a capsule or manufactured into a tablet, and this medicine can be carried out through this method, and Alzheimer's disease can be reliably treated. Functions and effects that do not cause any adverse side effects can be achieved.

As described above, the present invention is a medicament for treating Alzheimer's disease with monacolins, anti-inflammatory substances, and antioxidants in red yeast rice, and is applied to tablets, capsules, powders, beverages, etc. Can be used for taking.

Detailed contents and techniques of the present invention will be described below.
The present invention is a medicine for treating Alzheimer's disease. Before introducing the medicine of the present invention, the concept of the present invention will be explained first.
A major predisposition to Alzheimer's disease formation is the large amount of amyloid β-protein (Aβ) precipitated in the brain, which causes neurotransmitter deficiency and an oxidative inflammatory response that gradually increases the severity of the disease. To go. Aβ is a slice protein that is generated after secretase cleaves a specific position to amyloid precursor protein (APP). Cleavage enzymes include α, β and γ-secretase.

  Aβ has passed β-secretase and can cut the amino acid bond connecting 671 and 672, and γ-secretase cuts the position near 713 on APP, Can be generated. When the enzyme cleaves against an amino acid sequence, other sections are generated in addition to the 1-40 and 1-42 sections.

If APP alone is cleaved into α-secretase and generates sAPP-α and p10 kDa sections, p10 is also cleaved with γ-secretase and p3 and p7 sections are cut. appear. Of these, p3 is Aβ of a small section.
Separately, if APP alone is cleaved into β-secretase to generate sAPP-β and p12 kDa sections, p12 sections are again cleaved with γ-secretase and Aβ and p7 sections. (Evin et al. 2003; Shoji et al. 1992).

  These small sections do not have the ability to assemble in the brain, but can demonstrate the cleavage activity performance of different forms of secretases. APP generates Aβ of each form through degradation of β-secretase and γ-secretase. Among them, soluble Aβ is not toxic, and is toxic to neurons for the first time after forming fibrils through polymerization. Soluble Aβ is not toxic and forms a fibrillated starch-like protein (Aβfibrils) through polymerization, and then poisons nerve cells only through mechanisms such as disruption of intracellular calcium ion balance and induction of oxidative pressure. Aβ polymer also promotes hyperphosphorylation of intracellular tau protein, prevents neurite outgrowth and kills cells.

  In addition, Aβ fiber bundles also activate brain microglia by binding to special receptors on the astrocyte membrane. The former releases various types of neurotoxins, causing substances such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α), as well as nitric oxide and superoxygen. Free radicals such as negative ions attack nerve cells and cause their death. In recent years, there is an association between the apolipoprotein E (ApoE, apolipoprotein E) gene on the chromosome 19 located in the 19th pair and Alzheimer's disease, and ApoE and Aβ bind rapidly and precipitate in the brain to form senile plaques. And was found to cause neuronal necrosis.

In addition, many literatures point out that there is a certain correlation between cardiovascular disease and Alzheimer's disease.
In a study of elderly people over 65 years old, such as Martha, a large number of elderly people who consumed abundant saturated fatty acids, which are likely to cause cardiovascular disease due to eating habits, suffered from Alzheimer's disease after an average of 4 years. Conversely, elderly people who consume more polyunsaturated and monounsaturated fatty acids due to diet have an inverse correlation (Freund-Levi et al. 2006).

  Many studies have also demonstrated a correlation between the generation of Aβ causing Alzheimer's disease and intracellular lipid metabolism (Frears et al. 1999; Kuo et al. 1998; Roher and Kuo 1999).

Recent studies point out that Aβ undergoes changes in intracellular cholesterol distribution and cholesterol esterification (Frears et al. 1999).
ApoE is one of the risk factors that increase plasma cholesterol and cause cardiovascular disease.

  Puglielli et al. Pointed out in 2001 that the activity of intracellular acetylcholine degrading enzymes in hamsters was positively correlated with cholesterol ester content (Puglielli et al. 2001; Zhao et al. 2005). Therefore, it can be said that there is a positive correlation between cardiovascular disease and Alzheimer's disease.

Therefore, the medicament of the present invention treats Alzheimer's disease by focusing on saturated fatty acids that reduce Aβ precipitation in the brain and reduce cardiovascular disease.

  In recent years, research on Monascus species has increased, and red yeast rice is expected to develop as a multifunctional health food. Monacholine K (monacolin K), γ-aminobutyric acid (GABA), and antioxidants in red yeast rice may be able to treat Alzheimer's disease by demonstrating the present invention. Greatly improved.

  Monacolin K, also known as monacolin K, includes lovastatin, an enzyme that limits the rate of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG CoA reductase) and belongs to the statins class of compounds. Clinically, this class of compounds has already been demonstrated to be effective in improving cardiovascular disease (CAD).

  Recent epidemiological studies have pointed out that statins have a positive effect on the treatment of patients with Alzheimer's disease. The UK General Practitioners Research Database states that 70% of patients have a clear improvement effect (Jick et al. 2000) when statin drugs treat Alzheimer's disease .

  Similar experiments also include an experiment conducted by Wolozin et al. In 2000 in three different clinics in the United States with elderly people suffering from Alzheimer's disease over 60 years old. The diagnostic results are based on NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) standards. In this study, subjects were divided into three groups, group A treated with control group, group B treated with statins, group C treated with other cardiovascular drugs (including blood pressure lowering drugs) It was. The results surprisingly show that patients treated with statins have a 70% reduction in the incidence of Alzheimer's disease, of which lovastatin and pravastatin are most effective (Wolozin et al 2000).

  In the brain of patients with Alzheimer's disease, nicotinic, muscarinic, serotonin, glutamate receptors and γ-aminobutyric acid (GABA), serotonin, norepinephrine frine Nerve impulse transmission factors such as (norepinephrine) are all deficient. The cerebrum is reduced in volume by 10% during the aging process, but the main cause is a decrease in the number of cerebral cortical nerves, which in some areas is reduced by 30-50%. Separately, neurotransmitters such as acetylcholine, GABA, catecholamine are also reduced. The decrease in these substances reduces cerebral cognitive function or impairs memory ability. The earliest symptom is a decline in memory and the ability to judge things, and it is easy to get lost, and at the end of the period, language impairment, abnormal behavior, convulsions, and loss of vitality appear (Mohr et al. 1994).

Mitochondria are O ₂ or H ₂ O ₂ , OH. Excessive deficiency results in highly reactive OH. Form. Aβ undergoes free radical oxidation to produce insoluble Aβ, further exacerbating Alzheimer's disease (Hsieh and Tai 2003). Experiments have found that the use of antioxidants such as vitamin C and vitamin E combined preparations alleviates the phenomenon of Alzheimer's disease (Yallampalli et al. 1998; Yamada et al. 1999). . Natural nerve myelin such as ceramlde can also counter the effects of hippocampal nerve damage caused by Aβ and FeSO ₄ (Abousalham et al. 2002). Antioxidant capacity of red yeast has been announced anti-oxidation mechanism of Jimerumikku acid in the red yeast by Aniya, such as in 1999 (dimerumic acid), it is OH, O ₂ ^-, ferryl -Mb (ferryl-Mb), Pero The inhibitory action on peroxyl radicals and lipid peroxidation (LPO) can be eliminated, providing electrons to the oxide, which oxidizes itself to nitroxide radicals. All this nitroxide radical is removed to achieve an antioxidant effect (Taira et al. 2002). The antioxidant effect of red yeast rice can be used to prevent Alzheimer's disease, and it can prevent the disease from getting worse by attack of oxidized free radicals.

  The present invention was already published on July 20, 2007, Journal of Neuroscience Research (Lee CL, Kuo TF, Wang JJ, Pan TM: Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid beta-infused rat via repressing amyloid beta accumulation. J Neurosci Res. 2007, 85, 3171-7182.).

  The animals employed in the study of the present invention are male rats of the Wistar breed, which are 8 weeks old and weigh about 250 g, from the National Taiwan University Hospital. Each group is kept in a space with air conditioning, the temperature is maintained at 23 ± 1 ° C, the light is controlled for 12 hours and 12 hours off (08:00 on, 20:00 off), food and water Does not limit. Rats are raised to a body weight of 300 g, and experimental grouping and pump transplantation into the brain are performed. The daily intake of red yeast rice and the injection amount of Aβ40 for each group are shown in 3-2.

  The vehicle group is operated, but Aβ40 is not inoculated and the rats have normal memory learning ability.

  The Aβ group is operated and inoculated with Aβ40 to become Alzheimer's disease rats with impaired memory learning ability.

The intake of red yeast rice was calculated based on the body surface area conversion formula (Boyd's Formula of Body Surface Area) published by the FDA (Boyd 1935; Lee et al. 2006). Double dose of red yeast rice in this study is equivalent to 2 g of red yeast rice per day for adults (170 cm, 65 kg).
The RH group is a high-dose red yeast rice intake group, the LS group is a daily dose of lovastatin (1.43 mg / kg rat) similar to that of the RL group, and simple monacolin K and monacolin, antioxidants, To compare the efficacy of anti-inflammatory substances containing red yeast medicine in the treatment of Alzheimer's disease.

The experiment of the present invention injects Aβ40 into the rat brain for 28 consecutive days, causing a large amount of Aβ40 to precipitate directly into the brain, causing Alzheimer's disease. During the test period, a red yeast rice fermentation product or a homologous concentration of lovastatin is given per day, and the effect of red yeast rice on the already produced Aβ toxicity is observed and its influence on memory learning ability is evaluated. Aβ40 was infused into the rat brain for 28 consecutive days to increase brain acetylcholine degrading enzyme activity, reactive oxygen species (ROS) production and lipid peroxidation, and increase total antioxidant power and superoxide dismutase (Superoxide dismutase). The experimental results of the present invention show that the damage caused by injecting Aβ40 into these brains can be remarkably suppressed by reducing the dismutase, SOD) activity and then giving red yeast rice. Moreover, the effect was better than that of the lovastatin drug treatment group. In addition, by suppressing the oxidative inflammation reaction, the injected Aβ40 does not precipitate in large quantities in the hippocampal tissue. This proved for the first time that red yeast rice has the effect of reducing Alzheimer's disease risk factors and improving memory learning ability, and that the effect is more prominent than the lovastatin drug.
Table 1 shows the test groupings of the present invention.

  As shown in FIG. 1, the test apparatus of the present invention includes a bright room 11 and a dark room 12 having the same size. There is a 10 (W) × 10 (D) cm gate 13 at the center of both chambers. When the gate 13 is opened, the bright room 11 and the dark room 12 communicate with each other. The bright room 11 is irradiated with light, and the dark room 12 is not irradiated with light. In addition, a metal wire 14 arranged in parallel with an interval of 1 cm is installed at the bottom, and a current flows.

  The flow of the experiment is as follows. First, each group of rats is put in the light room 11 in turn, and at the same time the gate 13 is opened. Immediately after the rat entered the dark room 12, the gate 13 was closed, and at the same time, a current (100 V, 0.3 mA, 2 sec) was applied to the metal wire 14, and 5 seconds after the current stimulation, the rat was taken out of the dark room and placed in a breeding case return. If the rat does not enter the dark room 12 after 300 seconds, the rat is forced to enter the dark room 12 and the gate 13 is closed. At the same time, an electric current is passed through the metal wire 14 at the bottom of the dark room 12 and returned to the breeding case again. At 24 and 48 hours after training, the rat is placed in the light room 11, and simultaneously the gate 13 is opened, and the rat's step-through latency in the light room 11 is measured and recorded. When the residence time in the light room 11 is 300 seconds or more, the learning memory ability of the rat is considered normal.

  The time until the rat stops in the light room 11 and enters the dark room 12 can be regarded as an index for evaluating the memory learning ability during the passive avoidance test. As shown in FIG. 2, all the rats immediately enter the dark room 12 at the first test due to the characteristics toward darkness, but the rats with normal memory learning ability by the electric shock in the dark room 12 Barking during the test, do not enter dark room 12. Therefore, the time for which each group of experimental animals in the second test stays in the bright room 11 has a significant difference due to the difference in memory learning ability. As the results of the second test show, the time that the Aβ group stays in the light room is significantly lower than the vehicle group. The test groups RL and RH have significantly longer stop times in the light room than the Aβ group (p <0.05). The effect of the lovastatin group is not as good as that of the RL group with homologous monacolin K content, but the effect of memory learning is still significantly higher than the Aβ group.

  Another test apparatus of the present invention, as shown in FIG. 3, is a water labyrinth apparatus 20, whose circular pool 21 has a diameter of 140 cm and an altitude of 45 cm. The pool includes a mobile resting platform P1 (or escape platform). The platform diameter is 12 cm and the altitude is 25 cm. Prior to the experiment, water is added to the circular pool 21 to a liquid level of 27 cm. The circular pool 21 is divided into four quadrants (zones I, II, III and IV), and five are set. The resting platform P1 is installed at the center point of a single quadrant. During the test period, a camera will be installed just above the pool center point, and the swimming route of the experimental animals will be recorded.

  The effect of Alzheimer's disease rats infused with Aβ into the brain of red yeast rice on reference memory learning ability damage is shown in FIG. The time taken for the experimental animal to start from the water labyrinth apparatus 20 and find the resting platform P1 can be regarded as an index for evaluating the reference memory test.

  As the results of memory training from the 2nd to the 9th show, Alzheimer's disease rats infused with Aβ generally found a resting platform P1 compared to the vehicle group with normal memory ability It takes longer time. However, Alzheimer's disease rats (RL and RH pairs) fed with red yeast rice can significantly reduce the time to find (p <0.05). Giving lovastatin reduces the time taken compared to the Aβ group, but the effect is lower than the RL and RH groups, and the homologous search time reveals similar swimming route lengths. In addition, there is no significant difference (data not shown) in the swimming speed between each experimental animal (p> 0.05).

  Spatial sounding test is performed following the last one reference memory test on the 24th day. Resting platform P1 is taken out of the water labyrinth device 20 after the reference memory test is completed, and the time for the experimental animal to crawl in the quadrant where the resting platform P1 was originally placed can be regarded as a memory learning ability index of the spatial exploration test it can. As a result, as shown in FIG. 4A, the time for the Aβ group to search in the target quadrant is significantly lower than that of the vehicle group (p <0.05). The search time in the target quadrant of RL group and RH group is 38.2% (p <0.05) and 48.0% (p <0.01) higher than Aβ group, respectively. This proves that red glutinous rice definitely improved the impairment of memory learning ability in Alzheimer's disease rats. Swimming routes can help determine the truthfulness of memory learning ability performance during laboratory animal spatial exploration testing. As shown in FIG. 4B, the Aβ group searches for the target quadrant in a state where there is no directionality and target during the spatial search test, and the swimming route extends to the entire circular pool 21. Conversely, the RL, RH, and vehicle pairs with optimal memory learning ability swim directly into the target quadrant and stay in the target area for a longer time. However, the group given lovastatin still shows an effect between the RL group and the Aβ group in improving memory learning ability (FIGS. 4B and 4C). The working memory test is a kind of evaluation method for short-term memory learning ability. As shown in FIG. 5, the result of searching for the resting platform P1 in the Aβ group is significantly longer than that in the vehicle group (p <0.01). However, the RL group and the RH group showed the same memory learning effect as the vehicle group of normal memory ability during the working memory test, and the search time was 57.3% and 58.9% respectively compared with the Aβ group. Shortened (p <0.01). The LS group significantly shortened the search time by 26.7% compared to the Aβ group (p <0.05), but the effect is lower than the RL group and the RH group (p <0.05).

  Aβ has already been demonstrated to be a major risk factor for lack of memory learning in Alzheimer's disease patients (Hashimoto et al. 2005; Stephan and Phillips 2005). It has already been demonstrated that the method of injecting Aβ40 into the temporal area of the rat brain can produce an animal pattern of Alzheimer's disease (Stephan and Phillips 2005). Moreover, pattern animals made in this way also have characteristics of memory behavior and poor learning ability (Kar et al. 1998; Schubert et al. 1995; Townsend and Pratico 2005). Injected Aβ induces free radicals and reactive oxygen atoms, and nerve damage and protrusion extension are suppressed, leading to a lack of memory learning ability (Townsend and Pratico 2005). Thus, several studies now reduce these oxidative inflammation risk factors in Alzheimer's disease brains with antioxidants and anti-inflammatory substances and reduce memory learning ability damage (Chauhan et al. 2004; Cordle et al. 2005) .

  Morris water labyrinth test is one of the main methods to evaluate memory learning ability. Of these, the reference memory test is representative of an evaluation method for long-term memory ability, and the working memory test belongs to an evaluation method for short-term memory ability. According to the results of the above memory learning test, Alzheimer's disease rats given double and five times the amount of red yeast rice were able to shorten the search time of the reference memory test and the working memory test (p < 0.05). In addition, the group that gave the red rice was able to extend the search time in the target quadrant during the spatial exploration test. From these results, it can be clearly pointed out that giving red yeast rice can improve memory learning ability and find a resting platform for water labyrinth in a shorter time. In contrast, untreated Alzheimer's rats seek the entire water labyrinth with no target. Thus, more time is spent during the reference memory and working memory tests.

  Monacolin K is one of the main functions and effective components of red yeast rice that lowers cholesterol, and statins are effective in treating Alzheimer's disease because they have anti-inflammatory and anti-inflammatory effects on brain Aβ. (Chauhan et al. 2004; Li et al. 2006). A number of studies on the treatment of Alzheimer's disease all use statins, which suppress the production of brain Aβ in mice transplanted with Alzheimer's disease genes (Yamada et al. 1999). None of the currently known studies yet alleviate the impairment of memory learning ability in Alzheimer's disease pattern rats infused with Aβ by lovastatin. This study uses lovastatin as a substitute for monacolin K in red yeast rice, and the only monacolin K in red yeast rice can reduce memory impairment of Alzheimer's memory learning ability Check if it is a substance. However, as the results of the memory learning test show, the effect of reducing the memory learning ability damage of the group given lovastatin is weaker than that of the RL group having a homologous monacolin K concentration. Thus, it is demonstrated that monacolin K in red yeast rice is not the only effective ingredient to reduce memory damage caused by Aβ.

  Monacolin K is one of the main functions and effective components of red yeast rice that lowers cholesterol, and statins are effective in treating Alzheimer's disease because they have anti-inflammatory and anti-inflammatory effects on brain Aβ. (Chauhan et al. 2004; Li et al. 2006). A number of studies on the treatment of Alzheimer's disease all use statins, which suppress the production of brain Aβ in mice transplanted with Alzheimer's disease genes (Yamada et al. 1999). None of the currently known studies yet alleviate the impairment of memory learning ability in Alzheimer's disease pattern rats infused with Aβ by lovastatin. This study uses lovastatin as a substitute for monacolin K in red yeast rice, and the only monacolin K in red yeast rice can reduce memory impairment of Alzheimer's memory learning ability Check if it is a substance. However, as the results of the memory learning test show, the effect of reducing the memory learning ability damage of the group given lovastatin is weaker than that of the RL group having a homologous monacolin K concentration. Therefore, the consumption of monacolin K can surely and effectively improve the symptoms of Alzheimer's disease caused by Aβ.

  The treatment of Alzheimer's disease is currently focused on suppressing acetylcholine degrading enzyme activity, increasing acetylcholine levels, and improving cognitive and memory behavior (Nabeshima and Nitta 1994). Correlation studies that create Alzheimer's disease pattern animals also demonstrate that continuous infusion of Aβ into the rat brain causes cholinergic neurological decline and deficient neurotoxicity. The study also demonstrates that brain acetylcholine content in Alzheimer's disease rats injected with Aβ into the brain is clearly deficient compared to normal rats (Arendt et al. 1984; Darvesh et al. 2004). As the acetylcholine concentration decreases and the acetylcholine degrading enzyme activity increases, neuronal loss becomes even worse (Stephan and Phillips 2005). In addition, an increase in acetylcholine degrading enzyme activity has also been shown to worsen the extent of Aβ polymerization, and it has been shown to form fibrotic starch-like proteins (Aβfibrils) that are more stable and toxic. (Stephan and Phillips 2005). Therefore, suppression of acetylcholine degrading enzyme activity is recognized as having a neuroprotective action that indirectly suppresses the lack of memory learning ability caused by Aβ. FIG. 6 shows the effect on acetylcholine degrading enzyme activity in rat cerebral cortex and hippocampal tissue injected with Aβ40 of red yeast rice into the brain. In the figure, it can be seen that the acetylcholine degrading enzyme activity of the Aβ group cerebral cortex is 50.5% higher than that of the vehicle group and 179.1% higher in the hippocampal tissue. When double and five times the amount of red yeast rice is given, acetylcholine degrading enzyme activity that Aβ increases is markedly suppressed. However, lovastatin has no inhibitory effect on acetylcholine degrading enzyme activity in cerebral cortex and hippocampal tissue. This result demonstrates that red yeast rice has a substance that suppresses acetylcholine degrading enzyme activity. This substance is not monacolin K but another functional metabolite. There are few studies that lovastatin inhibits acetylcholine degrading enzyme activity, and one study shows that lovastatin has no significant inhibitory effect on acetylcholine degrading enzyme activity. The results of this study agree with the trend of the present invention. In addition to monacolin K, the complex functional metabolite of red yeast rice contains other acetylcholine degrading enzyme inhibitors. Moreover, the metabolite GABA in red yeast rice is also a kind of neurotransmitter and can improve the cognition and memory ability of Alzheimer's disease.

  Aβ has been demonstrated to cause oxidative pressure in the brain of Alzheimer's disease patients. Therefore, suppression of Aβ-induced oxidative pressure is considered to be an important indicator for Alzheimer's disease drug development. As shown in FIG. 7, when Aβ is injected into the brain, it causes total antioxidants status (TAS) in the cerebral cortex and hippocampal tissue, 20.9% and 20.4%, respectively, compared to the vehicle group. Can be reduced. Giving lovastatin can increase TAS in the cerebral cortex by 13.9%, but has no effect in hippocampal tissue. TAS in cerebral cortex and hippocampal tissue of RL group is significantly improved by 24.6% and 46.2%. Moreover, in this study, it was discovered that TAS in the cerebral cortex and hippocampal tissue of Alzheimer's disease rats that give five times the amount of red yeast rice was significantly higher than the Aβ group.

The effect of red yeast rice on the cortical and hippocampal tissue malondialdehyde (MDA) concentration is shown in FIG. MDA concentrations in the cerebral cortex and hippocampal tissue rose significantly by 95.3% and 112%, respectively, after injecting Aβ into the brain, but this increase in MDA concentration effectively increased the amount of red yeast rice given. Can be reduced.
The superoxide dismutase (SOD) activity in the cerebral cortex and hippocampal tissue of the RL and RH groups also exhibits a similar neuroprotective effect (see FIG. 9). SOD activity in cerebral cortex and hippocampal tissue is reduced by 19.8% and 25.2%, respectively, by Aβ injected into the brain.However, when double doses of red yeast rice are given, the SOD activity in cerebral cortex and hippocampal tissue is 27.2%, respectively. % And 52.7% increase, and giving 5 times as much red yeast rice will increase 27.2% and 60.9%, respectively.

  As can be seen from the above results, both cerebral cortex and hippocampal tissue of Alzheimer's disease pattern rats with impaired memory learning ability have severe oxidative pressure. However, these oxidation pressures are improved by giving red yeast rice per day, and the effect is not only having a dose-effect relationship but also superior to the group given lovastatin. Antioxidants in red yeast rice fermentation products that are already known include dimerumic acid, tannin, phenol, monounsaturated fatty acid and sterol ( sterols) (Aniya et al. 1999; Wang et al. 2006).

  Thus, the antioxidants of the present invention are dimerumic acid, tannin, phenol, monounsaturated fatty acid, sterols and superoxide dismutase (SOD). Select any kind from.

  The results of the in vivo animal test of the present invention are as shown in FIG. 10A. When Aβ is injected into the brain, the reactive oxygen species (ROS) concentrations in the rat cerebral cortex and hippocampal tissue are significantly 39.8% and 28.7%, respectively. Go up (p <0.05). ROS concentrations in both cerebral cortex and hippocampal tissues of Alzheimer's disease rats fed red yeast rice per day decrease. Among them, the RL group can reduce 16.0% (p <0.05) and 21.2% (p <0.05), respectively, and the RH group can decrease 35.4% (p <0.01) and 21.3% (p <0.05), respectively. it can. Ingestion of lovastatin reduces ROS levels in the cerebral cortex by 29.3% and in hippocampal tissues by 15.7% (p <0.05). As shown in the immunohistochemical staining in FIG. 10B, the expression level of inducible nitric oxide synthase (iNOS) in hippocampal tissue markedly increases the inducible nitric oxide synthase (iNOS) expression level. The expression level of inducible nitric oxide synthase (iNOS) expressed in the hippocampal tissues of the RL group and the RH group is remarkably suppressed. However, it can be seen that the effect on anti-inflammation is inferior to the lovastatin intake group compared to the double and 5-fold dose of red yeast rice intake group.

  ROS concentrations in cerebral cortex and hippocampal tissues of Alzheimer's disease rats decrease more markedly when the amount of red yeast rice intake is increased. Lovastatin has been demonstrated to effectively reduce the inflammatory response caused by Aβ in cell patterns, but such effects have not been demonstrated in animal patterns. Moreover, the anti-inflammatory effect of statins has also not been applied to reduce memory learning ability damage in Aβ brain-injected Alzheimer's disease rats. In this study, ingestion of lovastatin can significantly reduce the ROS content in brain tissue and the expression level of inducible nitric oxide synthase (iNOS). Proven to be inferior. In recent years, the health function of red yeast rice metabolites has been gradually developed and researched, and many anti-inflammatory substances have been discovered one after another. Among them, various forms of monacolins, 6 types of azaphilones, monascin, ankaflavin, rubropunctatin, monascorburin, rubropunctamine ), Monascorburamine, two furanoisophthalides, xanthomonasin A and xanthomonasin B, and two amino acids, (+)-monascu Contains monascumic acid and (-)-monascumic acid (Schubert et al. 1995). Thus, monacolin K is not the only metabolite that reliably suppresses the inflammatory response caused by Aβ. In 2005, Akihisa et al. Suppressed the inflammatory reaction caused by 12-O-tetradecanoylphorbol-13-acetate (TPA) by red rice in the mouse animal pattern. It was proved that the new anti-inflammatory substances are compounds of azaphilones and furanoisophthalides. By combining the results of in vitro and in vivo animal assessments and correlative studies of red yeast rice anti-inflammation, the suppression of red yeast rice Aβ-induced inflammatory response is mainly due to monacolin K and other anti-inflammatory substances. It can be said that this is due to the joint mechanism presented jointly.

  Therefore, the anti-inflammatory substances shown by the present invention are γ-aminobutyric acid (GABA), monascin, ankaflavin, rubropunctin, monascorburin, monascorburin, Bropuncamine, monascorburamine, xanthomonasin A, xanthomonasin B, (+)-monascumic acid and (-)-monascumic acid ) Select any one of them.

  After continuous injection of Aβ40 into rat hippocampal tissue for 28 days, as can be seen from the comparison results in FIG. 11 and the vehicle group, a large amount of Aβ40 precipitates are found in the Aβ group of hippocampal tissue. As can be seen from the above results and known studies, injected Aβ40 causes oxidative pressure and inflammatory reaction in the brain, causing precipitation of Aβ40. Increasing the content of precipitated Aβ40 causes severer oxidative pressure and inflammatory reaction, and repeats the vicious cycle, leading to continuous deterioration of brain damage. Lovastatin has the effect of suppressing the inflammatory response caused by Aβ40, but has a relatively weak capacity for antioxidant pressure. Thus, the results show that Aβ40 in the hippocampal tissue of the LS group is somewhat lower than the Aβ group, but there is still a large amount of Aβ40 precipitated. RL group and RH group of red yeast rice intake show a remarkable effect of reducing the cumulative amount of Aβ40. Red yeast rice reduces the cumulative amount of Aβ40 in hippocampal tissue, mainly due to suppression of oxidative pressure and inflammatory response. Aβ40 injected into the brain is not affected by oxidative inflammatory substances and does not precipitate. Thus, Aβ40 cannot cause damage to the brain, thus effectively improving the ability of memory learning.

All of the pharmaceuticals containing monacolins, anti-inflammatory substances and antioxidants for treating Alzheimer's disease of the present invention can improve the symptoms of Alzheimer's disease in red rice.
In the first embodiment, the effective minimum content of monacolins in 1 g of red yeast rice is at least 100 μg and the effective minimum content of antioxidants in 1 g of red rice is at least 40 μg and 1 g The effective minimum content of anti-inflammatory substances in red yeast rice is at least 10 μg or more.
Among them, when the optimum weight ratio of monacolins, inflammatory substances, and antioxidants was 40: 2: 1, the optimum effect was achieved in the first embodiment. In addition, the effective weight ratio of monacolins, inflammatory substances, and antioxidants can be implemented from 10: 4: 1 to 90: 2: 1, and can be applied in the form of tablets, capsules, powders, beverages, etc. Can be provided for consumer use.

In addition, in the second embodiment, the effective minimum content of monacolins in 1 g of red yeast rice is at least 200 μg and the effective minimum content of anti-inflammatory substances in 1 g of red rice is at least 60 μg. In some medicines , the benefits during the above process are also seen. In this second embodiment, monacolins and anti-inflammatory drugs can be used to treat Alzheimer's disease, and the optimal weight ratio of monacolins to inflammatory substances is 10: 1. In the second embodiment, the optimum effect was achieved. In addition, the effective weight ratio range of Monacolins and inflammatory substances can be implemented in the second embodiment from 10: 3 to 45: 1, and can be applied to consumer systems such as tablets, capsules, powders and beverages. Can be used for taking.

  The anti-inflammatory substance contained in red yeast rice is γ-aminobutyric acid (GABA), and since red yeast rice is a natural food and is fermented and refined by a specific method, it is clear to the human body. Does not cause any adverse side effects. Therefore, if red yeast rice is used as a cooked food for treating Alzheimer's disease, not only the effect is remarkable, but various side effects caused by general medicines on patients do not occur. In other words, it is an invention that brings happiness to mankind.

As shown in FIGS. 12, 13, and 14, the method for producing a medicament for treating Alzheimer's disease of the present invention is as follows.
First, the rice is washed and sterilized in a high pressure and high temperature environment (step 100). This kind of rice is, for example, a rice variety peculiar to Taiwan. This high pressure and high temperature environment is a pressure environment of 121 ° C. and 1 kg / cm 2.
Subsequently, the red yeast strain is planted in the inoculum culture medium, and is contacted in the first specific temperature and humidity environment, the specific vibration environment, and the first specific time limit (step 110). This inoculum culture medium is composed of at least 5 g of the rice soaked in 100 ml of distilled sterile water. This first specific time limit refers to 48 hours later, and this first specific temperature is maintained at 30 ° C. Hold at 100 to 150 rpm (revolutions per minute). In other words, inoculate the red yeast strain into the inoculum culture medium, maintain the vibration at 30 ° C and 125 rpm, and incubate for about 48 hours. Weigh 500 g of solid culture medium, soak in water for 6-8 hours after washing. After draining with gauze, place it on the cloth, spread it flatly on the grid, and sterilize (121 ℃, 20-25 min). Sprinkle 100 mL of water. The second sterilization is performed (121 ° C, 20 min), followed by sterilization after cooling. Take the seed solution in a solid substrate (5%) and stir well to make it uniform.

  Subsequently, the inoculum culture medium is stirred in the first specific temperature environment, and a specific ratio of water is continuously provided within the second specific time limit (step 120). This second specific time limit refers to within 72 hours, this specific ratio of water refers to 20% distilled sterile water, and within 72 hours, the inoculum culture medium is stirred every 24 hours, and 20% Refill with distilled sterile water and incubate in a constant temperature box at 30 ° C.

  Further, afterripening is achieved by appropriately stirring within the third specific time limit and at a constant time in the first specific temperature environment (step 130). Afterripening refers to the stage of metabolite production, within this third specific time limit refers to within 96 hours, and this fixed time refers to every 10 hours. Within 96 hours, stir the seed culture medium appropriately every 10 hours on average.

  Next, the fermented red yeast rice after the completion of fermentation is taken out, and the second specific temperature is maintained within the fourth specific period and dried (step 140). The fourth specific period refers to within 24 hours, and the second specific temperature refers to maintaining 55-60 ° C. Take the koji at this step, take out the fermented red koji ferment after completion of the fermentation, and perform a drying process at 60 ° C. for 24 hours in a drying box.

Subsequently, the already dried fermented red yeast rice powder is crushed into a powder form and analyzed to determine whether it meets the component ratio conditions (step 150). The component ratio conditions the medicament and is monacolin (monacolins), anti-inflammatory agents, including antioxidants, the range of effective weight ratio of the three types of substance 10: it is a 1: 4: 1 to 90: 2 Point to. In this range, it is confirmed whether or not the component ratio condition is satisfied. If not, the process is terminated because it indicates that the manufacturing process has failed.

  The range confirmation further includes step A and step B. As shown in FIGS. 13 and 14, after step A, the prepared red yeast rice fermented powder is added to the edible beverage in a specific ratio to produce a red yeast rice beverage that can treat Alzheimer's disease. (Step 160), and the manufacturing process is completed. This specific proportion is between 1.0 and 4.0%.

After Step B, the prepared fermented red yeast rice powder is filled in a capsule or manufactured into a tablet (Step 170) to complete this manufacturing process.
This production method can be cultivated through a traditional grid. Produces relatively small grids with lengths, widths and heights of about 20 x 30 x 5 cm each.

  When culturing, place a cloth on the bottom layer and wrap the solid substrate. This is advantageous for turning the jar upside down, and at the same time, the humidity can be maintained.

The upper layer can be covered with cocoon cloth to prevent contamination from the outside world, and at the same time, the humidity of red yeast rice can be maintained during the fermentation process. The entire culture process is performed in an open space. Thus, the medicine of the present invention can be reliably implemented through this production method, and can be applied to tablets, capsules, powders, beverages and the like.

  Although the present invention has been disclosed above with respect to the preferred embodiment, this is not intended to limit the invention. Anyone who is familiar with the technology, as long as it does not depart from the product and domain of the present invention, includes any monacolins, anti-inflammatory substances, antioxidants that treat Alzheimer's disease. Various fluctuations and moist colors can be added. Therefore, the protection scope of the present invention is based on the contents specified in the claims.

It is an instruction | indication figure of this invention test device. It is a time statistic chart until a rat stops in a bright room and enters into a dark room. It is an indication figure of the water labyrinth device of the present invention and a branch area. It is a memory learning ability influence figure in a reference memory test and a probe test with respect to the rat which inject | poured the red amyloid beta40 (Abeta40) into the brain. This is the memory learning ability during working memory test on rats injected with Aβ40 of red yeast rice into the brain. It is an influence figure on rat cerebral cortex and hippocampal tissue acetylcholine degrading enzyme activity which injected Aβ40 of red yeast rice into the brain. FIG. 2 is a comparison of total antioxidant status (TAS) in rat cerebral cortex and hippocampal tissue injected with Aβ into the brain. It is an influence figure on the rat cerebral cortex and hippocampal tissue malondialdehyde (MDA) concentration of red yeast rice. It is an influence figure with respect to the superoxide dismutase (Superoxide dismutase, SOD) activity of a red yeast rice in rat cerebral cortex and hippocampal tissue. This is the effect on the reactive oxygen atom (ROS) content in hippocampal tissue and the expression level of inducible nitric oxide synthase (iNOS) in hippocampal tissue and rat cerebral cortex injected with Aβ40 into the brain of red yeast rice. It is a precipitation instruction | indication figure of A (beta) 40 after continuously inject | pouring A (beta) 40 into the hippocampal tissue of a rat. It is the manufacturing method of the pharmaceutical for treating Alzheimer's disease of this invention. It is the manufacturing method of the pharmaceutical for treating Alzheimer's disease of this invention. It is the manufacturing method of the pharmaceutical for treating Alzheimer's disease of this invention.

10 Test apparatus 11 Light room 12 Dark room 13 Gate 14 Metal line 20 Water labyrinth apparatus 21 Circular pool P1 Rest platform step 100 Some rice is washed and sterilized in a high-pressure and high-temperature environment.
Step 110 A specific red yeast strain is planted in an inoculum culture medium, and is contacted in a first specific temperature / humidity environment, a specific vibration environment, and a first specific time limit.
Step 120 The inoculum culture medium is stirred in the first specific temperature environment to continuously provide a specific ratio of water within a second specific time limit.
Step 130: After the third specific time limit and within the first specific temperature environment, after stirring for a certain period of time, afterripening is achieved.
Step 140 Take out the fermented red yeast rice after fermentation, hold the second specific temperature within the fourth specific period, and dry it.
Step 150 The already dried dried red yeast rice fermented product is ground and powdered, and analyzed to determine whether the composition ratio is met.

Claims (22)

The drug for treating Alzheimer's disease is red yeast rice , the effective minimum content of monacolins is 100 μg or more per 1 g of the red yeast rice , and the effective minimum content is 10 μg or more per 1 g of the red yeast rice . medicament for treatment with an anti-inflammatory agent, an Alzheimer's disease effective minimum content to the red yeast rice 1g is characterized the early days including the more antioxidants 40 [mu] g. The antioxidant is a combination of dimerumic acid, tannin, phenol, monounsaturated fatty acid, sterols and superoxide dismutase (SOD). The medicament for treating Alzheimer's disease according to claim 1, wherein one is arbitrarily selected. The anti-inflammatory substances are γ-aminobutyric acid, monascin, ankaflavin, rubropuntine, rubropunctatin, monascorburin, rubropunctamine, monascorburamine ), Xanthomonasin A, xanthomonasin B, (+)-monascumic acid and (-)-monascumic acid The medicament for treating Alzheimer's disease according to claim 1. The medicament for treating Alzheimer's disease according to claim 1, wherein the optimal weight ratio of the monacolins, the anti-inflammatory substance, and the antioxidant is 40: 2: 1. 2. The Alzheimer's disease according to claim 1, wherein the effective weight ratio of the monacolins, the anti-inflammatory substance, and the antioxidant is 10: 4: 1 to 90: 2: 1. For medicine . The drug for treating Alzheimer's disease is red yeast rice , the effective minimum content of monacolins with a minimum effective content of 200μg per 1g of red yeast rice, and the effective minimum content of 60μg or higher with respect to 1g of red yeast rice medicament for treatment with an anti-inflammatory agent, an Alzheimer's disease characterized by the early days including the. The anti-inflammatory substances include γ-aminobutyric acid, monascin, ankaflavin, rubropunctin, rubropunctatin, monascorburin, rubropunctamine, monascorburamine ), Xanthomonasin A, xanthomonasin B, (+)-monascumic acid and (-)-monascumic acid The medicament for treating Alzheimer's disease according to claim 6. A method for producing a medicament for treating Alzheimer's disease, comprising:
The rice is washed and sterilized under high pressure and high temperature,
A red yeast strain is planted in a fungus culture medium and contacted in a first specific temperature / humidity environment, a specific vibration environment, a first specific time limit,
Stirring the inoculum culture medium in the first specific temperature environment, continuously providing a specific ratio of water within a second specific time limit;
Within the third specified time limit and in the first specified temperature environment to achieve after ripening with proper stirring at regular intervals,
Take out the fermented red yeast rice after the completion of fermentation, keep it at the second specified temperature within the fourth specified period and dry it,
The dried dried red yeast rice fermented product is ground and powdered, and the effective weight ratio of monacolins, anti-inflammatory substance and antioxidant contained in the medicine is from 10: 4: 1 to 90: 2: 1 Analyzes whether the component ratio condition is within the predetermined ratio range,
A pharmaceutical for treating Alzheimer's disease, characterized in that the preparation of the fermented red yeast rice powder that has been prepared is added to the edible beverage at the predetermined ratio to produce a red yeast beverage that can treat Alzheimer's disease Manufacturing method. The method for producing a medicament for treating Alzheimer's disease according to claim 14, wherein the high-pressure and high-temperature environment is a pressure environment of 121 ° C and 1 kg / cm2. 9. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the inoculum culture medium is composed by soaking at least 5 g of the rice in 100 ml of distilled sterile water. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the first specific temperature is maintained at 30 ° C. 9. The method for producing a medicine for treating Alzheimer's disease according to claim 8, wherein the specific vibration environment is maintained between 100 and 150 rpm (revolutions per minute). 9. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the first specific time limit refers to 48 hours later. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the second specific time limit refers to within 72 hours. 9. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the specific ratio of water refers to 20% distilled sterile water. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the third specific time limit is within 96 hours. The method for producing a medicine for treating Alzheimer's disease according to claim 8, wherein the fixed time refers to every 10 hours. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the fourth specific period is within 24 hours. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the second specific temperature refers to maintaining between 55 ° C and 60 ° C. 9. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the optimal weight ratio of the monacolins, the anti-inflammatory substance and the antioxidant is 40: 2: 1. The method for producing a medicament for treating Alzheimer's disease according to claim 8, wherein the specific proportion is between 1.0 and 4.0%. The step of analyzing the already dried dried red yeast rice fermented powder into a powder form and analyzing whether or not it meets the component ratio conditions further comprises filling the ready-made red yeast rice fermented powder in a capsule or tablet The method for producing a medicament for treating Alzheimer's disease according to claim 8, comprising the step of:

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