Herbal Drugs in Traditional Japanese Medicine

Western medicine often regards patients as sets of individual organs, and illnesses are often at‐ tributed to pathogens or morbid organs that should be removed. However, Asian traditional medicine, including TJM and TCM, understand patients from a holistic perspective that em‐ phasizes the importance of balancing and harmonizing the entire patient, including her or his mind and body. Asian forms of medicine explain changes in symptoms in terms of causes, and treatments are prescribed based on a view of diseases as dynamic processes [1,2].


Introduction
Medicinal herbs are used in the context of ethnic traditions in various regions of the world. Although modern medicine, based on Western medicine, is practiced in developed countries, traditional medicine is also an important part of treatment in Asian countries.
Traditional Chinese medicine (TCM) influences traditional medicine in Asian countries as a function of the cultural and historical relationships between each country and China. That is, traditional medicine has developed in each country under the influence of TCM in the context of its own cultural background.
This chapter examines traditional Japanese medicine (TJM), an alternative form of medicine used in Japan. Although acupuncture, moxibustion, and several related medical practices also play important roles in TJM, herbal medicine, as the most characteristic treatment within TJM, is the focus of this chapter.

Relationship between TJM and TCM
Western medicine often regards patients as sets of individual organs, and illnesses are often attributed to pathogens or morbid organs that should be removed. However, Asian traditional medicine, including TJM and TCM, understand patients from a holistic perspective that emphasizes the importance of balancing and harmonizing the entire patient, including her or his mind and body. Asian forms of medicine explain changes in symptoms in terms of causes, and treatments are prescribed based on a view of diseases as dynamic processes [1,2].
Basic medical concepts are common to both TJM and TCM, and practitioners of these disciplines arrive at diagnoses via four basic approaches.
Historical books, such as Koji-ki (Records of Ancient Matters) (712), include descriptions of the use of reed mace (Typha spp., Fig. 2) for injury. Koji-ki records historical matters or folklores of the prehistoric ages in Japan.
Cultural exchanges, including those involving envoys to the Tang Dynasty (7th-9th centuries), and trade with China brought various crude drugs to Japan. Some of these drugs are the "Shosoin drugs" of today.TJM was practiced by Buddhism priests during those eras. Chinese medicine changed based on historical changes in the dynasties, and the Chinese medicine of each era, until the present one, has influenced Japanese medicine. Chinese medicine was introduced during the Yuan dynasty in Japan and was practiced by Sanki Tashiro (1465-1537) and his successors, including Dosan Manase (1507-1594), who developed the medicines. They were known as the Gosei-ho-ha (the Latter-day Medicine School). The medicine taught by this school was based on two principles [Yin (active/positive) and Yang (inactive/negative)] combined with five elements (wood, fire, earth, metal, and water). The pharmacological characteristics of the herbal/crude drugs were separated into five tastes (pungent, sweet, sour, bitter, and salty) based on the five-element theory. Other characteristics, such as emotions, which may affect illnesses, are also attributed to the five elements (Table 1) [2,3].
A trend toward a return to the fundamentalism of Confucianism appeared in China during the Ming Dynasty (14th-17th centuries), and an analogous fundamentalism was also seen in Chinese medicine. Some leaders in this field advocated reliance on the ideas or spiritual content related to medicine in the Shokan-zatsubyo-ron (Shang-Han-Za-Bing-Lun in Chinese, "Treatise on Cold Damage Disorders and Accompanied Various Diseases") edited by Zhong-Jing Zhang during the Han Dynasty (BC200-AD200).  These ideas affected the leading physicians in Japan, who stressed that medicine in Japan should be based on Shokan-zatsubyo-ron, which was established in the Han Dynasty. Gonzan Goto (1659-1733) was such a physician, and he insisted on considering diseases to be based on ki (qi in Chinese) stagnation. Goto mentored many younger physicians, who were known as Koho-ha (fundamentalists). Toyo Yamawaki, one such physician, guided dissections and prepared a book entitled Zo-shi ("Records of Human Organs"), in which he clarified the differences between the actual structure of the human body and the structure depicted by TCM. Followers of this school insisted on practical evidence or actual results from medical trials. Todo Yoshimasu established a new approach to medicine based on this foundation.

Yoshimasu's TJM
Todo Yoshimasu established a new approach to medicine based on the notions described above. He was regarded as a highly skilled physician and contributed to new developments in the area of medical diagnosis. He stressed the importance of the abdomen, in addition to that of the radial artery pulse, in diagnosis. He actually simplified the causes of various diseases based on his unique "one-poison theory" and thereby eliminated conceptual confusion [1,[3][4][5].
However, Yoshimasu's most important contribution concerned the use of herbal prescriptions. During the Edo era, Honzo-komoku (Ban-Cao-Gang-Mu in Chinese, "Compendium of Materia Medica") (1590, Ming Dynasty), written by Shi-Zhen Li (1518-1593), was the most authoritative book in Asia, including Japan, to describe the efficacy of herbal drugs. However, Yoshimasu decided to revise sections on the effects of herbal drugs as he thought that the descriptions in the book were useless in terms of practical clinical applications. Yoshimasu thought that the descriptions were written under the influence of delusions/superstitions based on ethnic religion.
Thus, he first addressed cases in which major prescriptions are used for Shokan-zatsubyoron. Shokan-zatsubyo-ron is composed of two parts, which were identified separately. Shokan-ron (Shang-Han-Lun in Chinese, "Treatise of Cold Damage Disorders"), which addresses acute feverish diseases and Kinki-yoryaku (Jin-Gui-Yao-Lue in Chinese, "Essential Prescriptions as A Treasure Box"), which addresses sub-acute and chronic diseases.
He also added discussion based on his clinical experience concerning the uses of each prescription. These were gathered in Ruiju-ho ("a classified collection of prescriptions"). In Shokan-zatsubyo-ron, the author indicated the uses of each prescription during the course of an illness. However, the author did not explain the reasons for using each prescription, but instead stated that the physician should "just use it in exemplar cases." In this way, Todo Yoshimasu clarified the actions of the prescriptions by analyzing the kind of case in which it should be used.
Yoshimasu then began to collect the herbal drugs to be used in prescriptions. He gathered descriptions of the prescriptions containing each herbal drug from Shokan-zatsubyo-ron and discussed the effects of each herbal drug based on commonalities in the properties of prescriptions containing the drug. In other words, common symptoms referenced in the descriptions of the prescriptions were regarded as related to the herbal drug that was common to the prescriptions. He learned about the efficacy of each of the herbal drugs from Shokanzatsubyo-ron by comparing it with his clinical experience. Such knowledge was collected in Yaku-cho ("Properties of Herbal Drugs").
For example, the action of the herbal drug licorice is discussed as follows: Although licorice (root with stolon of Glycyrrhiza uralensis Fisch. or G. glabra L.) is included in many prescriptions, prescriptions containing a particularly large quantity of licorice are shakuyaku-kanzoto ("peony and licorice combination"), kanzo-kankyo-to ("licorice and ginger combination"), kanzo-shashin-to ("pinellia and licorice combination"), and kan-baku-taiso-to ("licorice and jujube combination"). Based on the cases described in the literature that involved use of these prescriptions and on comparisons with his own clinical experience, he concluded that licorice suppressed various otherwise imminent symptoms.
He next listed the effects of each prescription based on the actions of the constituent crude drugs he had examined. These findings are summarized in the book Ho-kyoku ("The Ultimate Properties of the Prescriptions").
For example, the keishi-to ("cinnamon combination") prescription, which is composed of cinnamon (bark of Cinnamomum cassia Blume), peony (root of Paeonia lactiflora Pall.), licorice, jujube (fruit of Zizyphus jujuba Mill. var. inermis Rehd.), and ginger (rhizome of Zingiber officinalis Rosc.), is used for patients with some upward streams such as hot flashes, headaches, fevers, sweats, and dislike of wind (feeling sick when exposed to wind). According to Yoshimasu, keishi-ka-kakkon-to ("cinnamon and pueraria combination"), formed by adding pueraria (root of Pueraria lobata Ohwi), should be used for patients with keishi-to symptoms in combination with "tension from the nape to the back," which indicated that pueraria should be added.
Another example is seen in the addition of peony (i.e., an increase in the amount of peony in keishi-to) to form keishi-ka-shakuyaku-to ("cinnamon and peony combination"). If the patient exhibited intense convulsions of the rectus abdominis in addition to the symptoms of keishi-to, a prescription with an excess amount of peony was used, as per Ho-kyoku.
In summary, Yoshimasu reorganized descriptions of the efficacy of prescriptions using the following analytical procedures: 1. Collecting information on the uses of prescriptions from Shokan-zatsubyo-ron.

2.
Clarifying the efficacy of the respective herbal drugs based on the uses of the prescriptions containing those herbal drugs.

3.
Identifying the effectiveness of prescriptions based on the efficacy of the constituent herbal drugs.
This simplification by Yoshimasu was quite useful for understanding the uses of herbal prescriptions in TJM today and also for clarifying the pharmacological properties of the herbal drugs constituting the prescriptions. Based on this simplification, herbal drugs can be linked to modern analyses of Oriental medicine to understand drug actions in ways that are analogous to those that enable understanding of Western medicine.
However, such a simplification ignores the notion that an illness should be understood in terms of sequential stages or states of the patient. Considering that, physicians of the Secchu (compromising) School, including Sohaku Asada (1815-1894), avoided extreme simplification and proposed that the good points of the theories underpinning both the Koho and the Gosei-ho should be used. The current major trend in TJM is based on his efforts.

Differences in herbal drugs used in TJM and TCM
The two forms of herbal medicine differ with respect to prescriptions and crude drugs. Many herbal drugs used in TCM are also used in TJM. However, it had been difficult to import herbal products from China to Japan during the Edo era because of the Japanese national policy of isolation. During this era, Japanese herbalists searched for plant materials that could act as alternatives to Chinese materials. Thus, the following are examples of differences between the plant materials used in TCM and TJM [6].
1. (Fig. 3a and b) Nin-jin: Japanese ginseng (chiku-setsu-nin-jin in Japanese, rhizome of Panax japonicus C. A. Meyer, family Araliaceae) used in TJM is much more effective than is Korean ginseng (ninjin in Japanese, root of P. ginseng C. A. Meyer, ren-shen in Chinese) for stomach diseases accompanied by an epigastric obstruction (shin-ka-hi, Xin-xia-pi in Chinese). Thus, TJM and TCM both use P. ginseng root as a nourishing tonic.
2. (Fig. 3c) To-ki: Root of Angelica acutiloba Kitagawa (or A. acutiloba Kitagawa var. sugiyamae, family Umbelliferae) is used as To-ki (for soothing pain, corresponding to donggui in Chinese) in TJM, whereas the root of A. sinensis Diels is used in TCM.
3. (Fig. 3d) Sen-kyu (Kyu-kyu): Rhizome of Cnidium officinale Makino (family Umbelliferae) is used as sen-kyu (Cnidium rhizome) in Japan (corresponding to chuan-xiong in Chinese) for soothing pain and is often used in combination with to-ki. The use of Ligusticum chuangxiong (family Umbelliferae) originated in TCM.

5.
Ko-boku: Magnolia bark is used in both TJM and TCM for distension from the chest to the stomach that is due to a digestive organ disorder, which is often accompanied by pain, and also for relief of bronchitis.  These differences should be understood when these herbal drugs are used clinically and studied in research settings.

Constituents of herbal drugs used in TJM
This section discusses studies on the constituents of the herbal drugs that are used in TJM and in our laboratory. Yoshimasu's work on the practical aspects of herbal drugs is quite useful for researchers attempting to understand the uses of herbal drugs in TJM, and the researchers in our laboratory are searching for new constituents based on such materials rather than considering the implications of the complex theories underlying TCM.

Hydrolyzable tannins of Geranium thunbergii
Hydrolyzable tannins are esters of galloyl and related polyphenolic acyl groups with glucose or some other sugars/polyalcohols. Although various types of hydrolyzable tannins have been found in plants, geraniin (1) is a representative one among them [7]. One of the most important herbal drugs in Japan is the geranium herb, the overground parts of G. thunbergii. The main constituent is crystalline tannin geraniin (1), and the structure containing a dehydrohexahydroxydiphenoyl group (1') was reported in 1977 [8]. Although this compound equilibrates in a mixture, the structural factor forming the mixture was not clarified at that time. Detailed analysis with 1 H and 13 C nuclear magnetic resonance spectra revealed that it forms a mixture of six-membered (1a) and five-membered hemi-ketal structures (1b) (Fig. 4) [9]. An X-ray analysis of crystalline geraniin revealed the 1a form with seven molecules of water [10].  (1) forming an equilibrium mixture of six-membered hemi-ketal (1a) and five-membered hemi-ketal (1b) forms. Structure 1 was assigned to geraniin, firstly.
Because some hydrolyzable tannins show noticeable effects on β-lactam resistance of methicillin-resistant Staphylococcus aureus (MRSA) [16][17][18], we examined the effects of several available tannins, and repandusinic acid A and corilagin showed a noticeable suppressive effect on oxacillin resistance of MRSA [13].

Proanthocyanidins of Saxifraga stolonifera
Saxifraga stolonifera Curtis (family Saxifragaceae) is used as an ethnic medicine in Japan and China. A study of the constituents of this plant revealed that the major polyphenolic constituents of the overground part are proanthocyanidins, which are highly galloylated at O-3 of the respective flavan [(-)-epicatechin unit] in addition to 11-O-galloylbergenin (7) [20,21]. An oligomeric proanthocyanidin fraction, Ss-tannin-1 (8), with a molecular weight of 2300 shows potent antioxidant effects on lipid peroxidation in rat mitochondria induced by adenosine diphosphate (ADP) and ascorbic acid, and on that in rat microsomes induced by ADP and nicotinamide adenine dinucleotide phosphate [21]. Among the isolated constituents from this plant (Fig. 6),    (11)] are the major constituents of A. princeps and A. montana [23] (Fig. 7). The aboveground part of Perilla frutescens Brit. var. acuta Kudo (or P. frutescens Brit. var. crispa Decne., family Labiatae) is used as so-yo or shi-so-yo for regulating energy flow or treating bronchial asthma and bronchitis in TJM and is used in analogous ways in TCM under the name zi-su-ye. Our study on the leaf constituents revealed that rosmarinic acid (an ester of caffeic acid with 3,4-dihydroxyphenyllactic acid, 12) is a major constituent and showed that instability during the drying process of the leaves should be considered when using this herbal drug [24] (Fig. 7).
Caffeoylquinic acids show inhibitory effects on histamine release from rat peritoneal mast cells [25,26] and also on the formation of leukotriene B4 (LTB4) in human polymorphonuclear leukocytes (PMN-L). Rosmarinic acid shows a strong inhibitory effect on the formation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid and LTB4 in PMN-L [25]. Because arachidonate metabolism is related to allergic inflammation and asthma, these results suggest that the effects of these constituents may participate in the actions of the herbal drugs containing them.

Flavonoids and 3-arylcoumarins from licorice
Licorice, the root (with stolon) of Glycyrrhiza uralensis and G. glabra, is widely applied in various TCM and TJM prescriptions. Although glychyrrhizin and related triterpene glycosides are regarded as the major constituents, Japanese researchers have reported on the importance of flavonoids and related phenolics [27].

Licoricidin
These findings suggest that licorice is a useful herbal source for the development of the primary constituents of the compounds used in modern medicine.

Ameliorating effect of extracts from Polygala root and Uncaria hook on scopolamineinduced impairment of spatial cognition
It is very important to develop new drugs for the treatment of patients with dementia as the number of individuals with this condition is now rapidly increasing due to the increase in the elderly population. The root of Polygala enuifolia Willd. (on-ji in Japanese and yuan-zhi in Chinese; family Polygalaceae) is used in TJM and TCM prescriptions for forgetfulness, neurasthenia, and insomnia. An investigation to identify the constituents of this herbal drug that are effective for impaired spatial cognition was conducted in rats using an eight-arm radial maze task. This task is useful for discriminating shshort-term memory from long-term one. The results showed that sinapic acid had the most potent effect among the cinnamic acid derivatives examined. Sinapoyl derivatives such as 3,6'di-O-sinapoylsucrose (21) are contained in this plant [33]. Analogous results have been obtained for phenolic constituents, including (+)-catechin of Uncaria hook (stem with hooks of Uncaria rhynchophylla Miq., U. sinensis Havil., and U. macrophylla Wall.; cho-to-ko in Japanese, gou-teng in Chinese; family Rubiaceae) [34]. Further studies of the adsorption/metabolism process and the mechanisms are required.

Conclusion
Explanations of the pharmacological properties of herbal drugs based on TJM concepts have been useful for identifying new compounds with various structures. These explanations are also useful for understanding the roles of herbal prescriptions and applications in modern medicine. Modern medicine should consider some of the basic concepts of traditional medicine as they may contain wisdom.