Agarwood from Aquilaria plants, also known as Chen Xiang (沉香), is traditionally used for the treatment of abdominal pain and as a sedative. Because of the great demand and the rareness of agarwood, extensive harvesting of Aquilaria plants has nearly led to the extinction of the species. To fully utilize this resource, the use of different parts of Aquilaria needs to be investigated. This article will focus on the pharmacological properties and the mechanism of action of different parts of Aquilaria plants.
Agarwood is a dark resinous material found in the trunk of wounded Aquilaria plants. It is also known as Chen Xiang (沉香) in Chinese, Kritsana in Thai, and Agar in India. The word Chen (沉) means sink, while Xiang (香) means fragrance or incense. As the Chinese name implies, this wood has a strong fragrance and is burnt as incense. The aromatic oils present in agarwood mean agarwood to be heavier than water; thus, agarwood sinks rather than floats when placed in water. Currently, there are 17 species of Aquilaria known to produce agarwood. Among these species, Aquilaria malaccensis and Aquilaria crassna are the most well-known species and are commonly found in the Southeast Asian countries such as Thailand, Indonesia, Cambodia, Laos, Vietnam, and Malaysia. Agarwood is formed unevenly in the stem of the plant. Naturally grown Aquilaria generally does not contain a large amount of agarwood, and it is estimated that only 10% of natural Aquilaria species are potent to produce agarwood. Generally, agarwood can only be obtained from injured Aquilaria plants. When injured, the plant responds to the stimulation by activating secondary biosynthetic pathways to produce a resinous compound. This response is initiated by injuries, such as wounds and bacterial and fungal infections. The main markets for agarwood are in the Middle East, South Asia, and East Asia. As the use of agarwood is increasing, there is a growing demand for agarwood. Because of both the difficulties in the production of agarwood and the high demand for the product, the price of agarwood ranges from 20-6000 USD/ kg per kilogram. In addition, the price of essential oils extracted from agarwood can be as high as 30, 000 USD/kg, depending on the grade and quality of the agarwood. The quality of agarwood was traditionally assessed by the resin content, density, color, scent/aroma, the agarwood-inducing method, formation time, and place of origin. Now, the quality assessment of agarwood is performed by chemical analysis which identifies the constituents in the agarwood.
Agarwood is widely used in many areas of religion, literature, art, and medicine. In many religions, incense is burnt as a symbolic form of worship or offering to deities and spirits. This tradition can be traced back to ancient Egypt, where frankincense and myrrh resins were used to produce incense. In China, the tradition of burning incense was widespread during the Song Dynasty. During that period, incense burning was considered one of the four arts of scholars, along with tea sipping, picture, and flower-branches arranging.The ingredients for making incense mainly come from agarwood. Agarwood was a symbol of nobility. Incense can also be used for expelling insects that transmit diseases, such as mosquitoes and flies, which is a practice for disease prevention. The fragrance from incense can also be used for aromatherapy. The essential oil extracted from agarwood is added to cosmetics to enhance the scent of the products. The use of other parts of Aquilaria is often neglected when harvesting, as the wood from Aquilaria is soft and not suitable for making furniture. However, in some religions, Aquilaria wood is crafted into sculptures or ornaments.
Because of the great demand on agarwood, the extensive harvesting of Aquilaria has disrupted the natural growing cycle. In the past, agarwood was harvested from forests and the entire Aquilaria trees were cut down to obtain the dark resin inside the infected trunk. The resulting deforestation has led to the near extinction of the species. In 2005, Aquilaria species were listed as the endangered under the Convention on International Trade in Endangered Species Appendix II as endangered. The governments of many countries are undertaking legal action to control the trade in Aquilaria species. More sustainable ways of producing agarwood have been investigated to increase the production rate and stop the destruction of natural forests. In addition, methods for agarwood induction have been investigated to increase the production of agarwood and prevent the extinction of Aquilaria. One of the methods used to harvest agarwood more sustainably is the infection and wounding of the trees. Farmers in Southeast Asia are starting to cultivate Aquilaria trees, and simple wounding techniques, such as cutting with an axe, nailing, or bark removal, are used to induce agarwood production. Because these techniques do not always produce the same amount of agarwood, therefore the production is not stable and can only produce a small amount of resin, and the products are considered to be low-grade agarwood. Recently, scientific methods, such as fungal infection and chemical induction, have been investigated to increase the production of agarwood. The following of this article will cover the medicinal use of agarwood in traditional Chinese medicine (TCM) and the pharmacological properties of agarwood.
In the TCM theory, agarwood has a spicy flavor, a warm property, and enters to the spleen, stomach, and kidney meridians. Agarwood was first described by Tao Hongjing (陶弘景) in the Ming Yi Bie Lu (《名医别录》 Miscellaneous Records of Famous Physicians) and has many different names, such as Xun Lu Xiang (薰陆香), Ji She Xiang (鸡舌香), and Feng Xiang (枫香). Agarwood was described in the Ming Yi Bie Lu as being effective for the treatment of cholera and heart troubles. In a another book, the Hai Yao Ben Cao (《海药本草》 Overseas Materia Medica) described the use of agarwood for the treatment of psychological and neurological symptoms, such as mental problems and coma. The Overseas Materia Medica also mentioned the use of agarwood in ointments for treating swollen wounds.The Ri Hua Zi Ben Cao (《日华子本草》 Materia Medica of Ri Hua Zi) included the use of agarwood to treat cold and dampness related to pains in the joints. The Yao Xing Fu (《药性赋》 Medicine Properties in Verse) added alleviating nausea and asthma to the uses of agarwood. The Ben Cao Jing Shu (《本草经疏》 Commentary on the Materia Medica) described the effect of agarwood in regulating the ascending or descending of qi. It also mentioned the property of agarwood to alleviate edema; the flavor of agarwood is spicy; thus, agarwood can dry dampness in the spleen and reduce the edema. The contraindications of agarwood are also mentioned in the Commentary on the Materia Medica. Agarwood is not suitable for patients with qi weakness of middle jiao affecting the flow of qi back to its origin and patients with excess pathogens in the heart meridian. The warming kidney property of agarwood is mentioned in the Yao Xing Jie (《药性解》 Exploration on Medicine Properties). Li Zhongzi (李中梓) observed that agarwood sinks when placed in water, and pointed out the properties of agarwood to direct qi downward and nourish yin. Thus, agarwood is said to have an effect on the lower parts of the human body, such as the life gate (命门) and the kidneys. Because the use of aromatic and spicy herbs will lead to dryness, agarwood is suitable for slows down deficiency cold pattern but not in the case of excessive ministerial fire. The actions of agarwood are summarized in the Chinese Pharmacopoeia as moves qi and relieves pain, directs rebellious qi downward and stops vomiting, and warms kidneys to aid in qi absorption. The following section will describe the use of agarwood in TCM and the pharmacological properties and mechanisms of action of the constituents of agarwood.
Use of Agarwood in Traditional Chinese Medicine
Moving qi and relieving pain
When exogenous pathogenic cold attacks the body, it slows the flow of qi, and if the cold congeals in the stomach, it will cause stagnation of qi and lead to pain. Agarwood, with its warming property, can be used for pain related to stagnation of qi. Therefore, agarwood is suitable for use in qi stagnation caused by cold congealment. Additionally, dampness may affect the spleen's function in transportation and transformation, butagarwood, with its aroma, can be used to awaken the spleen. Thus, agarwood can be effective to treat cold dampness encumbering the spleen.
Directing inverse qi downward and stopping vomiting
Nausea and vomiting often occur with abdominal pain, mainly because of the counter flow of stomach qi. As mentioned, agarwood is heavier than water; this promotes a descending movement of qi. Therefore, the ability of agarwood to reduce nausea and vomiting will be more effective when combined with medicines that alleviate vomiting.
Warming kidneys to aid in qi absorption
One of the functions of the kidneys in TCM theory is absorbing qi. The life gate of the kidney requires yang to keep ministerial fire (相火) functional. If the kidneys lack yang, normal functions such as absorbing qi are not maintained. One of the common outcomes of this dysfunction is that the kidneys fail to receive qi in the lung. This failure leads to many symptoms, such as difficulty in inhalation, shortness of breath, and asthma. Many TCM practitioners have suggested that agarwood is warm in property and spice in flavor. It was recorded in the Ben Cao Qiu Zhen (《本草求真》 Seeking Accuracy in Materia Medica) that agarwood has the function of tonifying yang. And it enters the kidney meridian. Thus, agarwood can treat failure of the kidneys in absorbing qi pattern. Furthermore, agarwood can also be used for treating weakness and coldness in the lower back and knee joint pains caused by the weakness of kidney fire that is unable to warm the lower back and the knees.
Pharmacological Properties and Mechanism of Action of Agarwood
As mentioned, agarwood has been traditionally used for treating many abnormal physical conditions, including gastrointestinal disorders, asthma, and pain. Recent pharmacological research has revealed new bioactive compounds as possible drug candidates and the mechanism of action of compounds from agarwood. Traditionally, only the resin of Aquilaria has been used for medicinal purposes and the other parts of Aquilaria are often wasted during the harvesting process. This waste will not be sustainable in the long term, neither is it economically nor environmentally viable. Thus, it is important that the use of different parts of Aquilaria, such as the leaves and trunk, is to be considered. With the support from new technologies, the chemical compounds in agarwood can be isolated and identified. Recently, more than 300 types of compounds have been isolated from Aquilaria, including potentially new active compounds. The main constituents of agarwood are 2-(2-phenylethyl)-4H-chromen-4-one derivatives, terpenoids, and flavonoids, including sesquiterpenes and diterpenes. The pharmacological properties and the mechanisms of action of these compounds can be grouped as follows.
Effects on the neurological system
Agarwood has been used as a sedative in many traditional medicines by inhalation of the burnt fumes or oral ingestion. Much research has focused on the effect of agarwood in neural activity. A study conducted by Okugawa et al. compared the sedative effects of petroleum ether, benzene, chloroform, and water extracts from agarwood. The results showed that only the benzene extract had a sedative effect. In particular, the benzene agarwood extract reduced spontaneous motility, increased the sleeping time when administered with a barbiturate, reduced the rectal temperature, and had the potential to provide pain relief from acetic acid-induced pain. The extract demonstrated similar effects after both peritoneal and intracerebroventricular administration. Further studies by this group have suggested that agarospirol from agarwood can reduce the incidence of writhing in mice from acetic acid-induced pain. Agarwood oil contains benzylacetone, calarene, and alpha-gurjunene. Takemoto et al. have reported that inhalation of these compounds produced a sedative effect in mice. One of the components released from burning agarwood is benzylacetone. Miyoshi et al. investigated 17 benzylacetone derivatives from agarwood and found that the most effective derivatives that have sedative effects were (S)-4-phenyl-2-butanol and (R)-4-phenyl-2-butanol. Agarwood essential oil administered at 60 mg/kg had a sedative-hypnotic effect in pentobarbital-induced sleeping mice. The sedative-hypnotic effect of agarwood essential oil is mediated through regulating the gene expression of gamma-aminobutyric acid (GABAA) receptors and potentiating GABAA receptor function. Agarwood may also be used for treating anxiety. For example, a study has shown that alpha-agarofuran and the derivative 4-butyl-alpha-agarofuran can regulate serotonin and dopamine in rats with serotonin-induced anxiety. Agarwood essential oil had anxiolytic and antidepressant effects in rats, and the mechanism of action was via inhibition of corticotropin-releasing factor and hyperactivity of the hypothalamic-pituitary-adrenal axis. Chronic inflammation in physically ill patients and metabolic syndromes can lead to many neurological disorders such as depression. Studies showed glutamate and corticosterone often associated with depression. A 2-(2-phenylethyl) chromone derivative isolated from the ethanolic extract of agarwood showed a significant neuroprotective effect in glutamate and corticosterone-induced neurotoxicity. Inhibitors of serotonin and norepinephrine reuptake may be potential antidepressants. Two sesquiterpene derivatives (+)-8β-hydroxy-longicamphenylone and 11β-hydroxy-13-isopropyl-dihydro-dehydrocostus lactone have been isolated from agarwood petroleum ether extract. An in vitro study of these compounds showed that both compounds have potent antidepressant activity by inhibiting serotonin reuptake in rat brain synaptosomes. In another in vitro study, antidepressant activity of 11 agarwood compounds was preliminarily evaluated using rat brain synaptosomes and the compounds displayed antidepressant activity by inhibiting both serotonin and norepinephrine reuptake. Among the 11 compounds investigated, aquilarabietic acid A, aquilarabietic acid H, and aquilarabietic acid I showed antidepressant activity in vitro by inhibiting norepinephrine reuptake in rat brain synaptosomes.
Effect on digestive system
Traditionally, agarwood has been used for pain relief, particularly for abdominal pain. A methanol extract of Aquilaria agallocha had a protective effect on the intestinal mucosa after 5-fluorouracil-induced intestinal mucositis. Administration of the A. agallocha methanol extract also improved food intake and the injury to the intestinal mucosa, and alleviated the weight loss and severe diarrhea. The mechanism of action occurred through an increase in the expression of proliferating cell nuclear antigen and inhibition of cyclooxygenase-2 (COX-2) and tumor necrosis factor-α. An A. agallocha ethanol extract had a spasmolytic effect on gastrointestinal motility by decreasing gastric emptying and small intestinal transit. They observed that a decrease in the contractions induced by acetylcholine in vitro was probably mediated through inhibition of muscarinic receptors and blockade of calcium influx and NO release. One study has indicated that ethanol extract produced by the whole-tree, agarwood-inducing technique can alleviate intestinal damage, suggesting that this extract could be used as an intestinal protective adjuvant therapy drug for intestinal injury induced by chemical drugs. This effect may be mediated by reducing pro-inflammatory mediators, such as NO, interleukin-17 (IL-17), and IL-13, and increasing glutathione and superoxide dismutase levels. The possible mechanism of this effect may be realized via the regulations of the nuclear factor-E2-related factor 2-antioxidant response element and nuclear factor-κ B pathways. Apart from pain relief, agarwood also has a laxative effect. Kakino et al. found that an ethanol extract of Aquilaria sinensis and A. crassna leaves had laxative effect in a mouse constipation model and did not cause diarrhea. A possible mechanism for this effect is realized via acetylcholine receptors.The main constituent of acetone extract of A. sinensis, genkwanin 5-O-β-primeveroside, has been shown to increase bowel movement. The mechanism of action of this effect may involve stimulation of intestinal motility via acetylcholine receptors. Another study has shown that mangiferin and iriflophenone 2-O-α-L-rhamnopyranoside were the most abundant compounds in the extracts of Aquilaria leaf tea. These compounds may possess laxative effect. Another less well-known property of agarwood is the regulation of blood sugar. Pranakhon et al. have reported that a methanolic extract from A. sinensis, containing iriflophenone 3-C-β-glucoside as the main constituent, reduced blood glucose levels and enhanced glucose uptake in rat adipocytes. Methanol and water extracts of agarwood leaf enhanced glucose uptake activity in rat adipocytes, and the effect was comparable to insulin.
Anti-inflammatory effect
Inflammation is a defensive process in which the immune system reacts to antigens. However, an overreaction of the immune system or chronic inflammation can lead to a variety of diseases. 1-(12-O-(2ʹE,4ʹE)-6-oxohexa-2ʹ,4ʹ-dienoylphorbol-13-acetate), 12-O-deoxyphorbol 13-decanoate, and 1,3-dioleoyl glyceride isolated from A. malaccensis seeds showed potent inhibitory activity against formyl-methionyl-leucyl-phenylalanine/cytochalasin B -induced elastase released by human neutrophils. Pilloin, a flavonoid compound from A. sinensis, significantly suppressed the production of pro-inflammatory molecules, such as tumor necrosis factor-α, IL-6, COX-2, and inducible nitric oxide synthase, in lipopolysaccharide-treated RAW 264.7 macrophages. A possible mechanism for this effect is through the inhibition of inflammatory-related mitogen-activated protein kinase pathways. Agarwood oil significantly reduced the skin thickness, ear weight, oxidative stress, and production of pro-inflammatory cytokines in a 12-O-tetradecanoylphorbol
-13-acetate-induced mouse ear inflammation model, which contributed toward validation of the traditional use of agarwood in the treatment of inflammation-related ailments. Three compounds from the whole-tree, agarwood-inducing technique also exhibited anti-inflammatory activity in lipopolysaccharide-induced inflammation in RAW264.7 cells. Microglial hyperactivation and neuroinflammation are known to induce neuronal death, which can lead to many neurodegenerative disorders, including Alzheimer's disease. Lee et al. found that a dichloromethane fraction of A. lignum reduced the levels of NO, COX2, prostaglandin E2, and IL-1β in lipopolysaccharide-stimulated BV2 microglial cells and the mechanism may involve the regulation of Nod-like receptor family pyrin domain-containing 3.
Anti-asthmatic effect
Agarwood has been used to treat shortness of breath, which is an asthma-like symptom. Aquimavitalin extracted from the seeds of A. malaccensis has inhibitory activity against antigen-induced degranulation; therefore, aquimavitalin is a potential drug to treat allergic reaction-related diseases. Although traditional use of agarwood to treat asthma has been recorded in ancient scripts, there are not many studies regarding the use of agarwood as an anti-asthma and anti-allergic agent; the mechanisms of action are not clear and need to be further investigated.
Effect on constraining bacteria and fungi
Although agarwood is not well favored for treating infectious diseases, many studies have reported antibacterial and antifungal activity from extracts of different parts of the Aquilaria plants. Kamonwannasit et al. have reported that A. crassna leaf extract was active against Staphylococcus epidermidis. The extract triggered swelling and distortion of the bacterial cells and inhibited bacterial biofilm formation. Rupture of the bacterial cell wall occurred after treatment with this extract for 24 h.Oxidoagarochromone A and oxidoagarochromone B from A. sinensis ethanolic extract showed inhibitory effects against Staphylococcus aureus and Ralstonia solanacearum. β-caryophyllene from the essential oil of A. crassna demonstrated selective antibacterial activity against S. aureus. Four compounds from agarwood oil exhibited antibacterial activity against both S. aureus and R. solanacearum and one compound had inhibitory activity against S. aureus only. An inhibitory effect of agarwood oil against the growth of Bacillus subtilis has been demonstrated.There are some concerns regarding artificially inducing the formation of agarwood. One study has shown that artificial agarwood obtained by a comprehensively stimulated method had an antibacterial effect on the bacterial strains, S. aureus and anti-methicillin-resistant S. aureus, and an antifungal effect on seven fungal strains: Penicillium melinii, Penicillium adametzii, Penicillium urticae, Penicillium notatum, Paecilomyces variotii, Mucor saturninus Hagem, and Aspergillus niger.
Antitumor effect
Many compounds derived from Chinese herbs have shown promising cytotoxic effects, and some of these compounds are candidates for new antitumor drugs. Agarwood essential oil generated a reduction in the cell numbers in both cell viability and attachment assays, suggesting a cumulative effect on cell death, inhibition of cell attachment, and/or causing cells to detach.[51] 4ʹ,7-dimethoxy-6-hydroxy chromone isolated from methanol extract of agarwood from Aquilaria filaria had antitumor activity against multidrug-resistant tumor cell lines, including lung carcinoma, epidermoid carcinoma of the nasopharynx, and breast cancer cell lines.[52] Seven compounds from ethanol extract of agarwood from A. sinensis inhibited the growth of SMMC-7721, MGC-803, and OV-90 cell lines; however, these compounds showed only weak cytotoxic activity
