Biebersteinia spp.

 BOTANY AND ETHNOMEDICINE OF BIEBERSTEINIA

Biebersteinia is the only genus in the family Biebersteiniaceae and includes only 4 species, namely B. heterostemon, B. multifida, B. odora and B. orphanidis. The genus was named after the German botanist Friedrich August Freiherr Marschall von Bieberstein. Formerly the genus included 5 species, however B. leiosepala is now considered a synonym of B. multifida. Also in other places it is stated that Biebersteinia contains a total of 5 species, but if one investigates a little more closely, it turns out that these are also today probably only synonyms of the 4 other species.

All Biebersteinia species are perennial herbaceous plants and their geographic distribution ranges from Greece to southwestern Siberia and western and central China. (Biebersteinia Stephan | Plants of the World Online | Kew Science)

Biebersteinia heterostemon ("Xun Dao Niu" in China) is found on the Qinghai-Tibet Plateau, where it is also known in Traditional Tibetan Medicine. This species inhabits dry and semi-dry mountainous deserts, rocky slopes and other environments.

Biebersteinia multifida is a plant commonly known as "Adamak" in folk medicine in Iran.

Biebersteinia odora is found in Central Asia (e.g.: Kazakhstan, Kyrgyztan, Pakistan, India, China, Mongolia) where it grows in alpine meadows and in dry, rocky and boulder-heavy areas. Biebersteinia odora appears to have long been used against fever and migraine by people in the Shigar Valley (Pakistan) (see Zhang et al. 2020: 12).

Biebersteinia orphanidis is the only species found in Europe and Greece, respectively - it usually grows at higher altitudes. Biebersteinia orphanidis was long considered extinct in its natural habitat in Europe (Greece). This species was first described by the Greek botanist Theodoros Georgios Orphanides in 1851, who discovered this Biebersteinia species on Mt. Killini. Subsequent researchers searched for this species in vain, so it was considered extinct. Only in 1994 it was rediscovered on a mountain near Mt. Killini in Greece (see Yannitsaros et al. 1996: 239f).

Of these 4 species, Biebersteinia heterostemon and Biebersteinia multifida have a long history as folk medicines in Iran (B. multifida) and Tibet (B. heterostemon). They possess various ethnomedicinal properties, for example, they are considered analgesic, antispasmodic, anti-inflammatory and anti-microbial, anti-anxiety, anti-hypertensive, etc. (see Zhang et al. 2020: 2)

TRADITIONEL TIBETAN MEDICINE (TTM)

TTM has a Buddhist history of over 2500 years. It understands the human being as a holistic being, which consists of body, mind and soul, to which the therapies in TTM are tailored. The training to become a Tibetan doctor (Amchi/Amchila) can take up to 10 years. The most important text or systematic guide of Traditional Tibetan Medicine is the rgyud bchi.

Tibetan herbal medicine in the form of beads (Photo: WikiMedia Commons)

The diagnostic methods of TTM include:

- Observation, with special attention paid to tongue and urine diagnostics.

- Touch, which includes pulse diagnosis in particular.

- Questioning, whereby the Tibetan doctor (Amchi/Amchila) determines causes of illness and symptoms

Therapeutic measures include:

- Change of lifestyle

- Changes in diet

- External applications, such as bloodletting, cupping, moxibustion, acupuncture, massage

- Application of natural remedies

In TTM more than 1000 different plants are known for the production of medicines. In this process, the medicinal plants are often administered as combination preparations. The composition of medicinal plant preparations can be divided into 3 categories:

The first category includes ingredients responsible for the main effect, the 2nd category refers to ingredients that support the main effect and the 3rd category includes additions to neutralize any side effects. 

In Traditional Tibetan Medicine, it is common to administer the herbal medicinal mixtures in the form of powders with hot water. However, today it is often preferred to process the powder into pellets/pills. The disadvantage of this is that the dose can no longer be individually adjusted to the patient, as is the case with the powder. However, pills are easier to take because of the often bitter taste of the powder. The powder is moistened with foreign substances such as water, milk or an alcoholic extract and kneaded into pellets. Tibetan medicinal plants and preparations are often used for any kind of disease.

Tibetan medicinal mixtures can consist of up to 50 ingredients or more, using plants, minerals and, in the past, animal ingredients. Over 500 ancient formulas are still in common use today.

 (see Berling-Aumann 2012: 49ff; Bin Saif et al. 2010; Frass et al. 2019).

BIEBERSTEINIA HETEROSTEMON AND MEDICINALLY IMPORTANT FLAVONOIDS

Biebersteinia heterostemon has been used in Traditional Tibetan Medicine for diseases of the cardiopulmonary system and neuropsychiatric diseases.

Biebersteinia heterostemon (Photo: 科学网—20200710——熏倒牛（Biebersteinia heterostemon Maxim.） - 栗茂腾的博文 (sciencenet.cn)

γ-Aminobutyric acid type A (GABA-A) receptors are among the most important receptors in the central nervous system and are the main targets of substances used for the treatment of various diseases such as seizures, anxiety, insomnia, etc. It is known that benzodiazepine binding sites located at the GABA-A receptor are quite well studied. Benzodiazepines are used as anticonvulsants, anxiolytics and sedatives or hypnotics in clinical treatment.

Recently, flavonoids (usually contained, for example, in green tea or in some fruits, etc.) and their effects on the central nervous system have received much attention. Some flavonoids showed anticonvulsant and anxiolytic effects, but without the sedative and muscle relaxant effects. From there, flavonoids seem to be interesting compounds and a possible alternative for benzodiazepines in terms of searching and developing agents with anticonvulsant or anxiolytic effects (see Liu et al.2018: 1f).

6 Flavonoids were isolated from Biebersteinia heterostemon for one study and their effects at the GABA-A receptor complex were investigated. The flavones that exhibited the strongest affinity for the benzodiazepine binding site of the GABA-A receptor complex included:

- demethoxysudachitine (DMS)

- isothymusine

- 2', 4', 5, 7-tetrahydroxy-5', 6-dimethoxyflavone (DMF)

- 2', 4', 5, 8-tetrahydroxy-5', 6, 7-trimethoxyflavone

DMF was closely followed by DMS in exhibiting the highest affinity for the benzodiazine binding site (see Liu et al. 2020: 8)

No significant muscle relaxation or sedation was observed after administration of DMF (anticonvulsant) or DMS (antianxiety). It was found that the antianxiety effect of DMS or the anticonvulsant effect of DMF could be reversed with flumazenil (blocks the effect of benzodiazepines), from which Liu et al. (2018) conclude that benzodiazine binding sites are involved in the mechanism of action of DMF or DMS (cf. Liu et al. 2020: 12).

The lack of side effects of these flavonoids may possibly be attributed to the fact that they bind to GABA-A receptor binding sites that may be independent of the classical benzodiazepine binding sites, or that they may act at as yet unexplored binding sites (see Liu et al. 2020: 3).

BIEBERSTEINIA MULTIFIDA, A PLANT OF ETHNOMEDICAL INTEREST

Biebersteinia multifida is a plant known as "Adamak" in Iran. The tuberous roots of this plant were used superficially in folk medicine in the western region of Iran for the treatment of inflammation and diseases of the musculoskeletal system. Internally, plant parts were used in the treatment of multiple nocturnal urination in children and in phobias and anxiety (see Monsef-Esfahani et al. 2013: 1; Farsam et al. 2000: 443).

Biebersteinia multifida (Photo: Fotos von Biebersteinia multifida · iNaturalist)

Researchers isolated 3 compounds from the extract of the root, which they held responsible for the anxiety-relieving effect. These coumarin derivatives include umbelliferone, scopoletine, and ferulic acid (see Monsef-Esfahani et al. 2013: 6). Although they mention that flavonoids have also been found in Biebersteinia multifida, they omit them from their study.

Greenham et al. (2001) suggest that the pattern of flavonoid production may be similar in the genus Biebersteinia: "Related work on B. heterostemon [...] and our own preliminary investigation on the flavonoids of B. odora suggest, that this pattern of flavonoid production is common throughout this small genus." (Greenham et al. 2001: 90).

The mechanism of action underlying the antianxiety effect of B. multifida root extract is not fully known. Among other things, it is thought that the coumarin derivatives may interact with the benzodiazepine binding site (see Monsef-Esfahani et al.2013:7).

In addition, Biebersteinia multifida is reported to possess analgesic, anti-mutagenic, and gastroprotective properties. (see Dabaghian et al. 2014; Raeesi et al. 2018).

Sources:

- Berling-Aumann, Nadine. (2012). Tibetische Medizin: Regionale Entwicklung, Anwendung und Wirkung von Heilpflanzen. Diplomica Verlag GmbH

- Bin Saif, Bernhard et al. (2010). Tibetische Medizin für den Westen. Springer Verlag: Wien.

- Frass Michael et al. Hrsg. (2019). Integrative Medizin. Springer Verlag: Deutschland

- Dabaghian, Fataneh Hashem;  Maliheh Entezari, Ali Ghobadi and Mehrdad Hashemi. (2014). Antimutagenicity and Anticancer Effects of Biebersteinia multifida DC. In: Annual Research & Review in Biology

4(6): 906-913

- Farsam, Hassan; Massoud Amanlou, Ahmad Reza Dehpour, Fereshteh Jahaniani. (2000). Anti-inflammatory and analgesic activity of Biebersteinia multifida DC. root extract. In: Journal of Ethnopharmacology 71 (2000) 443–447

- Greenham, Jenny; Dionyssios D. Vassiliades, Jerey B. Harborne, Christine A. Williams, John Eagles, ReneÂe J. Grayer, Nigel C. Veitch. (2001). A distinctive Flavonoid chemistry for the anomalous genus Biebersteinia. In: Phytochemistry 56 (2001) 87±91

- Liu, Zenggen; A. Kerstin Lindemeyer, Jing Liang, Martin Wallnerc, Xuesi M. Shaoe, Yun Shaoa, Yanduo Taoa,b, Richard W. Olsen. (2018). Flavonoids isolated from Tibetan medicines, binding to GABAA receptor and the anticonvulsant activity. In: Phytomedicine 50 (2018) 1–7

- Liu, Zenggen; Joshua Silva, Amy S. Shao, Jing Liang, Martin Wallner, Xuesi M. Shao, Mingzhu Li, Richard W. Olsen. (2020). Flavonoid compounds isolated from Tibetan herbs, binding to GABAA receptor with anxiolytic property. In: Journal of Ethnopharmacology

- Mahdi Raeesi, Narges Eskandari-Roozbahani, Tahoora Shomali. (2019). Gastro-protective effect of Biebersteinia multifida root hydro-methanolic extract in rats with ethanol-induced peptic ulcer. In: Avicenna J Phytomed, 2019; 9(5): 410-418

- Monsef-Esfahani, Hamid Reza et al. (2013). Coumarin compounds of Biebersteinia multifida roots show potential anxiolytic effects in mice. In:  DARU Journal of Pharmaceutical Sciences 2013, 21:51

- YANNITSAROS, ARTEMIOS G.; THEOPHANIS A. CONSTANTINIDIS. (1996). The rediscovery of Biebersteinia orphanidis Boiss. (Geraniaceae) in Greece. In: BotanicalJournal of the Linnean Society (1996), 120: 239-242

- Zhang, Benyin; Xiaona Jin, Hengxia Yin, Dejun Zhang, Huakun Zhou, Xiaofeng Zhang and Lam-Son Phan Tran. (2020). Natural Products, Traditional Uses and Pharmacological Activities of the Genus Biebersteinia (Biebersteiniaceae). In: Plants 2020, 9, 595