A Systematic Review of the Efficacy and Safety of Teucrium Species; from Anti-oxidant to Anti-diabetic Effects

INTRODUCTION

For a very long time, plants were used in the treatment of many diseases especially in the East region countries. In the recent years, the popularity of alternative medicine has increased again. Surveys conducted in Australia and US indicates that almost 48.5 and 34% of respondents had used at least one form of unconventional therapy, including herbal medicine, respectively. The World Health Organization (WHO) has also recommended evaluation of effective plants for conditions like diabetes due to lack of safe modern drugs (Kim et al., 2007). In some countries, herbal medication is the most popular complementary and alternative medicine (CAM) modality (Sadighi et al., 2004; Rahimi et al., 2010).

Most pharmacists are not adequately prepared educationally to meet patients' requests for information on herbal products. Many herbs have been identified as unsafe, including borage, calamus, coltsfoot, comfrey, life root, sassafras, chaparral, Teucrium (Germander), Licorice and Ma-huang. Potentially safe herbs include Feverfew, Garlic, Ginkgo, Asian Ginseng, Saw-palmetto, St. John's wort and Valerian. The clinical trial results are suggestive of efficacy of some herbal therapies for some conditions (Klepser and Klepser, 1999).

Commonly called Germanders, the Teucrium species are perennials, subshrubs, or shrubs with attractive aromatic simple or lobed leaves that can be evergreen or deciduous (Ellis, 1999). Teucrium species are rich of neo-clerodane diterpenoids. Although, several furanoid diterpenes with neo-clerodane skeleton have been isolated from many plants, the genus Teucrium is the most abundant natural source of these components. Therefore, Teucrium species are accepted as chemotaxonomic markers for neo-clerodanes. Flavonoids and aromatic compounds, although not as abundant as in the genus salvia from the same family, have been found in the genus Teucrium (Atta-ur-Rahman, 2003).

Teucrium species have been used for over 2000 years in traditional medicine for their diuretic, diaphoretic, tonic, anti-pyretic, anti-spasmodic and cholagogic properties (Ljubuncic et al., 2006). Teucrium polium and Teucrium persicum are wild-growing flowering plant belonging to the family Labiatae found abundantly in Iran and used in traditional Iran and Arab medicine (Azaizeh et al., 2005). This plant has been used for the treatment of diabetes, gastric inflammation and convulsion (Shahraki et al., 2007). Teucrium buxifolium the Spanish endemic, has been used for the treatment of rheumatic and other inflammatory disorders (Puntero et al., 1997).

The present study aimed to evaluate the current science on the efficacy and safety of Teucrium species by reviewing all human and animal studies.

MATERIALS AND METHODS

Data sources: Embase, Scopus, Pubmed, Google Scholar and IranMedex databases were searched up to 11th May 2010 for studies investigating Teucrium as a medicinal plant. The initial search terms were Teucrium or germander or calpoureh and diabetes, anti-oxidant, anti-inflammatory, analgesic, anti-nociseptive, anti-ulcer, anti-microbial, toxicity or side effect. Then searches were done by Teucrium alone as a key word without narrowing or limiting search elements and continued manually for relevant data. The reference lists of articles were also reviewed for additional studies.

Study selection: Inclusion criteria: All of the human and animal studies considered the effects of Teucrium with the key outcome of glucose, lipids, anti-oxidant parameters, hepatic enzymes, anti-inflammation, analgesic, anti-ulcer, anti-microbial and toxic effects were included. Exclusion criteria: In vitro studies, studies performed on cell lines, review articles and letters to editor were excluded. Unpublished data such as thesis were not included.

One reviewer independently examined the title and abstract and references of each article to eliminate duplications and in vitro studies. The reviewers independently extracted data according to Teucrium species, dose, trial duration, outcome, results and side effects.

RESULTS AND DISCUSSION

Of publications identified in the initial database, 7325 search results were reviewed for inclusion or exclusion and finally, 68 studies were included.

Beneficial effects of Teucrium species: Information of human and animal studies considering beneficial effects of Teucrium is summarized in the Table 1.

Studies on blood glucose, lipid and pressure: Some animal (Esmaeili and Yazdanparast, 2004; Gharaibeh et al., 1988; Karimi et al., 2002; Rasekh et al., 2001; Roman-Ramos et al., 1991; Shahraki et al., 2007; Vessal et al., 2003; Yazdanparast et al., 2005; ZaI et al., 2001) and one human study showed significant decrease in blood glucose after treatment with Teucrium. Three animal studies showed ineffectiveness of Teucrium in treated animals (Afifi et al., 2005; Iriadam, 2004; Konuklugil et al., 1997). Glicazide an oral anti-diabetic agent was more potent than Teucrium (Konuklugil et al., 1997). One animal study showed reduction of serum cholesterol and triglyceride in hyper-lipidemic rats treated with Teucrium (Rasekh et al., 2001) but in another study cholesterol, triglyceride and LDL increased after treatment with Teucrium (Shahraki et al., 2007). Different species of Teucrium reduced mean arterial blood pressure and heart rate (Bello et al., 1997; Catalayud et al., 1998a, b). One of these studies showed that both methanol and dichloromethanol extracts of Teucrium have antihypertensive effect (Catalayud et al., 1998b).

Anti-oxidant effect: Teucrium species possess free radical and hydroxyl radical scavenging activity as well as anti-oxidant activity in vitro (Azaizeh et al., 2005). Seven animal studies showed anti-oxidant properties of Teucrium that are summarized in the Table 1. In Panovsca study the inhibitory effect of the extract in NADPH-induced lipid peroxidation was greater than that of reference substance, luteonin and similar with that of thymol.

Anti-nociceptive and anti-inflammatory effects: Anti-spasmodic, anti-nociceptive, anti-inflammatory and CNS-depressant properties of different Teucrium species (Abdollahi et al., 2003a; Abdolghaffari et al., 2010: Barrachina et al., 1995; Baluchnejadmojarad et al., 2005; Beitran et al., 1998; Bello et al.,1995, 1998; Capasso et al., 1983; Heidari et al., 1999; Parsaei and Shafiei Nik, 2006; Radhakrishnan et al., 2001; Shahraki et al., 2006b; Shakhanbeh and Atrouse, 2001; Tariq et al., 1989), are summarized in Table 1. Some studies showed anti-ulcer, anti-pyretic or hepatoprotective effects (Ansari et al., 2009; Autore et al., 1984; Galati et al., 1997, 2000; Islam et al., 2002; Mehrabani et al., 2009; Niazmand et al., 2007; Orhan and Aslan, 2009; Panovska et al., 2007; Rasheed et al., 1995; Wasfi et al., 1995).

Adverse effect and toxicity of Teucrium species: In the recent years, terpenoid-containing dietary supplements have been implicated in causing severe and sometimes fatal hepatotoxicity. Germander was the first of these herbal products to be clearly linked to cases of acute liver failure. Similar hepatotoxicity was observed with other members of the Teucrium genus (Chitturi and Farrell, 2008). Human and animal studies considering adverse effects of Teucrium are summarized in Table 2.

Table 1:	Human and animal studies considering beneficial effects of Teucrium



T: Teucrium; ip: intraperitoneal; iv: intravenous; DM: Diabetes mellitus, m: month, w: week, d: day, h: hour; HDL: high density lipoprotein, LDL: low density lipoprotein, Ch: Cholesterol, TG: triglyceride, BMI:body mass index; MPO: myeloperoxidase; TNF-alpha: tumor necrosis factor-alpha; IL-1beta: interlukin-1beta; FRAP : ferric reducing antioxidant power; w: week; MDA: malondialdehyde; JNK: c-Jun N-terminal kinase; ERK1/2: extracellular signal-regulated kinase; CAT: catalase; SOD: superoxide dismutase; GSH: reduced glutathione; NO: nitric oxide; PCO: protein carbonyl content; AOPP: advanced oxidation protein products; BG: blood glucose; TGF-β: transforming growth factor-β

Animal studies for acute and chronic toxic effects: Histopathological and biochemical studies revealed that high doses of Teucrium species or its long-term administration may induce progressive impairment of neuromuscular coordination and reversible or irreversible hepatic damage (Al-Ashban et al., 2005; De Vincenzi et al., 2003; Kouzi et al., 1994; Rasekh et al., 2005; Shahraki et al., 2006a, b; Tanira et al., 1996, 1997). There was no significant difference in hematological parameters according to sex (De Vincenzi et al., 2003).

Hepatotoxicity with Teucrium in human: Drug-induced hepatotoxicity due to administration of medicinal plants has been infrequently reported. In Table 2, multiple case reports of hepatotoxicity by Teucrium species are described. Most of patients were presented with very high liver aminotransferases or developed jaundice. Hepatitis and intrahepatic cholestatic liver disease were the etiology of liver damage in these cases (Ben Yahia et al., 1993; Castot and Larrey, 1992; Dourakis et al., 2002; Larrey et al., 1992; Mazokopakis et al., 2007; Mimidis et al., 2009; De Miera Olivera et al., 2009; Pauwels et al., 1992; Perez Alvarez et al., 2001; Poon et al., 2008; Savvidou et al., 2007; Soylu et al., 1998; Starakis et al., 2006).

In this study, the activities of Teucrium, as a traditionally-used medicinal plant has been evaluated using a systematic search and review. Most of studies showed anti-diabetic effect of Teucrium. Insulinotropic potential of Teucrium has been tested by an in vitro investigation using isolated pancreatic rat islets (Esmaeili and Yazdanparast, 2004). Data indicated that Teucrium crude extract is able to enhance secretion of insulin by almost 135% after a single dose of the plant extract (equivalent to 0.1 mg plant leaf powder mL^-1 of the culture medium) at high glucose concentration (16 mmol L^-1). Meanwhile, the time pattern of insulin secretion was not affected by the plant extract in comparison to the untreated islets. These data clearly show that the plant extract, probably without metabolic transformation, is able to reduce blood glucose levels through enhancing pancreatic secretion of insulin (Esmaeili and Yazdanparast, 2004; Yazdanparast et al., 2005). Another study showed that the number of pancreatic islets unit^-1 area was increased and activity of glucokinase was elevated by Teucrium (Vessal et al., 2003).

In two other studies, negative results on blood glucose level by Teucrium was obtained in normoglycemic and alloxan-induced hyperglycemic rabbits. Teucrium was administered intranasal as crude extract (10%) dissolved in 5% (w/w) Pluronic F127. No significant difference between the extract-treated and non-treated control animals receiving only water was observed (Afifi et al., 2005). The rout and the dose of administration might be responsible for these negative results.

The aqueous extract of Teucrium aerial parts, given intraperitoneally at doses of 50 to 150 mg kg^-1 for 10 days, reduced serum cholesterol and triglycerides in hyperlipidemic rats (Rasekh et al., 2001). Considering other studies with negative result (Esmaeili and Yazdanparast, 2004; Karimi et al., 2002), further studies are needed for confirmation.

In another study, the essential oil of Teucrium was introduced as responsible component for analgesic effects. The anti-spasmodic properties of Teucrium was found comparable to hyoscin and indomethacin. The presence of flavonoids and sterols was suggested responsible for anti-inflammatory effects of Teucrium (Abdollahi et al., 2003a, b).

Several studies showed cytoprotective and anti-ulcer effects of Teucrium (Galati et al., 1997, 2000; Islam et al., 2002; Wasfi et al., 1995). Treatment with Teucrium blocked secretion of acid from parietal cells while stimulated forming of zymogen granules in chief cells (Wasfi et al., 1995). Another study indicated that ethanolic extract of Teucrium contains hepatoprotective constituents (Rasheed et al., 1995). Further works should be conducted to isolate and characterize the hepatoprotective constituents of Teucrium.

As a matter of fact, the therapeutic benefit of many medicinal plants is often attributed to their anti-oxidant properties. The aqueous extract of the leaves and stems of Teucrium was found to inhibit iron-induced lipid peroxidation in rat liver homogenate. In addition, organic extract of the aerial parts of Teucrium inhibited oxidative processes (Ljubuncic et al., 2006). Oxidative stress is known responsible in pathogenesis of various diseases like inflammatory bowel disease, diabetes, hyperlipidema, hepatothoxicity, osteoporosis and exposure to xenobiotics. In most of these conditions, use of antioxidants have been beneficial in ameliorating or even reversing the disease (Abdollahi et al., 2003a, b, 2005; Ben Yahia et al., 1993; Castot and Larrey, 1992; Chitturi and Farrell, 2008; Larrey et al., 1992; Pauwels et al., 1992; Rahimi et al., 2005; Rezaie et al., 2007; Sarkhail et al., 2007; Soylu et al., 1998). Medicinal plants with antioxidative properties may be useful for the prevention of atherosclerosis and cardiovascular diseases by reducing formation of oxidized lipids and altering their metabolism (Hasani-Ranjbar et al., 2008, 2009).

Table 2:	Human and animal studies considering adverse effects of Teucrium

Herbal remedies have become increasingly popular throughout the globe as a result of disappointment with conventional medicines and also of the alleged belief that herbal preparations are basically harmless. On the other hand, their effects can be exceedingly potent or even lethal if used improperly. Drugs and other chemicals account for less than 5% of cases of jaundice or acute hepatitis and smaller number of cases of chronic liver disease. Drug reactions can mimic any hepatobiliary disease, posing a diagnostic challenge for physicians and pathologists (Starakis et al., 2006). Teucrium species are rich in neo-clerodane diterpenoids that is possibly the cause of hepatotoxicity (Sundaresan et al., 2006). Therefore, using Teucrium in those with hepatic abnormalities should be cautiously (Perez Alvarez et al., 2001).

ACKNOWLEDGMENT

This study is the outcome of an in-house study and has not been supported financially.