Therapeutic potential of Zataria multiflora: A narrative review of current evidence

Reza Nosratabadi ,Fatemeh Anaeigoudari ,Akbar Anaeigoudari

1Department of Medical Immunology,Afzalipour Faculty of Medicine,Kerman University of Medical Sciences,Kerman,Iran

2Student Research Committee,Afzalipour Faculty of Medicine,Kerman University of Medical Sciences,Kerman,Iran

3Student Research Committee,Jiroft University of Medical Sciences,Jiroft,Iran

4Department of Physiology,School of Medicine,Jiroft University of Medical Sciences,Jiroft,Iran

ABSTRACT Zataria multiflora Boiss is a perennial plant with a wide spectrum of biological and pharmacological activities including antidiabetic,antinociceptive,anti-asthmatic,anti-fever,anti-spastic,anti-oxidative,anti-inflammatory,and antimicrobial properties.This paper reviews the therapeutic effects of Zataria multiflora based on recent reports.The relevant reports were extracted by checking the electronic databases including PubMed,Scopus,Web of Science,and Google Scholar from the beginning of 2010 until the end of May 2023.The neuroprotective effects of Zataria multiflora can be attributed to inhibition of acetylcholinesterase,enhancement of brain-derived neurotrophic factor,and alleviation of brain oxidative damage.Zataria multiflora also exerts its protective effects on the respiratory system,liver,and kidney by reducing the level of inflammatory cytokines,scavenging the free radicals,and augmenting the antioxidant enzymes.Additionally,Zataria multiflora accelerates wound healing via upregulating transforming growth factor-β,insulin-like growth factor 1,fibroblast growth factor 2,and vascular endothelial growth factor,and inducing angiogenesis and collagen biosynthesis.Overall,the protective impacts of Zataria multiflora on different organs are mainly attributed to its antioxidant and antiinflammatory properties.

KEYWORDS: Zataria multiflora;Anti-inflammmatory;Antioxidative;Neuroprotective;Organs

1.Introduction

Zataria multiflora (Z.multiflora) Boiss is a perennial plant from Laminaceae family with limited geographic distribution in the world.It mainly grows in Iran,Afghanistan,and Pakistan[1].Among the people of Iran,it is known as Avishan-e-Shirazi.Z.multiflora is an herbaceous plant with 60-90 cm in height.This aromatic plant possesses small and egg-shaped leaves and white flowers.The presence of compounds including carvacrol,thymol,alkanes,fatty acids,phytosterols,hydroxycinnamic acids,flavonoids,tannins,saponins,and resins has been confirmed in the extract and essential oil of Z.multiflora[2].These compounds especially carvacrol and thymol have been demonstrated to be responsible for biological and pharmacological activities of Z.multiflora[3,4].

Z.multiflora often is used as a flavoring component in food.In traditional medicine,Z.multiflora has been suggested to have properties such as diuretic[2],anti-cough[5],anti-bronchitis,antiasthmatic[6],anti-spasmodic[7],anti-fever and analgesic[8] activities.In the gastrointestinal tract,Z.multiflora can relieve bloating and irritable bowel syndrome (IBS)[9].Attenuation of headache and migraine symptoms[10] and treatment of vomiting[11] also are attributed to Z.multiflora.Previously,it has been recognized that Z.multiflora extract and carvacrol derived from it could inhibit muscarinic[12] and histamine receptors[13] and stimulate β-adrenoceptors[14].The researchers reported that Z.multiflora improves cognition deficits by inhibiting acetylcholinesterase(AchE) activity and the injurious effects of amyloid β[15].The ability of Z.multiflora to reduce blood glucose in diabetic rats has been also documented[16].Besides all these effects,the scientific evidence shows that Z.multiflora possesses anti-inflammatory,antioxidative[17],antimicrobial[18],and anti-septic activities[19].This paper aimed to review the therapeutic potential of Z.multiflora on different organs based on recent reports.

2.Method

In this paper,all known electronic databases including PubMed,Scopus,Web of Science,and Google Scholar were used for data extraction.The reports were collected from the beginning of 2010 until the end of May 2023 using the terms “Zataria multiflora” and“neuroprotective” or “l(fā)ung” or “renoprotective’ or “hepatoprotective”“gastroprotective” or “cardioprotective” or “antidiabetic” or“anticancer” and “antimicrobial”.

3.Neuroprotective effects

Alzheimer’s disease (AD) is a progressive neurological disorder associated with loss of neurons and memory impairment[20].The hippocampus is a principal brain area involved in learning and memory processes which are mainly affected by AD[21].Accumulation of intracellular neurofibrillary tangles and amyloid β protein (Aβ) in the brain tissue is the most important characteristic of AD[22].It has been also demonstrated that the inhibition of AchE[23] and use of natural antioxidant agents[24] can attenuate the symptoms of AD.In a rat model of AD,oral administration of 100μL/kg of essential oil of Z.multiflora improved spatial memory.The neuroprotective effect of Z.multiflora was associated with the decrease of AchE activity and increase of brain-derived neurotrophic factor level in the hippocampus tissue of rats[25].Majlessi et al.also examined the effect of 50,100,and 200 μL/kg of essential oil of Z.multiflora on memory deficits in a rat model of AD.They concluded that the doses of 100 and 200 μL/kg modulated spatial memory dysfunction in rats[26].Ahmadi et al.reported that 100μL/kg of essential oil of Z.multiflora can ameliorate cognitive deficits and reduce hippocampal tau protein and tumor necrosis factor-alpha (TNF-α) level[27].Scopolamine is an anti-muscarinic medication that can inhibit acetylcholine (Ach) effects in the nervous system[28].Additionally,anticholinergic drugs such as scopolamine are also used to induce amnesia and memory impairment in animal studies[29].In amnesic rats induced by scopolamine,100,200,and 400 mg/kg of Z.multiflora extract exerted anti-amnesic impacts and ameliorated memory disturbances.These effects of Z.multiflora extract were linked to its anticholinesterase properties[30].Taheri et al.also revealed that treatment with 200 mg/kg of methanolic extract of Z.multiflora had memory-enhancing effects against leadcaused memory damage in rats via exerting anticholinesterase and antioxidant effects[31].Moreover,80 and 200 mg/kg of hydroalcoholic extract of Z.multiflora reinforced learning and memory and improved inhaled paraquat-induced inflammation and oxidative stress in lung tissue[32].

In experimental studies,lipopolysaccharide (LPS) as a powerful bacterial toxin is employed to induce memory impairment and to evoke anxiety and depression-like behaviors[33].It has been demonstrated that the pernicious effects of LPS mainly are mediated by evoking inflammatory reactions and oxidative stress[34].The scientific findings show that intraperitoneal injection of 50,100,and 200 mg/kg of hydro-ethanolic extract of Z.multiflora attenuated LPS-caused anxiety and depression-like behaviors in rats,which is related to its anti-inflammatory properties[35].In a study achieved by Arab et al.,the beneficial effect of 50,100,and 200 mg/kg of Z.multiflora extract against LPS-induced memory impairment has also been confirmed.According to the biochemical resultsof this study,the memory-enhancing impacts of Z.multiflora were accompanied by a significant decline in interleukin (IL)-6,malondialdehyde (MDA),and nitric oxide (NO) concentration and a remarkable augmentation in total thiol content and catalase(CAT) and superoxide dismutase (SOD) activity in rats’ brain[36].Pentylenetetrazole is a gamma-aminobutyric acid (GABA) receptor antagonist causing seizure attacks when injected in high doses.Therefore,it is widely used for stimulating the seizure attracts and understanding the antiepileptic effects of drugs in animal models[37].Shamsizadeh et al.found that 300 and 600 mg/kg of hydroalcoholic extract of Z.multiflora alleviated pentylenetetrazole-induced seizure attacks in mice[38].The neuroprotective effects of Z.multiflora are summarized in Table 1.

Table 1.The neuroprotective effects of Zataria multiflora (Z.multiflora).

4.Protective effects on the respiratory system

Asthma and chronic obstructive pulmonary disease (COPD) are two respiratory diseases resulting from inflammation and obstruction of the airways[39].The symptoms of these disorders include coughing,shortness of breath,and wheezing[40].It has been found that antiinflammatory and antioxidant compounds exert positive impacts on asthma and COPD[41,42].

Therapeutic effects of 0.4,0.8,and 1.6 mg/kg of the hydro-ethanolic extract of Z.multiflora and 60,120,and 240 μg/mL of carvacrol on inflammatory,oxidative stress and blood parameters in the lung tissue of guinea pig exposed to cigarette smoke were evaluated.Based on the results,Z.multiflora and carvacrol significantly decreased IL-8,eosinophil,and neutrophil levels and increased the thiol content[43].In the study of Habibi et al,pretreatment with 50,100,200,and 400 mg/kg of the ethanolic extract of Z.multiflora protected the mice from cyclophosphamide-caused lung toxicity via inhibiting lipid peroxidation and improving oxidative stress[44].In a human study,5 and 10 mg/kg of Z.multiflora extract improved clinical symptoms and pulmonary function tests in asthmatic patients by modulating oxidative stress and decreasing the level of inflammatory cytokines[45].Administration of 20 mg/kg of the hydro-ethanolic extract of Z.multiflora induced a bronchodilatory effect comparable to theophylline in asthmatic patients[46].In patients with COPD,use of 3 and 6 mg/kg/day of Z.multiflora extract for two months remarkably reduced the serum level of inflammatory cytokines such as IL-6 and TNF-α and enhanced forced vital capacity and forced expiratory volume in 1 s (FEV1)[47].In another human research,treatment with 3 and 6 mg/kg/day for two months of Z.multiflora extract lessened the level of MDA,NO,and C-reactive protein,increased the thiol content and SOD and CAT activity,improved FEV1,and finally relived the symptoms of COPD[48].

Khazdair et al.reported that 5 and 10 mg/kg of Z.multiflora extract ameliorated respiratory symptoms including coughing,and wheezing,enhanced FEV1 and mitigated the serum level of TNF-α and vascular endothelial growth factor (VEGF) in veterans exposed to sulfur mustard.Treatment with 10 mg/kg of Z.multiflora also considerably lowered the serum level of monocyte chemotactic protein-1 and epidermal growth factor[49].The therapeutic effects of Z.multiflora on the respiratory system are depicted in Table 2.

Table 2.The therapeutic effects of Z.multiflora on the respiratory system.

5.Hepato-and reno-protective effects

The liver is a digestive organ that participates in multiple biological functions including protein synthesis[50],carbohydrates and lipids metabolism[51],and detoxification[52].Liver tissue can be threatened by drugs and toxins[53,54].One of the drugs causing hepatotoxicity in high doses is acetaminophen[55] In the liver,acetaminophen is converted into N-acetyl-p-benzoquinone imine(NAPQI) by cytochrome P450 enzymes.Acetaminophen-induced hepatotoxicity happens through generation of NAPQI in response to oxidative stress,glutathione (GSH) depletion,and mitochondrial dysfunction[56].It has been documented that oral administration of 200 mg/kg of Z.multiflora extract and 20 mg/kg of carvacrol could prevent the noxious effects of acetaminophen on the liver of rats via decrementing the lipid peroxidation and enhancing the thiol,CAT,and SOD level[57].Adriamycin (doxorubicin) is a drug employed against cancer cells[58].In experimental studies,adriamycin is usedto induce hepatotoxicity[59],nephrotoxicity[60] and cardiotoxicity[61].The detrimental impacts of adriamycin mainly are mediated by inducing inflammatory responses and releasing free radicals[62].In a rat model with adriamycin-induced hepatotoxicity,200 mg/kg of hydroalcoholic extract of Z.multiflora and 20 mg/kg of carvacrol lowered the MDA concentration and elevated the thiol,SOD,and CAT content in the liver tissue and improved the liver function[63].Cyclophosphamide is an immunosuppressive medication for the treatment of various types of cancers such as lymphoma[64],leukemia[65],multiple myeloma[66],and breast cancer[67].In the study accomplished by Shokrzadeh et al.,pretreatment with 50,100,200,and 400 mg/kg of the ethanolic extract of Z.multiflora had a noticeable hepatoprotective effect against cyclophosphamide in mice by reinforcement of antioxidant defense[68].Cisplatin is another anticancer medication that is used to induce liver toxicity[69].It has been confirmed that 50,100,200,and 400 mg/kg of metabolic extract of Z.multiflora reversed the harmful effects of cisplatin on the liver of rats by elevating the antioxidant indicators such as SOD,CAT and glutathione peroxidase and suppressing the lipid peroxidation[70].In addition,the clinical and experimental results demonstrated that cisplatin induces nephrotoxicity[71].Karimi et al.reported that oral administration of 200 mg/kg of Z.multiflora lightened the toxic impacts of cisplatin on the kidneys by mitigating the MDA content and enhancing the GSH level[72].Panahi Kokhdan et al.revealed 500 mg/kg of Z.multiflora displayed the nephroprotective impact against cisplatin via scavenging the free radicals[73].Additionally,adding 0.8 mg/mL of Z.multiflora extract to drinking water of rats alleviated the toxic effects of gentamicin on the kidney tissue by inhibiting the lipid peroxidation and reducing the free radicals[74].

Sodium nitrite (NaNO2) is a compound used as a flavoring in food industries[75].Over-intake of NaNO2can result in body organ damage via the induction of inflammation,DNA oxidation,and cancer[76].Ahmadi et al.examined the effect of 200 mg/kg of the hydroalcoholic extract of Z.multiflora on NaNO2-stimulated liver toxicity in rats and found that Z.multiflora extract modulated oxidative stress of liver tissue and finally reversed NaNO2-caused hepatic dysfunction[77].Liver fibrosis is a disorder characterized by the accumulation of extracellular matrix proteins such as collagen that can happen in various hepatic diseases[78].Stimulation of hepatocytes by oxidative agents is considered a crucial step in occurrence and development of liver fibrosis[79].Treatment with 500 μL/kg of Z.multiflora essential oil overturned the CCl4-induced liver fibrosis in rats by preventing oxidative stress[80].It has been also confirmed that 100,200,and 400 mg/kg of methanolic extract of Z.multiflora decremented the lipid peroxidation and protein carboxylation,incremented the activity of antioxidant enzymes and GSH levels,and consequently alleviated paracetamol-caused liver dysfunction in rats[81].In a study carried out by Arab et al.,50,100,and 200 mg/kg of hydroalcoholic extract of Z.multiflora attenuated LPS-evoked hepatic dysfunction in rats via reducing MDA,NO metabolites,and IL-6 levels and elevating thiol concentration and the activity of SOD and CAT[82].Moreover,in another study,1 000 mg/kg of the hydroalcoholic extract of Z.multiflora prevented liver damage in diabetic rats by modulating oxidative stress and improving the blood level of TNF-α and glucose[83].

Cystic echinococcosis (CE) or hydatid is a health-threatening disease that mostly affects liver and lung tissues.CE is induced by infection with Echinococcus granulosus sensu lato larvae[84].Albendazole is a drug selected for the treatment of CE that can cure only a third of infections in patients[85].Therefore,treatment with natural compounds is recommended.In a nonrandomized clinical trial,60 mg/day of essential oil of Z.multiflora reduced the volume of the hydatid cysts and the serum level of liver enzymes in CE patients compared to those treated with albendazole[86].The hepato-and reno-protective effects of Z.multiflora are demonstrated in Table 3.

Table 3.The hepato-and reno-protective effects of Z.multiflora.

6.Other effects

Besides the therapeutic effects presented above,other pharmacological properties of Z.multiflora include cardioprotective,gastroprotective,antimicrobial,antidiabetic,and anticancer activities.Sepsis is a serious condition in which the body’s immune system has an improper response to an infection[87].Intensive inflammation caused by sepsis can result in tissue injury,organ failure,and lastly death[88].Bacterial toxins such as LPS have been suggested for uncontrolled release of inflammatory mediators and induction of sepsis[89].Meanwhile,one of the organs severely affected by sepsis is the heart[90].Hosseini et al.found that oral injections of 50,100,and 200 mg/kg of Z.multiflora and 25,50,and 100 mg/kg of carvacrol had cardio-protective effects against LPS-induced sepsis in rats.The protective effect of Z.multiflora and carvacrol was mediated via a decrease in oxidant agents such as MDA and NO and an increase in antioxidant factors including SOD,CAT,and thiol in the heart and aorta tissue[91].

IBS is a gastrointestinal ailment associated with annoying abdominal pain and disturbance in bowel movements.Although the etiology of IBS has been not fully understood,environmental and genetic factors are listed as the main causes[92].Based on the report of Bordbar et al.,two soft gel capsules containing 180 mg of essential oils of Z.multiflora exerted a positive effect on IBS symptoms[93].It has been demonstrated that oral drops of Z.multiflora essential oil (2%) could apply analgesic,anti-spastic,anti-ulcer,and anti-inflammatory impacts and lastly alleviate IBS symptoms[94].Minaiyan et al.also reported that 100,200,and 400 mg/kg of Z.multiflora hydroalcoholic extract lessened the myeloperoxidase activity and ameliorated the indomethacinstimulated gastric ulcer in rats[95].

The skin is an important organ that prevents the penetration of harmful fungi and bacteria.Staphylococcus aureus[96] and Pseudomonas aeruginosa[97] are bacteria that induce infected wounds.The level of inflammatory cytokines including IL-1β and TNF-α increased in inflammation phase of wound healing process[98].In proliferative phase,insulin-like growth factor 1(IGF-1) promotes re-epithelialization of the wound site[99].VEGF,fibroblast growth factor-2 (FGF-2),and IL-10 also exert positive effects on the wound[100].Farahpour et al.showed the therapeutic effect of ointments containing 2% and 4% of Z.multiflora essential oil on wounds infected with Staphylococcus aureus and Pseudomonas aeruginosa in mice.This antibacterial property was accompanied by the mitigation of the wound size,total bacteria count and IL-1β and TNF-α expression,upregulation of IL-10,transforming growth factor-β (TGF-β),IGF-1,FGF-2,and VEGF and enhancement of angiogenesis and collagen biosynthesis[101].Furthermore,20 and 40μL/kg of Z.multiflora essential oil decreased replication of H9N2 influenza virus in challenged broiler chicks[102].

Diabetes mellitus is a metabolic disorder that is characterized by a high content of blood glucose and a low level of insulin.Uncontrolled diabetes can lead to cardiovascular dysfunction,liver and kidney damage,and blindness[103,104].Use of antioxidants has been suggested as a strategy for the treatment of diabetes[105].In an animal model of streptozotocin-induced diabetes,oral administration of 50 μL/kg of essential oil of Z.multiflora attenuated the diabetic injuries by removing the oxygen and nitrogen radicals[106].

Cancer is one of the main causes of death in the world.Breast cancer and melanoma are prevalent forms of cancer[107].It has been documented that essential oil of Z.multiflora dose-dependently inhibited the proliferation of breast cancer and melanoma cell lines[108].Based on the results of the study of Aghamohammadi et al.,25,50,100,150,and 200 μg/mL of Z.multiflora enhanced radiation-caused apoptosis in human glioblastoma cells[109].Ahani et al.also demonstrated that essential oil of Z.multiflora suppressed cell proliferation and stimulated apoptosis in human colon cancer cell lines in a time-and dose-dependent manner[110].

7.Conclusion

The scientific findings demonstrate that Z.multiflora has a wide spectrum of therapeutic properties including neuroprotective,antiasthmatic,hepatoprotective,renoprotective,cardioprotective,gastroprotective,antimicrobial,antidiabetic,and anticancer activities.Mechanisms such as suppression of inflammatory responses and attenuation of oxidative stress have a principal contribution to the therapeutic effects of Z.multiflora on different organs.It has been found that the neuroprotective effects of Z.multiflora may be mediated via a decreased level of AchE activity.In addition,the wound-healing activity of Z.multiflora can be attributed to upregulation of TGF-β,IGF-1,FGF-2,and VEGF and induction of angiogenesis and collagen biosynthesis.

Even though Z.multiflora has good protective effects against the injuries of various body systems in experimental studies,its effects in clinical studies are not fully known.Therefore,clinical tests are necessary to verify the safety and efficacy of this plant.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Funding

The authors received no extramural funding for the study.

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’contributions

RN contributed in supervision and revision of the manuscript.FA contributed in data collection and revised the amuscript.AA designed the work,collected the data,prepared and revised the manuscript.