Arthritic pain

The chronicity of osteoarthritis (OA), characterised by pain and inflammation in the joints, is linked to a glutamate receptor, N-methyl-D-aspartate (NMDA). The use of plant species such as D, ambrosioides as a NMDA antagonists offers a promising perspective. In relation to molecular docking, ascaridole showed NMDA receptor binding affinity. D. ambrosioides was effective in the treatment of OA because it reduced synovial inflammation and behavioural changes due to pain. This effect may be related to the antagonistic effect of ascaridole on the NMDA receptor.1

Treatment with D. ambrosioides at 5 mg/kg reduced the percentage of neutrophils and macrophages and the number of bone marrow cells and increased the lymphocyte numbers and the inguinal lymph node cellularity. This treatment inhibited the serum concentration of IL-6 and TNF-α, which may be related to the preservation of bone density and to the slight thickening of periarticular tissues, with minimal fibrosis and fibroblast proliferation in the joints. D. ambrosioides presented advanced articular erosion and synovial hyperplasia. HCE5 presented anti-arthritic potential and reduced IL-6 and TNF-α, which participate directly in the development and maintenance of the inflammatory process in rheumatoid arthritis.2

Infectious diseases

D. ambrosioides demonstrates effective bactericidal activity against H. pylori both in vitro and in vivo.3 D. ambrosioides is a plant traditionally used in Brazil to treat various infectious diseases. The study of the biological activities of this plant is of great importance for the detection of biologically active compounds. Extracts from D.ambrosioides showed high bioactivity against A. salina (LD50 < 1000 μg/mL), which might be associated with cytotoxic activity against cancer cells. D. ambrosioides showed specific activity against yeasts.4

Malaria

In an effort to identify novel therapeutic alternatives for the treatment of malaria, the antimalarial effect of the crude hydroalcoholic extract (HCE) from the leaves of Dysphania ambrosioides was investigated. It was found that HCE could inhibit the parasite growth in vitro (IC50 = 25.4 g/mL). The in vivo therapeutic treatment with HCE increased the survival and decreased the parasitaemia in the infected animals. Therefore, HCE treatment exhibited a significant anti-plasmodial effect.5

Cancer

Experimentally it was shown that D. ambrosioides inhibits the Ehrlich tumour growth, what could be due to an immunomodulatory effect of this product. The in vitro treatment with D. ambrosioides induced a dose-dependent NO production by resident macrophages. This treatment was able to increase the macrophages activity and also the cellular recruitment to secondary lymphoid organs, what could explain the previously related anti-tumour activity of D. ambrosioides.6

The leaves of D. ambrosioides have been indicated for the treatment of several diseases, including cancer. The treatments also increased the survival of tumour-bearing mice.

D. ambrosioides has a potent anti-tumoural effect which was evident with a small dose and even when the treatment was given two days after the tumour implantation. This effect is probably related with antioxidant properties of D. ambrosioides.7

Antibiotic Function

The oil presented the α-Terpinene as the major compound with 54.09% presence. The methanol extract shows antibacterial activity demonstrated significantly against Staphylococcus aureus (256 μg/mL) and moderate against Pseudomonas aeruginosa (512 μg/mL). The modulating effect of antibiotics was significant against P. aeruginosa potentiating the effect of all the antibiotics tested. Regarding the modulation, both were considered of clinical relevance, 3.3 and 6.4 μg/mL. OEDA has low antioxidant activity (>1024 μg/mL).8

MDR

The use of natural products is crucial to suppress the development of these micro-organisms and to reduce the concentration necessary to inhibit these micro-organisms, reducing the toxicity risks also. In this study, the essential oil from D. ambrosioides leaves and its main constituent α-Terpinene were used in the antibacterial and potentiating activity of antibiotics and ethidium bromide assays, against the bacterial strains Staphylococcus aureus IS-58, carriers of efflux pumps.

The Minimum Inhibitory Concentration (MIC) was determined using a microdilution method. The capacity of the aforementioned was also tested in combination with tetracycline and ethidium bromide, with the aim of improving the activity of the antibacterials. The MIC of the D. ambrosioides L. essential oil and of α-Terpinene were above 1024 μg/mL, comprising a clinically irrelevant value. However, when associated with the antibiotics, the D. ambrosioides L. essential oil, significantly decreased the MIC of tetracycline and ethidium bromide. The efflux pump is the only mechanism the bacteria possesses to reduce the toxicity of ethidium bromide, and thus this reduction in the MIC demonstrates that the D. ambrosioides L. essential oil is an effective option in the inhibition of the efflux pump present in these micro-organisms.9

Schistosomicidal action

The alcohol extract (Me DA) displayed weak activity against Streptococcus sobrinus and Enterococcus faecalis (minimum inhibitory concentration (MIC) = 1000 μg/ml).

On the other hand, DA-EO at 25 and 12.5 μg/ml presented remarkable schistosomicidal action in vitro and killed 100% of adult worm pairs within 24 and 72 h, respectively. The LC50 values of Me DA were 6.50 ± 0.38, 3.66 ± 1.06, and 3.65 ± 0.76 μg/ml at 24, 48, and 72 h, respectively.

However, Me DA at concentrations higher than 312.5 μg/ml significantly reduced the viability of GM07492-A cells (IC50  = 207.1 ± 4.4 μg/ml). The selectivity index showed that DA-EO was 31.8 times more toxic to the adult S. mansoni worms than GM07492-A cells.

Taken together, these results demonstrate the promising schistosomicidal potential of the essential oil of Dysphania ambrosioides.10

Antioxidant, intestinal immune status and anti-inflammatory potential

D. ambrosioides has been used for centuries as traditional medicine in many clinical situations. The objectives of this study were first to assess the nutraceutical potential of D. ambrosioides L. extract through analyses of its chemical composition and antioxidant properties, followed by assessing toxicity and antioxidative activities on fish splenocytes. The second one was to perform an in vivo study using dietary D. ambrosioides L. extract (0.0, 0.5, 1.0 and 2.0%; w/w) for 15 and 30 days (2-week and 4-week treatments) to assess associated-intestine health status by short-chain fatty production, antioxidant enzyme activities and anti-inflammatory effects.

Non-polar and polar fractions were detected by gas chromatography/mass spectrometry (GC-MS) in D. ambrosioides, of which the most abundant compounds were carvacrol, phytol, squalene, vitamin E and sucrose. The extract of D. ambrosioides L. enhanced a considerable antiradical and the splenocytes responded positively with higher (88%) cell viability than control. The production of nitric oxide and superoxide anion, as well as superoxide dismutase and catalase activities, were also enhanced in splenocytes treated with D. ambrosioides L.

The in vivo study results showed that acetate was the major short-chain fatty acid found in fish receiving D. ambrosioides L. after week four. Pro-inflammatory cytokine gene expression in intestine was modulated with D. ambrosioides L. at any time of the experimental trial.

In addition, the histological findings suggested that its extract did not cause inflammatory damage in intestine. Overall, the results suggest that D. ambrosioides L. is safe for immune cells and promoting intestinal health status of fish through antioxidant and anti-inflammatory effects, making it an interesting additive in functional diets.11

Note and caution

The leaves of Dysphania ambrosioides (Chenopodiaceae) have been used by native people to treat many diseases. Recently, we showed that the treatment with small dose (5mg/kg) of hydroalcoholic extract (HE) from D. ambrosioides' leaves has immunostimulatory effects. The aim of this study was to investigate the sub-chronic toxicity of the oral treatment with this HE in preclinical assays.

Swiss mice were divided into 4 groups (n=10/group). They received the HE daily at the doses of 5, 50 and 500 mg/kg by gavage for 15 days. The control group received only water.

There was neither death nor alterations in the body weight in the HE-treated groups, but there were alterations in the weight of some organs. There was an increase in the lymph node cells number in the highest two doses. The number of cells in the bone marrow was high in the HE-treated groups, but the number of peritoneal cells was smaller in the HE-treated groups when compared to the control. There was no alteration in the AST, but there was a reduction in the albumin levels in the HE500 group and in the triglycerides and VLDL in the highest doses.

The sub-chronic treatment with HE induced punctual alterations in the groups treated with the highest doses. However, the HE treatment was not lethal and did not induce toxic alterations using the therapeutic dose, suggesting that it is safe to use this product in the adequate dose.12

Hypertension

The hypotensive effect of aqueous extract (AqE) of the leaves of D. ambrosioides L., methanolic (MF), ethyl acetate (AcF), and aqueous (AqF) Soxhlet fractions, administrated intravenously, was evaluated in anesthetized rats. The recorded signals of blood pressure and heart rate were visualized and analysed.

Intravenous administration of AqE of the leaves of D. ambrosioides L. induces a dose-dependent hypotension. A similar effect was obtained with MF, AcF, and AqF. Atropine (1 mg/kg), used to block cholinergic system, significantly reduced the hypotensive response to MF and AcF suggesting the presence of the cholinomimetic-muscarinic components in these fractions.

However, the blood pressure lowering effect of MF and AcF in rats pre-treated with L-NAME 20 mg/kg was unchanged showing that the release of NO is not implicated in the hypotensive action of this plant.

The present study demonstrates that extracts from leaves of D. ambrosioides induce hypotensive effect that may be partially associated with its cardiac effects. These results may partly explain the traditional use of leaves of D. ambrosioides L. for the treatment of disorders such as hypertension.13

References

1. GP Calado et al. Chenopodium ambrosioides L. Reduces Synovial Inflammation and Pain in Experimental Osteoarthritis. PLoS One. 2015 Nov 2;10(11):e0141886. doi: 10.1371/journal.pone.0141886.

2. WS Pereira et al. Anti-arthritic properties of crude extract from Chenopodium ambrosioides L. leaves. J Pharm Pharmacol. 2018 Aug;70(8):1078-1091. doi: 10.1111/jphp.12926.

3. H Ye et al. Anti-Helicobacter pylori activities of Chenopodium ambrosioides L. in vitro and in vivo. World J Gastroenterol. 2015 Apr 14;21(14):4178-83. doi: 10.3748/wjg.v21.i14.4178.

4. ZL Sousa et al. Biological activities of extracts from Chenopodium ambrosioides Lineu and Kielmeyera neglecta Saddi. Ann Clin Microbiol Antimicrob. 2012 Jul 28;11:20. doi: 10.1186/1476-0711-11-20.

5. DN Cysne et al. Antimalarial potential of leaves of Chenopodium ambrosioides. Parasitology Research. November 2016, Volume 115, Issue 11, pp 4327–4334

6. GV Cruz et al. Increase of cellular recruitment, phagocytosis ability and nitric oxide production induced by hydroalcoholic extract from Chenopodium ambrosioides leaves. J Ethnopharmacol. 2007 Apr 20;111(1):148-54.

7. FR Nascimento et al. Ascitic and solid Ehrlich tumour inhibition by Chenopodium ambrosioides L. treatment. Life Sci. 2006 Apr 25;78(22):2650-3.

8. Chemical composition, antimicrobial, modulator and antioxidant activity of essential oil of Dysphania ambrosioides/ Comp Immunol Microbiol Infect Dis. 2019 Aug;65:58-64. doi: 10.1016/j.cimid.2019.04.010. Epub 2019 Apr 25.

9. Inhibition of the TetK efflux-pump by the essential oil of Chenopodium ambrosioides L. and α-terpinene against Staphylococcus aureus IS-58.Food Chem Toxicol. 2017 Nov;109(Pt 2):957-961. doi: 10.1016/j.fct.2017.02.031. Epub 2017 Feb 24.

10. Chemical Composition, Antibacterial, Schistosomicidal, and Cytotoxic Activities of the Essential Oil of Dysphania ambrosioides (L.) Mosyakin & Clemants (Chenopodiaceae).Chem Biodivers. 2017 Aug;14(8). doi: 10.1002/cbdv.201700149.

11 Antioxidant, intestinal immune status and anti-inflammatory potential of Chenopodium ambrosioides L. in fish: In vitro and in vivo studies. Fish Shellfish Immunol. 2019 Mar;86:420-428. doi: 10.1016/j.fsi.2018.11.059

12 Evaluation of the subchronic toxicity of oral treatment with Chenopodium ambrosioides in mice. J Ethnopharmacol. 2010 Feb 17;127(3):602-5. doi: 10.1016/j.jep.2009.12.018.

13 Chenopodium ambrosioides induces an endothelium-dependent relaxation of rat isolated aorta. Assaidi, I. Dib, M. Tits, L. Angenot, S. Bellahcen, N. Bouanani, A. Legssyer, M. Aziz, H. Mekhfi, M. Bnouham, M. Frederich, A. Ziyyat,Journal of Integrative Medicine (2019).