Pelargonium (Pelargonium sidoides) and Immune support: evidence and sources

Ethnopharmacological relevance Pelargonium sidoides DC. (Geraniaceae), a popular medicinal plant used in traditional medicine in the treatment of gastrointestinal ailments has been transformed into a phytopharmaceutical (EPs(®) 7360) for treating respiratory tract infections. The increasing international demand for Pelargonium sidoides has led to localised overexploitation of its wild populations in southern Africa. The aim of the review is to provide a synthesis of the current state of scientific knowledge on the phytochemical, pharmacological and toxicological properties of Pelargonium sidoides as well as the potential role of plant biotechnology in its conservation. The review highlights knowledge gaps in these research areas. Materials and methods A comprehensive literature search involving mainly electronic and library sources of information were used to collate and synthesise published data. Results Experimental results from in vitro studies indicate that bioactive phytochemical constituents of Pelargonium sidoides may not possess a direct antimicrobial effect, but instead act by interfering with microbial binding to host cell receptors, inhibition of key enzymes and the production of antimicrobial effector molecules such as nitric oxide and interferons (IFNs) by the host cells. Furthermore, clinical evaluations in randomised, double-blind, placebo-controlled trials have demonstrated the beneficial effect of Pelargonium sidoides in the treatment of respiratory tract infections with few side effects. However, there is lack of adequate information on the safety evaluation of the plant. On the other hand, the increasing demand for Pelargonium sidoides has led to localised illegal harvesting of wild plants. Conclusions Pharmacological data reported in literature suggest that Pelargonium sidoides shows a beneficial effect in the treatment of respiratory tract infections. However, more studies are required to elucidate the mode of action of the active constituents exhibited in the treatment of respiratory tract infections and other health conditions caused by microbial attack. Furthermore, the pharmacological usefulness of Pelargonium sidoides must take cognisance of the broader context involving the need for conservation-friendly approaches in its utilisation. In this regard, plant biotechnology applications can play a meaningful role in a holistic conservation strategy.

Extracts and isolated constituents (coumarins and phenols) of Pelargonium sidoides DC, a plant species used in folk medicine by the Southern African native population, were evaluated for their effects on nonspecific immune functions. Although this herbal medicine is also successfully employed in modern phytotherapy in Europe to cure infectious diseases of the respiratory tract, the scientific basis of its remedial effects is still unclear. Thus, functional bioassays including an in vitro model for intracellular infection with Leishmania parasites, an extracellular Leishmania growth assay, a fibroblast-virus protection assay (IFN activity), a fibroblast-lysis assay (TNF activity) and a biochemical assay for inorganic nitric oxides (iNO) were employed. None of the test samples revealed significant activity against extracellular, promastigote Leishmania donovani, the causative agent of human visceral leishmaniasis. In contrast, apart from the coumarin samples, all the Pelargonium extracts (EC(50) <0.1-3.3 microg/mL), gallic acid (EC(50) 4.4 microg/mL) and its methyl ester (EC(50) 12.5 microg/mL) significantly reduced the intracellular survival of L. donovani amastigotes within murine macrophages. These data indicate that the samples acted indirectly on Leishmania parasites, possibly by activating leishmanicidal macrophage functions. Macrophage activation was confirmed by detection of tumour necrosis factor (TNF-alpha) and inorganic nitric oxides (iNO) in supernatants of sample-treated macrophage cultures. Synthesis of iNO is a well-known effector mechanism of macrophages against microorganisms such as Leishmania. Interestingly, blocking iNO-synthase with L-NMMA had no substantial effect on sample-induced intracellular Leishmania kill. From bioassay-guided fractionation, gallic acid and its methyl ester present in large amounts in P. sidoides and in its active extracts, were identified as the prominent immunomodulatory principle for this herbal medicine. The results, when taken together with recent reported antibacterial activity, provide a rational basis for both the traditional and the present utilization of P. sidoides in the claimed conditions.

The importance of Pelargonium species, most notably Pelargonium reniforme and Pelargonium sidoides, in traditional medicine in the Southern African region is well documented. Nowadays, a modern aqueous-ethanolic formulation of the roots of P. sidoides (EPs) 7630) is successfully employed for the treatment of ear, nose and throat disorders as well as respiratory tract infections. To provide a scientific basis of its present utilization in phytomedicine, EPs 7630, extracts and isolated constituents of the titled Pelargoniums with emphasis on P. sidoides were evaluated for antibacterial activity and for their effects on nonspecific immune functions. The samples exhibited merely moderate direct antibacterial capabilities against a spectrum of Gram-positive and Gram-negative bacteria. Functional bioassays including an in vitro model for intracellular diseases, a fibroblast-lysis assay (tumour necrosis factor (TNF) activity), a fibroblast-virus protection assay (IFN activity) and a biochemical assay for nitric oxides revealed significant immunomodulatory properties. Gene expression experiments (iNOS, IFN-alpha, IFN-gamma, TNF-alpha, Interleukin (IL)-1, IL-10, IL12, IL-18) not only confirmed functional data, they also clearly showed differences in the response of infected macrophages when compared to that of noninfected cells. ELISA confirmed the protein production of TNF-alpha, IL-1alpha and IL-12, while FACS analyses reaffirmed the cytokines IL-1alpha and IL-12 at the singular cell level. The current data provide convincing support for the improvement of immune functions at various levels, hence, validating the medicinal uses of EPs 7630. Despite considerable efforts, the remedial effects cannot yet be related to a chemically defined principle.

Pelargonium species contribute significantly to the health care of a large population in the Southern African region, as part of a long-standing medical system intimately linked to traditional healing practices. Most notably, extracts of the roots of P. sidoides have commonly been applied for the treatment of dysentery and diarrhoea but only occasionally for respiratory complaints. Clinical trials have shown that a modern aqueous-ethanolic formulation of P. sidoides extracts (EPs ® 7630) is an efficacious treatment for disorders of the respiratory tract, for example bronchitis and sinusitis. It should be noted that EPs ® 7630 is the most widely investigated extract and therefore is the focus of this review. In order to provide a rationale for its therapeutic activity extracts have been evaluated for antibacterial activity and for their effects on non-specific immune functions. Only moderate direct antibacterial capabilities against a spectrum of bacteria, including Mycobacteria strains, have been noted. In contrast, a large body of in vitro studies has provided convincing evidence for an anti-infective principle associated with activation of the non-specific immune system. Interestingly, significant inhibition of interaction between bacteria and host cells, a key to the pathogenesis of respiratory tract infections, has emerged from recent studies. In addition, antiviral effects have been demonstrated, including inhibition of the replication of respiratory viruses and the enzymes haemagglutinin and neuraminidase. Besides, an increase of cilliary beat frequency of respiratory cells may contribute to the beneficial effects of P. sidoides extracts. This example provides a compelling argument for continuing the exploration of Nature and traditional medical systems as a source of therapeutically useful herbal medicines.