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Bioactive leishmanicidal alkaloid molecules from Galipea longiflora Krause with immunomodulatory activity
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

According to WHO, leishmaniasis is endemic in 98 countries, and has been placed ninth in a global analysis of infectious diseases. Treatment of leishmaniasis is based on pentavalent antimonials but toxicity and developing resistance have been reported. Traditional medicine and scientific studies have shown that the extract of Galipea longiflora Krause (Evanta) exhibits antileishmanial activity. We hypothesized that the healing observed when using this plant might not only be due to the direct action on the parasite, but possibly to a parallel effect on the host immune response. We found that an alkaloid extract of Evanta (AEE) inhibited the growth of Leishmania braziliensis promastigotes while viability of eukaryotic cells was practically not affected. We also found that AEE interfered with polyclonal activation or Leishmania-specific re-stimulation of lymphocytes, as revealed by a reduction of in vitro cellular proliferation and IFN-g production. More important, AEE treatment of mice hosting L. braziliensis showed that AEE is able to control both inflammation and parasite load. Additionally, the healing process was improved when AEE and meglumine antimoniate were administered simultaneously. Dendritic cells (DCs) play a pivotal role in T-cell stimulation and polarization of naïve T cells. Therefore, we investigated if AEE could alter the activation of DCs and if allostimulatory DCs properties were altered if activated in the presence of AEE. DCs activated in the presence of AEE reduced the production of IL-12p40 and IL-23. When we analyzed the allostimulatory capacity of AEE-treated DCs, we found that allogeneic CD4+ T-cells secreted lower levels of IFN-γ.

In conclusion, this thesis provides valuable insight into the effects of Evanta derived extract. The dual effect found for AEE, on Leishmania parasite and on the immune response, suggests that AEE may be useful in controlling the parasite burden and preventing over-production of inflammatory mediators and subsequently avoiding tissue damage.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University , 2012. , 75 p.
Keyword [en]
Leishmania infection, Leishmaniasis, herbal medicine, natural products, Galipea longiflora Krause, Evanta, cytokines, IFN-gamma, dendritic cells, inflammation, meglumine antimoniate
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-81439ISBN: 978-91-7447-586-9 (print)OAI: oai:DiVA.org:su-81439DiVA: diva2:561695
Public defence
2012-11-22, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Accepted. Paper 3: Submitted.

Available from: 2012-10-31 Created: 2012-10-20 Last updated: 2012-10-24Bibliographically approved
List of papers
1. An alkaloid extract of Evanta, traditionally used as anti-Leishmania agent in Bolivia, inhibits cellular proliferation and interferon-g production in polyclonally activated cells
Open this publication in new window or tab >>An alkaloid extract of Evanta, traditionally used as anti-Leishmania agent in Bolivia, inhibits cellular proliferation and interferon-g production in polyclonally activated cells
2009 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 69, no 3, 251-258 p.Article in journal (Refereed) Published
Abstract [en]

Traditional medicine and scientific studies have shown that the raw extract ofEvanta [Galipea longiflora, Angostura longiflora (Krause) Kallunki] exhibits antileishmanialactivity. We hypothesized that the healing observed when usingthis plant might not only be due to the direct action on the parasite, but possiblyto a parallel effect on the host immune response to the parasite involvedin the healing process. We show here that an alkaloid extract of Evanta (AEE)directly killed the parasite already at a dose of 10 lg ⁄ ml, but at this low concentration,AEE did not have a major effect on viability and proliferation ofeukaryotic cells. The whole extract was also found to be stronger than 2-phenylquinoline,the most prominent alkaloid in AEE. AEE was not directlystimulating B or T cells or J774 macrophages. However, it interfered with theactivation of both mouse and human T cells, as revealed by a reduction of invitro cellular proliferation and interferon-gamma (IFN-c) production. The effectwas more evident when the cells were pretreated with AEE and subsequentlystimulated with the polyclonal T-cell activators Concanavalin A and anti-CD3.Taken together, our results suggest that Evanta have a direct leishmanicidaleffect and due to the effect on IFN-c production it might contribute to controlthe chronic inflammatory reaction that characterize Leishmania infectionpathology, but in vivo studies are necessary to corroborate this finding.

Keyword
Evanta, Galipea longiflora, interferon-gamma, lesihmaniasis
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-81445 (URN)10.1111/j.1365-3083.2008.02219.x (DOI)000263258000009 ()
Available from: 2012-10-21 Created: 2012-10-21 Last updated: 2017-12-07Bibliographically approved
2. Quinolinic alkaloids from Galipea longiflora suppress inflammatory cytokine production in vitro and control inflammatory reaction in vivo upon Leishmania infection
Open this publication in new window or tab >>Quinolinic alkaloids from Galipea longiflora suppress inflammatory cytokine production in vitro and control inflammatory reaction in vivo upon Leishmania infection
Show others...
(English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083Article in journal (Refereed) Accepted
Abstract [en]

An antileishmanial activity of quinolinic alkaloids from Galipea longiflora Krause, known as Evanta, has been demonstrated. We have previously shown that, apart from its leishmanicidal effect, in vitro pretreatment of spleen cells with an alkaloid extract of Evanta (AEE) interfered with the proliferation and interferon-g production in lymphocytes polyclonally activated either with concanavalin A or anti-CD3. In the present study, we investigated if AEE could interfere with antigen-specific lymphocyte activation. We found that in vitro and in vivo treatment reduced recall lymphocyte responses, as measured by IFN-g production (55 % and 63 % reduction compared to untreated cells, respectively). Apart from IFN-g, the production of IL-12 and TNF were also suppressed. No effects were observed for meglumine antimoniate (SbV), the conventional drug used to treat leishmaniasis. When mice infected with Leishmania braziliensis promastigotes in the hind footpad were treated with AEE, the dynamics of the infection changed and the footpath thickness was efficiently controlled. The parasite load was also reduced but to a lesser extent than upon treatment with SbV. Combined treatment efficiently controlled both the thickness and parasite load since smaller lesions during the entire course of the infection were seen in the mice treated with AEE plus SbV compared with AEE or SbV alone. We discuss the benefits of combined administration of AEE plus SbV.

Keyword
Leishmania infection, Galipea longiflora Krause, Evanta, herbal medicine, cytokines, IFN-gamma, inflammation, meglumine antimoniate
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-81446 (URN)
Available from: 2012-10-21 Created: 2012-10-21 Last updated: 2017-12-07Bibliographically approved
3. Alkaloids from Galipea longiflora Krause modify the maturation of human dendritic cells and their ability to stimulate allogeneic CD4+ T cells
Open this publication in new window or tab >>Alkaloids from Galipea longiflora Krause modify the maturation of human dendritic cells and their ability to stimulate allogeneic CD4+ T cells
(English)Article in journal (Refereed) Submitted
Abstract [en]

Alkaloids obtained from the plant Evanta have been shown to have dual effects in Leishmania infection; a direct leishmanicidal effect on the parasite and more importantly, the alkaloids affect both polyclonal and Leishmania-specific stimulation of T-cells.  

Dendritic cells (DCs) play a pivotal role in stimulation and polarization of naïve T cells towards a Th1, Th2, Th17 or regulatory phenotype. In leishmaniasis, the interactions between the parasites and DCs are complex and involve contradictory functions that can stimulate or suppress T cell responses, leading to the control of infection or progression of disease.

 In this study the effect of an alkaloid extract of Evanta (AEE) or the purified alkaloid 2-phenilquinoline (2Ph) on the activation of human DCs and their ability to stimulate allogeneic CD4+ T cells was analyzed. The expression of surface activation molecules was not affected on DCs stimulated in the presence of AEE or 2Ph nor did AEE-DCs or 2Ph-CDs affect the expression of activation surface molecules on allogeneic CD4+ T cells. In contrast, as compared with control, the secretion of IL-12p40, IL-23 and IL-6 was lower from AEE-DCs and 2Ph-CDs and allogeneic CD4+ T cells co-cultured with these DCs secreted lower levels of IFN-γ and IL-10 but the same levels of IL-17.

These results demonstrate that AEE and 2Ph affect the stimulation of DCs and their ability to stimulate allogeneic CD4+ T cells by reducing the production of IFN-g, IL-12 p40, IL-6 and IL-23. This suggests that AEE and 2Ph may take part in regulation of inflammation.

Keyword
Leishmaniasis, Galipea longiflora Krause, natural products, dendritic cells, cytokines
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-81447 (URN)
Available from: 2012-10-21 Created: 2012-10-21 Last updated: 2012-10-22Bibliographically approved

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