Cinnamomum cassia exhibits antileishmanial activity against Leishmania donovani infection in vitro and in vivo.
Animals
Antiprotozoal Agents
/ administration & dosage
Cinnamomum aromaticum
/ chemistry
Cricetinae
Cytokines
/ genetics
Female
Gas Chromatography-Mass Spectrometry
Humans
Leishmania donovani
/ drug effects
Leishmaniasis, Visceral
/ drug therapy
Macrophages, Peritoneal
/ drug effects
Male
Mesocricetus
Mice
Mice, Inbred BALB C
Plant Bark
/ chemistry
Plant Extracts
/ administration & dosage
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
20
10
2018
accepted:
08
02
2019
revised:
21
05
2019
pubmed:
10
5
2019
medline:
24
10
2019
entrez:
10
5
2019
Statut:
epublish
Résumé
There is a pressing need for drug discovery against visceral leishmaniasis, a life-threatening protozoal infection, as the available chemotherapy is antiquated and not bereft of side effects. Plants as alternate drug resources has rewarded mankind in the past and aimed in this direction, we investigated the antileishmanial potential of Cinnamomum cassia. Dichloromethane, ethanolic and aqueous fractions of C. cassia bark, prepared by sequential extraction, were appraised for their anti-promastigote activity along with apoptosis-inducing potential. The most potent, C. cassia dichloromethane fraction (CBD) was evaluated for anti-amastigote efficacy in infected macrophages and nitric oxide (NO) production studied. The in vivo antileishmanial efficacy was assessed in L. donovani infected BALB/c mice and hamsters and various correlates of host protective immunity ascertained. Toxicity profile of CBD was investigated in vitro against peritoneal macrophages and in vivo via alterations in liver and kidney functions. The plant secondary metabolites present in CBD were identified by gas chromatography-mass spectroscopy (GC-MS). CBD displayed significant anti-promastigote activity with 50% inhibitory concentration (IC50) of 33.6 μg ml-1 that was mediated via apoptosis. This was evidenced by mitochondrial membrane depolarization, increased proportion of cells in sub-G0-G1 phase, ROS production, PS externalization and DNA fragmentation (TUNEL assay). CBD also inhibited intracellular amastigote proliferation (IC50 14.06 μg ml-1) independent of NO production. The in vivo protection achieved was 80.91% (liver) and 82.92% (spleen) in mice and 75.61% (liver) and 78.93% (spleen) in hamsters indicating its profound therapeutic efficacy. CBD exhibited direct antileishmanial activity, as it did not specifically induce a T helper type (Th)-1-polarized mileu in cured hosts. This was evidenced by insignificant modulation of NO production, lymphoproliferation, DTH (delayed type hypersensitivity), serum IgG2a and IgG1 levels and production of Th2 cytokines (IL-4 and IL-10) along with restoration of pro-inflammatory Th1 cytokines (INF-γ, IL-12p70) to the normal range. CBD was devoid of any toxicity in vitro as well as in vivo. The chemical constituents, cinnamaldehyde and its derivatives present in CBD may have imparted the observed antileishmanial effect. Our study highlights the profound antileishmanial efficacy of C. cassia bark DCM fraction and merits its further exploration as a source of safe and effective antieishmanial compounds.
Sections du résumé
BACKGROUND
There is a pressing need for drug discovery against visceral leishmaniasis, a life-threatening protozoal infection, as the available chemotherapy is antiquated and not bereft of side effects. Plants as alternate drug resources has rewarded mankind in the past and aimed in this direction, we investigated the antileishmanial potential of Cinnamomum cassia.
METHODOLOGY
Dichloromethane, ethanolic and aqueous fractions of C. cassia bark, prepared by sequential extraction, were appraised for their anti-promastigote activity along with apoptosis-inducing potential. The most potent, C. cassia dichloromethane fraction (CBD) was evaluated for anti-amastigote efficacy in infected macrophages and nitric oxide (NO) production studied. The in vivo antileishmanial efficacy was assessed in L. donovani infected BALB/c mice and hamsters and various correlates of host protective immunity ascertained. Toxicity profile of CBD was investigated in vitro against peritoneal macrophages and in vivo via alterations in liver and kidney functions. The plant secondary metabolites present in CBD were identified by gas chromatography-mass spectroscopy (GC-MS).
PRINCIPAL FINDINGS
CBD displayed significant anti-promastigote activity with 50% inhibitory concentration (IC50) of 33.6 μg ml-1 that was mediated via apoptosis. This was evidenced by mitochondrial membrane depolarization, increased proportion of cells in sub-G0-G1 phase, ROS production, PS externalization and DNA fragmentation (TUNEL assay). CBD also inhibited intracellular amastigote proliferation (IC50 14.06 μg ml-1) independent of NO production. The in vivo protection achieved was 80.91% (liver) and 82.92% (spleen) in mice and 75.61% (liver) and 78.93% (spleen) in hamsters indicating its profound therapeutic efficacy. CBD exhibited direct antileishmanial activity, as it did not specifically induce a T helper type (Th)-1-polarized mileu in cured hosts. This was evidenced by insignificant modulation of NO production, lymphoproliferation, DTH (delayed type hypersensitivity), serum IgG2a and IgG1 levels and production of Th2 cytokines (IL-4 and IL-10) along with restoration of pro-inflammatory Th1 cytokines (INF-γ, IL-12p70) to the normal range. CBD was devoid of any toxicity in vitro as well as in vivo. The chemical constituents, cinnamaldehyde and its derivatives present in CBD may have imparted the observed antileishmanial effect.
CONCLUSIONS
Our study highlights the profound antileishmanial efficacy of C. cassia bark DCM fraction and merits its further exploration as a source of safe and effective antieishmanial compounds.
Identifiants
pubmed: 31071090
doi: 10.1371/journal.pntd.0007227
pii: PNTD-D-18-01617
pmc: PMC6529017
doi:
Substances chimiques
Antiprotozoal Agents
0
Cytokines
0
Plant Extracts
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0007227Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Rev Soc Bras Med Trop. 2017 Sep-Oct;50(5):670-674
pubmed: 29160515
Nat Rev Microbiol. 2007 Nov;5(11):873-82
pubmed: 17938629
Am J Trop Med Hyg. 2016 Mar;94(3):489-93
pubmed: 26787156
Korean J Parasitol. 2007 Dec;45(4):247-53
pubmed: 18165706
PLoS Negl Trop Dis. 2016 Oct 24;10(10):e0005011
pubmed: 27776125
PLoS One. 2012;7(5):e35671
pubmed: 22693548
Clin Microbiol Rev. 2018 Aug 29;31(4):
pubmed: 30158301
Curr Med Chem. 2005;12(8):887-916
pubmed: 15853704
Evid Based Complement Alternat Med. 2014;2014:642942
pubmed: 24817901
Parasitol Res. 2009 Aug;105(2):499-505
pubmed: 19352709
BMC Cancer. 2010 May 18;10:210
pubmed: 20482751
Molecules. 2017 Jun 27;22(7):
pubmed: 28654013
Fitoterapia. 2007 Dec;78(7-8):510-4
pubmed: 17651913
Parasitol Int. 2013 Jun;62(3):253-61
pubmed: 23416156
Phytochemistry. 2011 Dec;72(17):2155-64
pubmed: 21885074
PLoS Negl Trop Dis. 2018 Mar 22;12(3):e0006038
pubmed: 29565970
Bioresour Technol. 2008 Jul;99(11):5145-9
pubmed: 17945485
Int J Parasitol Drugs Drug Resist. 2014 Mar 24;4(2):95-111
pubmed: 25057459
J Mycol Med. 2012 Mar;22(1):83-7
pubmed: 23177818
Clin Exp Immunol. 1977 Oct;30(1):119-29
pubmed: 606433
J Immunol. 2007 Oct 15;179(8):5592-603
pubmed: 17911647
Parasit Vectors. 2015 Mar 26;8:183
pubmed: 25884649
Int J Antimicrob Agents. 2016 Dec;48(6):695-702
pubmed: 27876275
Phytomedicine. 2010 Apr;17(5):375-8
pubmed: 19879121
Nutrients. 2015 Sep 11;7(9):7729-48
pubmed: 26378575
Front Microbiol. 2015 Dec 08;6:1368
pubmed: 26696979
Drug Des Devel Ther. 2014 Sep 04;8:1235-47
pubmed: 25214767
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 15;851(1-2):51-70
pubmed: 16950667
Am J Chin Med. 2006;34(3):511-22
pubmed: 16710900
Parasitol Res. 2003 Feb;89(3):221-7
pubmed: 12541065
J Ethnopharmacol. 2015 May 13;165:141-7
pubmed: 25725434
PLoS One. 2011 Feb 08;6(2):e14666
pubmed: 21346801
Med Microbiol Immunol. 2013 Feb;202(1):25-35
pubmed: 22661217
Biol Pharm Bull. 2006 Nov;29(11):2214-21
pubmed: 17077517
J Antimicrob Chemother. 2014 Dec;69(12):3268-74
pubmed: 25096077
Int J Dermatol. 2010 Aug;49(8):921-31
pubmed: 21128917
Ann Trop Med Parasitol. 1982 Feb;76(1):37-43
pubmed: 7082077
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5569-73
pubmed: 22832320
J Nat Prod. 2018 Jun 22;81(6):1333-1342
pubmed: 29883114
J Enzyme Inhib Med Chem. 2005 Aug;20(4):333-40
pubmed: 16206827
Infect Immun. 1997 Jun;65(6):2371-7
pubmed: 9169776
J Nat Med. 2009 Jul;63(3):345-50
pubmed: 19308653
Parasit Vectors. 2016 Aug 22;9:460
pubmed: 27549162
Bioorg Med Chem Lett. 2011 Dec 15;21(24):7451-4
pubmed: 22055204
Genes Dev. 2008 Jun 15;22(12):1577-90
pubmed: 18559474
Environ Toxicol. 2017 Feb;32(2):456-468
pubmed: 26919256
Front Immunol. 2014 May 05;5:193
pubmed: 24829566
J Immunol. 2005 Apr 15;174(8):4916-23
pubmed: 15814719
J Antimicrob Chemother. 2008 Aug;62(2):376-80
pubmed: 18453526
Am J Trop Med Hyg. 2013 Apr;88(4):778-84
pubmed: 23382167
Evid Based Complement Alternat Med. 2012;2012:429320
pubmed: 22536283
Apoptosis. 2000 Nov;5(5):415-8
pubmed: 11256882
Evid Based Complement Alternat Med. 2013;2013:761323
pubmed: 23864897
Crit Rev Anal Chem. 2016;46(2):139-45
pubmed: 25831406
Epidemics. 2017 Mar;18:67-80
pubmed: 28279458
Parasitology. 2018 Feb;145(2):219-236
pubmed: 28805165
Front Biosci (Landmark Ed). 2018 Jan 1;23(5):967-996
pubmed: 28930585
Braz J Med Biol Res. 2004 Dec;37(12):1847-52
pubmed: 15558191
Int J Antimicrob Agents. 2010 Jul;36(1):43-9
pubmed: 20403680
Phytother Res. 2003 Aug;17(7):726-30
pubmed: 12916067
Acta Trop. 2007 Sep;103(3):172-85
pubmed: 17655815
J Biol Chem. 1951 Nov;193(1):265-75
pubmed: 14907713
Am J Chin Med. 1996;24(2):103-9
pubmed: 8874667
Antimicrob Agents Chemother. 2001 May;45(5):1349-54
pubmed: 11302794
Food Funct. 2015 Mar;6(3):910-9
pubmed: 25629927
Phytomedicine. 2011 Sep 15;18(12):1056-69
pubmed: 21596544
Planta Med. 1999 Apr;65(3):263-6
pubmed: 10232076