title: Curcumin-arteether combination therapy of Plasmodium berghei-infected mice prevents recrudescence through immunomodulation.
abstract: Earlier studies in this laboratory have shown the potential of artemisinin-curcumin combination therapy in experimental malaria. In a parasite recrudescence model in mice infected with Plasmodium berghei (ANKA), a single dose of alpha,beta-arteether (ART) with three oral doses of curcumin prevented recrudescence, providing almost 95% protection. The parasites were completely cleared in blood with ART-alone (AE) or ART+curcumin (AC) treatments in the short-term, although the clearance was faster in the latter case involving increased ROS generation. But, parasites in liver and spleen were not cleared in AE or AC treatments, perhaps, serving as a reservoir for recrudescence. Parasitemia in blood reached up to 60% in AE-treated mice during the recrudescence phase, leading to death of animals. A transient increase of up to 2-3% parasitemia was observed in AC-treatment, leading to protection and reversal of splenomegaly. A striking increase in spleen mRNA levels for TLR2, IL-10 and IgG-subclass antibodies but a decrease in those for INFγ and IL-12 was observed in AC-treatment. There was a striking increase in IL-10 and IgG subclass antibody levels but a decrease in INFγ levels in sera leading to protection against recrudescence. AC-treatment failed to protect against recrudescence in TLR2(-/-) and IL-10(-/-) animals. IL-10 injection to AE-treated wild type mice and AC-treated TLR2(-/-) mice was able to prolong survival. Blood from the recrudescence phase in AE-treatment, but not from AC-treatment, was able to reinfect and kill naïve animals. Sera from the recrudescence phase of AC-treated animals reacted with several parasite proteins compared to that from AE-treated animals. It is proposed that activation of TLR2-mediated innate immune response leading to enhanced IL-10 production and generation of anti-parasite antibodies contribute to protective immunity in AC-treated mice. These results indicate a potential for curcumin-based combination therapy to be tested for prevention of recrudescence in falciparum and relapse in vivax malaria.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore, India.
authors.forename: Palakkod G
authors.initials: PG
authors.lastname: Vathsala
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Dende
authors.forename: Viswanathan Arun
authors.initials: VA
authors.lastname: Nagaraj
authors.forename: Debapriya
authors.initials: D
authors.lastname: Bhattacharya
authors.forename: Gobardhan
authors.initials: G
authors.lastname: Das
authors.forename: Pundi N
authors.initials: PN
authors.lastname: Rangarajan
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Padmanaban
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D003474:Curcumin / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D056747:Immunomodulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008288:Malaria / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010962:Plasmodium berghei / Q000187:drug effects* / Q000472:pathogenicity*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D003474:Curcumin; C055141:artemotil