Probucol-Induced α-Tocopherol Deficiency Protects Mice against Malaria Infection
The emergence of malaria pathogens having resistance against antimalarials implies the necessity for the development of new drugs. Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol,...
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| creator | Herbas, Maria Shirely Shichiri, Mototada Ishida, Noriko Kume, Aiko Hagihara, Yoshihisa Yoshida, Yasukazu Suzuki, Hiroshi |
| description | The emergence of malaria pathogens having resistance against antimalarials implies the necessity for the development of new drugs. Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol, a lipid-soluble antioxidant. However, dietary restriction induced α-tocopherol deficiency is difficult to be applied as a clinical antimalarial therapy. Here, we report on a new strategy to potentially treat malaria by using probucol, a drug that can reduce the plasma α-tocopherol concentration. Probucol pre-treatment for 2 weeks and treatment throughout the infection rescued from death of mice infected with Plasmodium yoelii XL-17 or P. berghei ANKA. In addition, survival was extended when the treatment started immediately after parasite inoculation. The ratio of lipid peroxidation products to parent lipids increased in plasma after 2 weeks treatment of probucol. This indicates that the protective effect of probucol might be mediated by the oxidative stressful environment induced by α-tocopherol deficiency. Probucol in combination with dihydroartemisin suppressed the proliferation of P. yoelii XL-17. These results indicated that probucol might be a candidate for a drug against malaria infection by inducing α-tocopherol deficiency without dietary α-tocopherol restriction. |
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Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol, a lipid-soluble antioxidant. However, dietary restriction induced α-tocopherol deficiency is difficult to be applied as a clinical antimalarial therapy. Here, we report on a new strategy to potentially treat malaria by using probucol, a drug that can reduce the plasma α-tocopherol concentration. Probucol pre-treatment for 2 weeks and treatment throughout the infection rescued from death of mice infected with Plasmodium yoelii XL-17 or P. berghei ANKA. In addition, survival was extended when the treatment started immediately after parasite inoculation. The ratio of lipid peroxidation products to parent lipids increased in plasma after 2 weeks treatment of probucol. This indicates that the protective effect of probucol might be mediated by the oxidative stressful environment induced by α-tocopherol deficiency. Probucol in combination with dihydroartemisin suppressed the proliferation of P. yoelii XL-17. These results indicated that probucol might be a candidate for a drug against malaria infection by inducing α-tocopherol deficiency without dietary α-tocopherol restriction.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0136014</identifier><identifier>PMID: 26296197</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>alpha-Tocopherol - antagonists & inhibitors ; alpha-Tocopherol - blood ; alpha-Tocopherol - pharmacology ; Animals ; Antimalarials - pharmacology ; Antioxidants ; Antioxidants - metabolism ; Antioxidants - pharmacology ; Artemisinins - pharmacology ; Diet ; Dietary restrictions ; Dihydroartemisin ; Drug Administration Schedule ; Drug development ; Drug Synergism ; Drug Therapy, Combination ; Erythrocytes ; Female ; Infections ; Inoculation ; Lipid peroxidation ; Lipid Peroxidation - drug effects ; Lipids ; Malaria ; Malaria - blood ; Malaria - drug therapy ; Malaria - parasitology ; Malaria - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Parasitemia - blood ; Parasitemia - drug therapy ; Parasitemia - pathology ; Parasites ; Peroxidation ; Plasma levels ; Plasmodium ; Plasmodium berghei - drug effects ; Plasmodium berghei - physiology ; Plasmodium falciparum ; Plasmodium yoelii - drug effects ; Plasmodium yoelii - physiology ; Probucol - pharmacology ; Proteins ; Science ; Survival Analysis ; Tocopherol ; Vector-borne diseases ; Vitamin E</subject><ispartof>PloS one, 2015-08, Vol.10 (8), p.e0136014</ispartof><rights>2015 Herbas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Herbas et al 2015 Herbas et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-9c43c29db7fe089241c5c581337b25344f06ea2f4d8498369384d9c2f69c67b03</citedby><cites>FETCH-LOGICAL-c526t-9c43c29db7fe089241c5c581337b25344f06ea2f4d8498369384d9c2f69c67b03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546625/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546625/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26296197$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tsuboi, Takafumi</contributor><creatorcontrib>Herbas, Maria Shirely</creatorcontrib><creatorcontrib>Shichiri, Mototada</creatorcontrib><creatorcontrib>Ishida, Noriko</creatorcontrib><creatorcontrib>Kume, Aiko</creatorcontrib><creatorcontrib>Hagihara, Yoshihisa</creatorcontrib><creatorcontrib>Yoshida, Yasukazu</creatorcontrib><creatorcontrib>Suzuki, Hiroshi</creatorcontrib><title>Probucol-Induced α-Tocopherol Deficiency Protects Mice against Malaria Infection</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The emergence of malaria pathogens having resistance against antimalarials implies the necessity for the development of new drugs. Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol, a lipid-soluble antioxidant. However, dietary restriction induced α-tocopherol deficiency is difficult to be applied as a clinical antimalarial therapy. Here, we report on a new strategy to potentially treat malaria by using probucol, a drug that can reduce the plasma α-tocopherol concentration. Probucol pre-treatment for 2 weeks and treatment throughout the infection rescued from death of mice infected with Plasmodium yoelii XL-17 or P. berghei ANKA. In addition, survival was extended when the treatment started immediately after parasite inoculation. The ratio of lipid peroxidation products to parent lipids increased in plasma after 2 weeks treatment of probucol. This indicates that the protective effect of probucol might be mediated by the oxidative stressful environment induced by α-tocopherol deficiency. Probucol in combination with dihydroartemisin suppressed the proliferation of P. yoelii XL-17. 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Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol, a lipid-soluble antioxidant. However, dietary restriction induced α-tocopherol deficiency is difficult to be applied as a clinical antimalarial therapy. Here, we report on a new strategy to potentially treat malaria by using probucol, a drug that can reduce the plasma α-tocopherol concentration. Probucol pre-treatment for 2 weeks and treatment throughout the infection rescued from death of mice infected with Plasmodium yoelii XL-17 or P. berghei ANKA. In addition, survival was extended when the treatment started immediately after parasite inoculation. The ratio of lipid peroxidation products to parent lipids increased in plasma after 2 weeks treatment of probucol. This indicates that the protective effect of probucol might be mediated by the oxidative stressful environment induced by α-tocopherol deficiency. Probucol in combination with dihydroartemisin suppressed the proliferation of P. yoelii XL-17. These results indicated that probucol might be a candidate for a drug against malaria infection by inducing α-tocopherol deficiency without dietary α-tocopherol restriction.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26296197</pmid><doi>10.1371/journal.pone.0136014</doi><oa>free_for_read</oa></addata></record> |
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| subjects | alpha-Tocopherol - antagonists & inhibitors alpha-Tocopherol - blood alpha-Tocopherol - pharmacology Animals Antimalarials - pharmacology Antioxidants Antioxidants - metabolism Antioxidants - pharmacology Artemisinins - pharmacology Diet Dietary restrictions Dihydroartemisin Drug Administration Schedule Drug development Drug Synergism Drug Therapy, Combination Erythrocytes Female Infections Inoculation Lipid peroxidation Lipid Peroxidation - drug effects Lipids Malaria Malaria - blood Malaria - drug therapy Malaria - parasitology Malaria - pathology Male Mice Mice, Inbred C57BL Oxidative Stress Parasitemia - blood Parasitemia - drug therapy Parasitemia - pathology Parasites Peroxidation Plasma levels Plasmodium Plasmodium berghei - drug effects Plasmodium berghei - physiology Plasmodium falciparum Plasmodium yoelii - drug effects Plasmodium yoelii - physiology Probucol - pharmacology Proteins Science Survival Analysis Tocopherol Vector-borne diseases Vitamin E |
| title | Probucol-Induced α-Tocopherol Deficiency Protects Mice against Malaria Infection |
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