Abstract
Curcumin has many pharmacological activities despite its poor bioavailability and in vivo stability. Here, we show that a nanoformulated curcumin (PLGA-curcumin) has better therapeutic index than native curcumin in preventing the onset of neurological symptoms and delaying the death of mice in experimental cerebral malaria. Oral PLGA-curcumin was at least as effective as native curcumin at a 15-fold lower concentration in preventing the breakdown of blood-brain barrier and inhibition of brain mRNAs for inflammatory cytokines, chemokine receptor CXCR3 and its ligand CXCL10, with an increase in the anti-inflammatory cytokine IL-10. This was also reflected in serum cytokine and chemokine levels. At equivalent concentrations, a single oral dose of PLGA-curcumin was more effective in inhibiting serum IFNγ levels and enhancing IL-10 levels than native curcumin. Even at low concentrations, PLGA-curcumin was superior to native curcumin in inhibiting the sequestration of parasitized-RBCs and CD8+ T cells in the brain. A single oral dose of 5 mg PLGA-curcumin containing 350 μg of curcumin resulted in 3-4 fold higher concentration and prolonged presence of curcumin in the brain than that obtained with 5 mg of native curcumin, indicating better bioavailability of PLGA-curcumin. PLGA-curcumin has potential as an adjunct drug to treat human cerebral malaria.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimalarials / chemistry
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Antimalarials / pharmacology*
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Biological Availability
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Brain / drug effects*
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Brain / parasitology
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Brain / pathology
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CD8-Positive T-Lymphocytes
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Chemokine CXCL10 / genetics
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Chemokine CXCL10 / immunology
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Curcumin / chemistry
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Curcumin / pharmacology*
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Disease Models, Animal
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Drug Carriers
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Drug Compounding / methods
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Erythrocytes
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Gene Expression Regulation / drug effects
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Humans
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-10 / genetics
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Interleukin-10 / immunology
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Malaria, Cerebral / drug therapy*
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Malaria, Cerebral / genetics
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Malaria, Cerebral / parasitology
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Malaria, Cerebral / pathology
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Mice
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Mice, Inbred C57BL
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Nanoparticles / administration & dosage*
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Nanoparticles / chemistry
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Nanoparticles / metabolism
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Plasmodium berghei / drug effects
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Plasmodium berghei / growth & development
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Plasmodium berghei / pathogenicity
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Polylactic Acid-Polyglycolic Acid Copolymer / chemistry
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Receptors, CXCR3 / genetics
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Receptors, CXCR3 / immunology
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Signal Transduction
Substances
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Antimalarials
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Chemokine CXCL10
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Cxcl10 protein, mouse
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Cxcr3 protein, mouse
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Drug Carriers
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IFNG protein, mouse
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IL10 protein, mouse
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Neuroprotective Agents
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Receptors, CXCR3
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Interleukin-10
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Polylactic Acid-Polyglycolic Acid Copolymer
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Interferon-gamma
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Curcumin