Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria

Matthew Rubach, J Brice Weinberg, Jackson Mukemba, Salvatore M. Florence, Keith Hyland, Alicia D. Volkheimer, Tsin Yeo, Nicholas Anstey, Esther D. Mwaikambo, Donald L. Granger

Research output: Contribution to journalMeeting AbstractResearch

Abstract

Background: Falciparum malaria causes over 600,000 deaths worldwide each year. Despite advances in anti-parasitic drug therapies, 10–20% of children treated for severe malaria die. We have previously documented that NO protects against development of severe malaria, and that NO levels are low in malaria patients. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthase that converts L-arginine to NO. Low or absent BH4 results in superoxide (instead of NO) production by NOS, with a consequent increase in “oxidative stress.”

Hypothesis: Systemic levels of BH4 are decreased in children with cerebral malaria, contributing to low NO bioavailability and increased severity of malaria.

Objective: Determine systemic levels of BH4 in children with malaria.

Methods: In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states [fully reduced biopterin (BH4), and the oxidized metabolites dihydrobiopterin (BH2) and biopterin (B0)] in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 46), as well as control children with non-malaria central nervous system conditions (NMC, n = 48) and healthy control children (HC, n = 111). Urine was collected into dithioerythritol and diethylene triamine penta-acetic acid (DETAPAC). Pterins were measured by high-performance liquid chromatography using sequential electrochemical and fluorescence detection.

Results: Urine BH4 concentrations [µmol/mmol creatinine; median (IQR)] in CM were significantly lower compared to those in children in each of the other three groups. Oxidized biopterins were increased, and the BH4:BH2 ratio was markedly reduced in CM. Blood mononuclear cell guanosine triphosphate cyclohydrolase I mRNA was not low in any of the groups compared to the HC children. In a multivariate logistic regression model, each unit decrease in urine BH4 was independently associated with a 3.85 (95% CI: 1.89–7.69) fold increase in odds of CM (p < 0.001).

Conclusions: Low systemic BH4 levels and increased oxidized biopterins likely contribute to the low NO bioavailability observed in cerebral malaria. Adjunctive interventions to increase BH4 may reduce occurrence of severe falciparum malaria in children.
Original languageEnglish
Article numberOral 1821-2
Pages (from-to)104-105
Number of pages2
JournalNitric Oxide - Biology and Chemistry
Volume42
Issue numberNovember
DOIs
Publication statusPublished - 15 Nov 2014

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Biopterin
Cerebral Malaria
Biological Availability
Malaria
Urine
Dithioerythritol
Pterins
Drug therapy
Falciparum Malaria
Oxidative stress
Coenzymes
High performance liquid chromatography
Neurology
Metabolites
Guanosine Triphosphate
Nitric Oxide Synthase
Superoxides
Acetic Acid
Arginine
Logistics

Cite this

Rubach, M., Weinberg, J. B., Mukemba, J., Florence, S. M., Hyland, K., Volkheimer, A. D., ... Granger, D. L. (2014). Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria. Nitric Oxide - Biology and Chemistry, 42(November), 104-105. [Oral 1821-2]. https://doi.org/10.1016/j.niox.2014.09.021
Rubach, Matthew ; Weinberg, J Brice ; Mukemba, Jackson ; Florence, Salvatore M. ; Hyland, Keith ; Volkheimer, Alicia D. ; Yeo, Tsin ; Anstey, Nicholas ; Mwaikambo, Esther D. ; Granger, Donald L. / Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria. In: Nitric Oxide - Biology and Chemistry. 2014 ; Vol. 42, No. November. pp. 104-105.
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title = "Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria",
abstract = "Background: Falciparum malaria causes over 600,000 deaths worldwide each year. Despite advances in anti-parasitic drug therapies, 10–20{\%} of children treated for severe malaria die. We have previously documented that NO protects against development of severe malaria, and that NO levels are low in malaria patients. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthase that converts L-arginine to NO. Low or absent BH4 results in superoxide (instead of NO) production by NOS, with a consequent increase in “oxidative stress.”Hypothesis: Systemic levels of BH4 are decreased in children with cerebral malaria, contributing to low NO bioavailability and increased severity of malaria.Objective: Determine systemic levels of BH4 in children with malaria.Methods: In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states [fully reduced biopterin (BH4), and the oxidized metabolites dihydrobiopterin (BH2) and biopterin (B0)] in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 46), as well as control children with non-malaria central nervous system conditions (NMC, n = 48) and healthy control children (HC, n = 111). Urine was collected into dithioerythritol and diethylene triamine penta-acetic acid (DETAPAC). Pterins were measured by high-performance liquid chromatography using sequential electrochemical and fluorescence detection.Results: Urine BH4 concentrations [µmol/mmol creatinine; median (IQR)] in CM were significantly lower compared to those in children in each of the other three groups. Oxidized biopterins were increased, and the BH4:BH2 ratio was markedly reduced in CM. Blood mononuclear cell guanosine triphosphate cyclohydrolase I mRNA was not low in any of the groups compared to the HC children. In a multivariate logistic regression model, each unit decrease in urine BH4 was independently associated with a 3.85 (95{\%} CI: 1.89–7.69) fold increase in odds of CM (p < 0.001).Conclusions: Low systemic BH4 levels and increased oxidized biopterins likely contribute to the low NO bioavailability observed in cerebral malaria. Adjunctive interventions to increase BH4 may reduce occurrence of severe falciparum malaria in children.",
author = "Matthew Rubach and Weinberg, {J Brice} and Jackson Mukemba and Florence, {Salvatore M.} and Keith Hyland and Volkheimer, {Alicia D.} and Tsin Yeo and Nicholas Anstey and Mwaikambo, {Esther D.} and Granger, {Donald L.}",
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Rubach, M, Weinberg, JB, Mukemba, J, Florence, SM, Hyland, K, Volkheimer, AD, Yeo, T, Anstey, N, Mwaikambo, ED & Granger, DL 2014, 'Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria', Nitric Oxide - Biology and Chemistry, vol. 42, no. November, Oral 1821-2, pp. 104-105. https://doi.org/10.1016/j.niox.2014.09.021

Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria. / Rubach, Matthew; Weinberg, J Brice; Mukemba, Jackson; Florence, Salvatore M.; Hyland, Keith; Volkheimer, Alicia D.; Yeo, Tsin; Anstey, Nicholas; Mwaikambo, Esther D.; Granger, Donald L.

In: Nitric Oxide - Biology and Chemistry, Vol. 42, No. November, Oral 1821-2, 15.11.2014, p. 104-105.

Research output: Contribution to journalMeeting AbstractResearch

TY - JOUR

T1 - Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria

AU - Rubach, Matthew

AU - Weinberg, J Brice

AU - Mukemba, Jackson

AU - Florence, Salvatore M.

AU - Hyland, Keith

AU - Volkheimer, Alicia D.

AU - Yeo, Tsin

AU - Anstey, Nicholas

AU - Mwaikambo, Esther D.

AU - Granger, Donald L.

PY - 2014/11/15

Y1 - 2014/11/15

N2 - Background: Falciparum malaria causes over 600,000 deaths worldwide each year. Despite advances in anti-parasitic drug therapies, 10–20% of children treated for severe malaria die. We have previously documented that NO protects against development of severe malaria, and that NO levels are low in malaria patients. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthase that converts L-arginine to NO. Low or absent BH4 results in superoxide (instead of NO) production by NOS, with a consequent increase in “oxidative stress.”Hypothesis: Systemic levels of BH4 are decreased in children with cerebral malaria, contributing to low NO bioavailability and increased severity of malaria.Objective: Determine systemic levels of BH4 in children with malaria.Methods: In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states [fully reduced biopterin (BH4), and the oxidized metabolites dihydrobiopterin (BH2) and biopterin (B0)] in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 46), as well as control children with non-malaria central nervous system conditions (NMC, n = 48) and healthy control children (HC, n = 111). Urine was collected into dithioerythritol and diethylene triamine penta-acetic acid (DETAPAC). Pterins were measured by high-performance liquid chromatography using sequential electrochemical and fluorescence detection.Results: Urine BH4 concentrations [µmol/mmol creatinine; median (IQR)] in CM were significantly lower compared to those in children in each of the other three groups. Oxidized biopterins were increased, and the BH4:BH2 ratio was markedly reduced in CM. Blood mononuclear cell guanosine triphosphate cyclohydrolase I mRNA was not low in any of the groups compared to the HC children. In a multivariate logistic regression model, each unit decrease in urine BH4 was independently associated with a 3.85 (95% CI: 1.89–7.69) fold increase in odds of CM (p < 0.001).Conclusions: Low systemic BH4 levels and increased oxidized biopterins likely contribute to the low NO bioavailability observed in cerebral malaria. Adjunctive interventions to increase BH4 may reduce occurrence of severe falciparum malaria in children.

AB - Background: Falciparum malaria causes over 600,000 deaths worldwide each year. Despite advances in anti-parasitic drug therapies, 10–20% of children treated for severe malaria die. We have previously documented that NO protects against development of severe malaria, and that NO levels are low in malaria patients. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthase that converts L-arginine to NO. Low or absent BH4 results in superoxide (instead of NO) production by NOS, with a consequent increase in “oxidative stress.”Hypothesis: Systemic levels of BH4 are decreased in children with cerebral malaria, contributing to low NO bioavailability and increased severity of malaria.Objective: Determine systemic levels of BH4 in children with malaria.Methods: In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states [fully reduced biopterin (BH4), and the oxidized metabolites dihydrobiopterin (BH2) and biopterin (B0)] in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 46), as well as control children with non-malaria central nervous system conditions (NMC, n = 48) and healthy control children (HC, n = 111). Urine was collected into dithioerythritol and diethylene triamine penta-acetic acid (DETAPAC). Pterins were measured by high-performance liquid chromatography using sequential electrochemical and fluorescence detection.Results: Urine BH4 concentrations [µmol/mmol creatinine; median (IQR)] in CM were significantly lower compared to those in children in each of the other three groups. Oxidized biopterins were increased, and the BH4:BH2 ratio was markedly reduced in CM. Blood mononuclear cell guanosine triphosphate cyclohydrolase I mRNA was not low in any of the groups compared to the HC children. In a multivariate logistic regression model, each unit decrease in urine BH4 was independently associated with a 3.85 (95% CI: 1.89–7.69) fold increase in odds of CM (p < 0.001).Conclusions: Low systemic BH4 levels and increased oxidized biopterins likely contribute to the low NO bioavailability observed in cerebral malaria. Adjunctive interventions to increase BH4 may reduce occurrence of severe falciparum malaria in children.

U2 - 10.1016/j.niox.2014.09.021

DO - 10.1016/j.niox.2014.09.021

M3 - Meeting Abstract

VL - 42

SP - 104

EP - 105

JO - Nitric Oxide - Biology and Chemistry

JF - Nitric Oxide - Biology and Chemistry

SN - 1089-8603

IS - November

M1 - Oral 1821-2

ER -