Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak

Gramagliaid, I; Velez, J; Chang, YS; Caparros-Wanderley, W; Combes, V; Grau, G; Stins, MF; Van Der Heyde, HC

Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak

Gramagliaid, I Velez, J Chang, YS Caparros-Wanderley, W Combes, V

Grau, G Stins, MF Van Der Heyde, HC

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Publication Type:: Journal Article
Citation:: PLoS ONE, 2019, 14 (3)
Issue Date:: 2019-03-01

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Field	Value	Language
dc.contributor.author	Gramagliaid, I	en_US
dc.contributor.author	Velez, J	en_US
dc.contributor.author	Chang, YS	en_US
dc.contributor.author	Caparros-Wanderley, W	en_US
dc.contributor.author	Combes, V https://orcid.org/0000-0003-2178-3596	en_US
dc.contributor.author	Grau, G	en_US
dc.contributor.author	Stins, MF	en_US
dc.contributor.author	Van Der Heyde, HC	en_US
dc.date.available	2019-02-21	en_US
dc.date.issued	2019-03-01	en_US
dc.identifier.citation	PLoS ONE, 2019, 14 (3)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/134790
dc.description.abstract	© 2019 Gramaglia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falcIParum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- And vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected IP on day 4 PI with quinine-injected IP on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recIPients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality.	en_US
dc.relation.ispartof	PLoS ONE	en_US
dc.relation.isbasedon	10.1371/journal.pone.0213428	en_US
dc.subject.classification	General Science & Technology	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Arginase	en_US
dc.subject.mesh	Arginine	en_US
dc.subject.mesh	Blood-Brain Barrier	en_US
dc.subject.mesh	Citrulline	en_US
dc.subject.mesh	Dietary Supplements	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Free Radical Scavengers	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Malaria, Cerebral	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Nitric Oxide	en_US
dc.subject.mesh	Plasmodium berghei	en_US
dc.subject.mesh	Superoxides	en_US
dc.subject.mesh	Urea	en_US
dc.title	Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	14	en_US
utslib.for	MD Multidisciplinary	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	14	en_US

Abstract:

© 2019 Gramaglia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falcIParum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- And vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected IP on day 4 PI with quinine-injected IP on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recIPients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality.

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http://hdl.handle.net/10453/134790