title: Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.
abstract: Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Reis
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Comim
authors.forename: Fernanda
authors.initials: F
authors.lastname: Hermani
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva
authors.forename: Tatiana
authors.initials: T
authors.lastname: Barichello
authors.forename: Aline C
authors.initials: AC
authors.lastname: Portella
authors.forename: Flavia C A
authors.initials: FC
authors.lastname: Gomes
authors.forename: Ive M
authors.initials: IM
authors.lastname: Sab
authors.forename: Valber S
authors.initials: VS
authors.lastname: Frutuoso
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Oliveira
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Bozza
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Bozza
authors.forename: Felipe
authors.initials: F
authors.lastname: Dal-Pizzol
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro-Faria-Neto
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000473:pathology* / Q000517:prevention & control*; D004338:Drug Combinations; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D016779:Malaria, Cerebral / Q000150:complications* / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D018512:Parasitemia / Q000473:pathology / Q000517:prevention & control; D010962:Plasmodium berghei / Q000187:drug effects*; D010967:Plasmodium yoelii / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015996:Survival Rate
chemical_list: D000962:Antimalarials; D000975:Antioxidants; D004338:Drug Combinations; D017382:Reactive Oxygen Species