Cognitive Dysfunction Is Sustained after Rescue Therapy in Experimental Cerebral Malaria, and Is Reduced by Additive Antioxidant Therapy

Autor: Fernanda V. Hermani, Tatiana Barichello, João Quevedo, Flávia Carvalho Alcantara Gomes, Hugo C. Castro-Faria-Neto, Guy A. Zimmerman, Fernando A. Bozza, Valber da Silva Frutuoso, Patrícia T. Bozza, Ive M. Sab, Marcus F. Oliveira, Felipe Dal-Pizzol, Patrícia A. Reis, Aline Cristina Portella, Clarissa M. Comim, B. V. Silva
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 6, Iss 6, p e1000963 (2010)
ISSN: 1553-7374
1553-7366
Popis: 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.
Author Summary Cerebral malaria (CM) is a deadly consequence of Plasmodium falciparum infection. Severe neurologic deficits are frequent during CM. Although most resolve within 6 months, several retrospective studies have described high frequencies of long-lasting cognitive impairment after an episode of CM. We developed behavioral tests to identify cognitive impairment due to experimental CM. During infection with Plasmodium berghei ANKA (PbA), mice susceptible to CM (C57BL/6) developed long-lasting cognitive impairment in contextual and aversive memory. The same profile was seen in Swiss Webster mice infected with Plasmodium yoelii XL, a lethal strain that also induces neurological dysfunctions in susceptible mice strains, confirming that the cognitive dysfunction is closely associated to the development of CM. Reactive oxygen species are described as mediators of neurological and cognitive impairment associated to sepsis and Alzheimer's disease. Here we found enhanced production of malondialdeyde and conjugated dienes in brains of PbA-infected C57BL/6 mice, indicating oxidative stress. Antioxidant therapy with N-acetylcisteine and desferroxamine, as an additive to chloroquine, prevented the cognitive impairment, confirming the importance of oxidative stress in CM-associated cognitive sequellae. Administration of additive antioxidants may be a successful therapeutic strategy to control long-lasting consequences of CM and in other severe systemic inflammatory syndromes with neurological involvement.
Databáze: OpenAIRE
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