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

PLoS Pathogens

Guy A. Zimmerman¹  Marcus F. Oliveira²  Aline C. Portella³  Flavia C. A. Gomes³  Fernando A. Bozza⁴  Felipe Dal-Pizzol⁵  Valber S. Frutuoso⁶  Ive M. Sab⁶  Patricia T. Bozza⁶  Patricia A. Reis⁶  Hugo C. Castro-Faria-Neto⁶  Bruno Silva⁷  Tatiana Barichello⁷  Clarissa M. Comim⁷  João Quevedo⁷  Fernanda Hermani⁷ 

[1] Department of Medicine and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, United States of America;Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;Instituto de Ciências Biomédicas Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;Instituto de Pesquisa Clínicas Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;Laboratório de Fisiopatologia Experimental, Universidade do Extremo Sul Catarinense, Criciúma, Brazil;Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;Laboratório de Neurociências and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Universidade do Extremo Sul Catarinense, Criciúma, Brazil

关键词: Cognitive impairment;    Cerebral malaria;    Chloroquine;    Parasitic diseases;    Antioxidant therapy;    Memory;    Mice;    Brain damage;   

DOI  :  10.1371/journal.ppat.1000963

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY