Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.
Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.
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DOI：
10.1371/journal.ppat.1000963
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发表时间：
2010-06-24
期刊：
影响因子：
6.7
通讯作者：
Castro-Faria-Neto HC
中科院分区：
文献类型：
--
作者：
Reis PA;Comim CM;Hermani F;Silva B;Barichello T;Portella AC;Gomes FC;Sab IM;Frutuoso VS;Oliveira MF;Bozza PT;Bozza FA;Dal-Pizzol F;Zimmerman GA;Quevedo J;Castro-Faria-Neto HC
脑型疟疾是恶性疟原虫感染最严重的神经系统并发症，在脑型疟疾存活儿童中经常发现神经损伤。寄生虫病治疗后疟疾患者长期认知缺陷的病理生理学和治疗是一个重要的研究领域。在本研究中，我们使用几种具有不同特征的实验性疟疾模型来研究救援治疗后的持续性认知损伤。C57BL/6和Swiss （SW）小鼠分别感染伯氏疟原虫ANKA （PbA）或致死性约利疟原虫XL (PyXL)，在用氯喹治疗急性寄生虫病后，通过一系列行为测试检测到记录的CM和持续的持续性认知损伤。引人注目的是，在初次感染后30天，认知障碍仍然存在。BALB/c小鼠感染PbA、感染chabaudi疟原虫的C57BL6和感染非致死性yoelii疟原虫NXL （PyNXL）的SW均未出现CM症状，急性寄生虫感染经氯喹治愈，且未出现持续性认知障碍。活性氧已被报道介导CM的神经损伤。在pba感染的C57BL/6 CM小鼠的大脑中检测到丙二醛（MDA）和偶联二烯的产生增加，表明高氧化应激。在首次出现CM症状时，用抗氧化剂加氯喹治疗pba感染的C57BL/6小鼠，可防止持续性认知损伤的发展。这些研究为CM抢救治疗后认知功能障碍的自然史提供了新的见解，可能具有临床意义，也可能与败血症和其他疾病的脑后遗症有关。脑型疟疾（CM）是恶性疟原虫感染的致命后果。严重的神经功能缺损是CM期间常见的。虽然大多数在6个月内消退，但一些回顾性研究已经描述了CM发作后长期认知障碍的高频率。我们开发了行为测试来识别实验性CM引起的认知障碍。在感染伯氏疟原虫ANKA （PbA）期间，CM （C57BL/6）易感小鼠在情境和厌恶记忆方面出现长期认知障碍。在感染约利疟原虫XL的瑞士韦伯斯特小鼠中也观察到同样的情况，这是一种致命的菌株，也会在易感小鼠菌株中引起神经功能障碍，证实认知功能障碍与CM的发展密切相关。活性氧被描述为与败血症和阿尔茨海默病相关的神经和认知障碍的介质。我们发现pba感染的C57BL/6小鼠的大脑中丙二醛和共轭二烯的产生增加，表明氧化应激。用n -乙酰半胱氨酸和去铁胺作为氯喹的添加剂进行抗氧化治疗，可预防认知功能障碍，证实氧化应激在cm相关认知后遗症中的重要性。添加抗氧化剂的管理可能是一个成功的治疗策略，以控制CM的长期后果和其他严重的系统性炎症综合征与神经受累。
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. 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.
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