Malaria is one of the most critical global infectious diseases. Severe systemic inflammatory diseases, such as cerebral malaria, lead to the development of cognitive and behavioral alterations, such as learning disabilities and loss of memory capacity, as well as increased anxiety and depression. The consequences are profound and usually contribute to reduce the patient’s quality of life. There are no therapies to treat the neurological sequelae of cerebral malaria. Mesenchymal stromal cells (MSCs) may be an alternative, since they have been used as therapy for neurodegenerative diseases and traumatic lesions of the central nervous system. So far, no study has investigated the effects of MSC therapy on the blood-brain barrier, leukocyte rolling and adherence in the brain, and depression like-behavior in experimental cerebral malaria. Male C57BL/6 mice were infected with Plasmodium berghei ANKA (PbA, 1 × 106 PbA-parasitized red blood cells, intraperitoneally). At day 6, PbA-infected animals received chloroquine (25 mg/kg orally for seven consecutive days) as the antimalarial treatment and were then randomized to receive MSCs (1 × 105 cells in 0.05 ml of saline/mouse) or saline (0.05 ml) intravenously. Parasitemia, clinical score, and survival rate were analyzed throughout the experiments. Evans blue assay was performed at 6, 7, and 15 days post-infection (dpi). Behavioral tests were performed at 5 and 15 dpi. Intravital microscopy experiments and brain-derived neurotrophic factor (BDNF) protein expression analyses were performed at 7 dpi, whereas inflammatory mediators were measured at 15 dpi. In vitro, endothelial cells were used to evaluate the effects of conditioned media derived from MSCs (CMMSC) on cell viability by lactate dehydrogenase (LDH) release. PbA-infected mice presented increased parasitemia, adherent leukocytes, blood-brain barrier permeability, and reduced BDNF protein levels, as well as depression-like behavior. MSCs mitigated behavioral alterations, restored BDNF and transforming growth factor (TGF)-β protein levels, and reduced blood-brain barrier dysfunction and leukocyte adhesion in the brain microvasculature. In a cultured endothelial cell line stimulated with heme, CMMSC reduced LDH release, suggesting a paracrine mechanism of action. A single dose of MSCs as adjuvant therapy protected against vascular damage and improved depression-like behavior in mice that survived experimental cerebral malaria.

中文翻译：

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间充质基质细胞可保护幸免于脑部疟疾的小鼠的血管损伤和抑郁样行为。

疟疾是全球最严重的传染病之一。严重的全身性炎性疾病，例如脑疟疾，导致认知和行为改变的发展，例如学习障碍和记忆力丧失，以及焦虑和抑郁的加剧。结果是深远的，通常会降低患者的生活质量。没有疗法可以治疗脑型疟疾的神经系统后遗症。间充质基质细胞（MSC）可能是一种替代方法，因为它们已被用作神经退行性疾病和中枢神经系统创伤性病变的治疗方法。迄今为止，尚无研究研究MSC治疗对实验性疟疾在脑中的血脑屏障，白细胞滚动和粘附以及抑郁样行为的影响。雄性C57BL / 6小鼠感染了伯氏疟原虫ANKA（腹膜内感染PbA，1×106 PbA寄生的红细胞）。在第6天，被PbA感染的动物接受氯喹（连续7天口服25 mg / kg）作为抗疟疾治疗，然后随机接受MSC（1×105细胞，0.05 ml生理盐水/小鼠）或生理盐水（0.05 ml）。 ）静脉注射。在整个实验过程中分析寄生虫血症，临床评分和存活率。感染后（dpi）第6、7和15天进行伊文思蓝分析。行为测试以5和15 dpi进行。活体显微镜实验和脑源性神经营养因子（BDNF）蛋白表达分析在7 dpi下进行，而炎症介质在15 dpi下进行测量。体外，内皮细胞用于评估乳酸脱氢酶（LDH）释放对MSCs（CMMSC）产生的条件培养基对细胞活力的影响。感染PbA的小鼠表现出更高的寄生虫病，白细胞粘附，血脑屏障通透性和BDNF蛋白水平降低，以及抑郁样行为。MSC缓解了行为改变，恢复了BDNF和转化生长因子（TGF）-β蛋白水平，并减少了脑微血管中的血脑屏障功能障碍和白细胞粘附。在用血红素刺激的培养的内皮细胞系中，CMMSC减少了LDH的释放，提示其旁分泌作用机制。在实验性脑疟疾中幸存下来的小鼠中，单剂量的MSC作为辅助治疗可防止血管损伤并改善抑郁样行为。