Wiese Lothar, Kurtzhals Jørgen A L, Penkowa Milena
Section of Neuroprotection, Department of Medical Anatomy, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Denmark.
Exp Neurol. 2006 Jul;200(1):216-26. doi: 10.1016/j.expneurol.2006.02.011. Epub 2006 Apr 19.
Cerebral malaria (CM) is an acute encephalopathy in humans due to the infection with Plasmodium falciparum. Neuro-cognitive impairment following CM occurs in about 10% of the treated survivors, while the precise pathophysiological mechanism remains unknown. Metallothionein I + II (MT-I + II) are increased during CNS pathology and disorders. As previously shown, MT-I + II are neuroprotective through anti-inflammatory, antioxidant and antiapoptotic functions. We have analyzed neuronal apoptosis and MT-I + II expression in brains of mice with experimental CM.
C57BL/6j mice, infected with Plasmodium berghei ANKA, were studied on day 7, day 9, and when presenting signs of CM on days 10-12. We investigated brain histopathology by immunohistochemistry and TUNEL (Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick end labeling). For statistics, we used quantitation (cellular counts) of the analyzed variables.
During CM, we observed significant inflammatory responses of F4/80+ microglia/macrophages and GFAP+ reactive astrocytes and increased immunoreactivity of 8-oxoguanine (marker of oxidative stress). As novel findings, we show: (1) a localized CM-induced neuronal apoptosis (detected by TUNEL) indicating severe and irreversible pathology. (2) A significant increase in MT-I + II expression in reactive astrocytes, macrophages/microglia and vascular endothelium.
This is the first report showing apoptosis of neurons in CM by TUNEL, pointing out a possible pathophysiological mechanism leading to persisting brain damage. The possible neuroprotective role of MT-I + II during CM deserves further attention.
脑型疟疾（CM）是人类因感染恶性疟原虫而引发的一种急性脑病。约10%接受治疗的CM幸存者会出现神经认知障碍，但其确切的病理生理机制尚不清楚。金属硫蛋白I + II（MT-I + II）在中枢神经系统病理和疾病过程中会增加。如先前所示，MT-I + II通过抗炎、抗氧化和抗凋亡功能发挥神经保护作用。我们分析了实验性脑型疟疾小鼠大脑中的神经元凋亡和MT-I + II表达。
对感染伯氏疟原虫ANKA的C57BL/6j小鼠在第7天、第9天以及在第10 - 12天出现脑型疟疾症状时进行研究。我们通过免疫组织化学和TUNEL（末端脱氧核苷酸转移酶（TdT）介导的脱氧尿苷三磷酸（dUTP）-地高辛标记法）研究脑病理组织学。对于统计分析，我们对所分析的变量进行定量（细胞计数）。
在脑型疟疾期间，我们观察到F4/80 +小胶质细胞/巨噬细胞和GFAP +反应性星形胶质细胞有显著的炎症反应，并且8 - 氧鸟嘌呤（氧化应激标志物）的免疫反应性增加。作为新发现，我们表明：（1）局部性的脑型疟疾诱导的神经元凋亡（通过TUNEL检测），表明存在严重且不可逆的病理变化。（2）反应性星形胶质细胞、巨噬细胞/小胶质细胞和血管内皮细胞中MT-I + II表达显著增加。
这是首次通过TUNEL法显示脑型疟疾中神经元凋亡的报告，指出了导致持续性脑损伤的一种可能的病理生理机制。MT-I + II在脑型疟疾期间可能的神经保护作用值得进一步关注。
