Institute of Anatomy, Neurobiology, University of Aarhus, Aarhus, Denmark.
PLoS One. 2010 Apr 9;5(4):e10131. doi: 10.1371/journal.pone.0010131.
Traumatic brain injury (TBI) is one of the leading causes of disability and death among young people. Although much is already known about secondary brain damage the full range of brain tissue responses to TBI remains to be elucidated. A population of neurons located in cerebral areas associated with higher cognitive functions harbours a vesicular zinc pool co-localized with glutamate. This zinc enriched pool of synaptic vesicles has been hypothesized to take part in the injurious signalling cascade that follows pathological conditions such as seizures, ischemia and traumatic brain injury. Pathological release of excess zinc ions from pre-synaptic vesicles has been suggested to mediate cell damage/death to postsynaptic neurons.
METHODOLOGY/PRINCIPAL FINDINGS: In order to substantiate the influence of vesicular zinc ions on TBI, we designed a study in which damage and zinc movements were analysed in several different ways. Twenty-four hours after TBI ZnT3-KO mice (mice without vesicular zinc) were compared to littermate Wild Type (WT) mice (mice with vesicular zinc) with regard to histopathology. Furthermore, in order to evaluate a possible neuro-protective dimension of chemical blocking of vesicular zinc, we treated lesioned mice with either DEDTC or selenite. Our study revealed that chemical blocking of vesicular zinc ions, either by chelation with DEDTC or accumulation in zinc-selenium nanocrystals, worsened the effects on the aftermath of TBI in the WT mice by increasing the number of necrotic and apoptotic cells within the first 24 hours after TBI, when compared to those of chemically untreated WT mice.
CONCLUSION/SIGNIFICANCE: ZnT3-KO mice revealed more damage after TBI compared to WT controls. Following treatment with DEDTC or selenium an increase in the number of both dead and apoptotic cells were seen in the controls within the first 24 hours after TBI while the degree of damage in the ZnT3-KO mice remained largely unchanged. Further analyses revealed that the damage development in the two mouse strains was almost identical after either zinc chelation or zinc complexion therapy.
创伤性脑损伤 (TBI) 是导致年轻人残疾和死亡的主要原因之一。尽管人们已经对继发性脑损伤有了很多了解,但仍需要阐明大脑组织对 TBI 的全面反应。位于与更高认知功能相关的大脑区域的神经元群体,含有一个与谷氨酸共定位的囊泡锌池。这个富含锌的突触小泡池被假设参与了癫痫发作、缺血和创伤性脑损伤等病理状态下的有害信号级联反应。突触前囊泡中过量锌离子的病理性释放被认为介导了对突触后神经元的细胞损伤/死亡。
方法/主要发现:为了证实囊泡锌离子对 TBI 的影响,我们设计了一项研究,通过多种方式分析损伤和锌离子的运动。在 TBI 后 24 小时,我们将缺乏囊泡锌的 ZnT3-KO 小鼠(无囊泡锌的小鼠)与同窝 WT 小鼠(有囊泡锌的小鼠)进行比较,观察组织病理学变化。此外,为了评估化学阻断囊泡锌的可能神经保护作用,我们用 DEDTC 或亚硒酸钠治疗受损的小鼠。我们的研究表明,通过 DEDTC 螯合或在锌-硒纳米晶体中积累,化学阻断囊泡锌离子会增加 TBI 后 24 小时内 WT 小鼠的坏死和凋亡细胞数量,从而加重 WT 小鼠 TBI 后的影响,与未经化学处理的 WT 小鼠相比。
结论/意义:与 WT 对照组相比,ZnT3-KO 小鼠在 TBI 后显示出更多的损伤。在 TBI 后 24 小时内,用 DEDTC 或硒处理的对照组中,死细胞和凋亡细胞的数量都增加了,而 ZnT3-KO 小鼠的损伤程度基本保持不变。进一步分析表明,两种小鼠品系在锌螯合或锌配合治疗后,损伤发展几乎相同。