Choi Bo Young, Kim Jin Hee, Kim Hyun Jung, Lee Bo Eun, Kim In Yeol, Sohn Min, Suh Sang Won
Department of Physiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea.
Inha University, Department of Nursing, Incheon, Republic of Korea.
J Trace Elem Med Biol. 2014 Oct;28(4):474-81. doi: 10.1016/j.jtemb.2014.07.007. Epub 2014 Aug 4.
Numerous studies have demonstrated that traumatic brain injury (TBI) increases hippocampal neurogenesis in the rodent brain. However, the mechanisms underlying increased neurogenesis after TBI remain unknown. Continuous neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in the adult brain. The mechanism that maintains active neurogenesis in the hippocampal area is not known. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ (mossy fiber). The mossy fiber of dentate granular cells contains high levels of chelatable zinc in their terminal vesicles, which can be released into the extracellular space during neuronal activity. Previously, our lab presented findings indicating that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia or epilepsy. Using a weight drop animal model to mimic human TBI, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after TBI. Thus, we injected a zinc chelator, clioquinol (CQ, 30mg/kg), into the intraperitoneal space to reduce brain zinc availability twice per day for 1 week. Neuronal death was evaluated with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after TBI. The number of degenerating neurons (FJB (+)) and live neurons (NeuN (+)) was similar in vehicle and in CQ-treated rats at 1 week after TBI. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX) immunostaining 1 week after TBI. The number of BrdU, Ki67 and DCX positive cell was increased after TBI. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. The present study shows that zinc chelation did not prevent neurodegeneration but did reduce TBI-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal neurogenesis after TBI.
大量研究表明，创伤性脑损伤（TBI）会增加啮齿动物大脑中海马体的神经发生。然而，TBI后神经发生增加的潜在机制仍不清楚。成人大脑海马齿状回（DG）的颗粒下区（SGZ）持续发生神经发生。维持海马区活跃神经发生的机制尚不清楚。高水平的囊泡锌定位于SGZ（苔藓纤维）的突触前终末。齿状颗粒细胞的苔藓纤维在其终末囊泡中含有高水平的可螯合锌，在神经元活动期间可释放到细胞外空间。此前，我们实验室的研究结果表明，低血糖或癫痫发作后，该区域突触锌定位与高神经发生率之间可能存在关联。我们使用重物坠落动物模型模拟人类TBI，检验了锌在调节TBI后海马神经发生中起关键作用的假设。因此，我们每天两次向腹腔注射锌螯合剂氯碘羟喹（CQ，30mg/kg），持续1周，以降低脑内锌的可利用性。用Fluoro Jade - B和NeuN染色评估神经元死亡情况，以确定CQ在TBI后是否具有神经保护作用。TBI后1周，在注射溶剂和CQ处理的大鼠中，退化神经元（FJB(+)）和存活神经元（NeuN(+)）的数量相似。TBI后1周，使用BrdU、Ki67和双皮质素（DCX）免疫染色评估神经发生情况。TBI后，BrdU、Ki67和DCX阳性细胞数量增加。然而，CQ处理后，BrdU、Ki67和DCX阳性细胞数量显著减少。本研究表明，锌螯合并不能预防神经变性，但确实减少了TBI诱导的祖细胞增殖和神经发生。因此，本研究表明锌在调节TBI后海马神经发生中起着至关重要的作用。
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