Melatonin attenuates neuronal apoptosis through up-regulation of K+-Cl- cotransporter KCC2 expression following traumatic brain injury in rats
Melatonin attenuates neuronal apoptosis through up-regulation of K+-Cl- cotransporter KCC2 expression following traumatic brain injury in rats
复制标题
褪黑素通过上调大鼠创伤性脑损伤后 K -Cl - 协同转运蛋白 KCC2 的表达来减轻神经细胞凋亡
DOI：
10.1111/jpi.12344
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发表时间：
2016-09-01
影响因子：
10.3
通讯作者：
Zhang, Jianmin
中科院分区：
文献类型：
--
作者：
Wu, Haijian;Shao, Anwen;Zhang, Jianmin
创伤性脑损伤（TBI）引发了一系列复杂的神经化学和信号变化，导致神经元凋亡，这导致TBI患者的预后不良。神经元特异性K ~+-Cl ~-协同转运蛋白-2（KCC 2）是成年神经元中Cl ~-的主要输出者，在Cl ~-稳态和神经元功能中起重要作用。本研究的目的是调查KCC 2的表达模式TBI后，并评估是否褪黑激素是能够防止神经细胞凋亡，通过调节KCC 2的表达在Sprague道利大鼠控制的皮质撞击模型TBI。时程研究显示，TBI后同侧顶叶皮质KCC 2的mRNA和蛋白表达降低。免疫荧光双标显示KCC 2定位于神经元的质膜上。另外，脑外伤后5 min腹腔注射褪黑素（10 mg/kg），并于伤后1、2、3、4 h重复注射，伤后24 h取脑组织。与溶剂组相比，褪黑激素治疗改变了TBI后KCC 2在mRNA和蛋白水平上的表达下调。此外，褪黑激素治疗增加了脑源性神经营养因子（BDNF）和磷酸化细胞外信号调节激酶（p-ERK）的蛋白水平。同时，褪黑激素管理改善皮层神经元凋亡，减少脑水肿，并衰减TBI后的神经功能缺损。总之，我们的研究结果表明，褪黑激素恢复KCC 2表达，抑制神经细胞凋亡，减轻TBI后继发性脑损伤，部分通过激活BDNF/ERK通路。
Traumatic brain injury (TBI) initiates a complex cascade of neurochemical and signaling changes that leads to neuronal apoptosis, which contributes to poor outcomes for patients with TBI. The neuron-specific K+-Cl- cotransporter-2 (KCC2), the principal Cl- extruder in adult neurons, plays an important role in Cl- homeostasis and neuronal function. This present study was designed to investigate the expression pattern of KCC2 following TBI and to evaluate whether or not melatonin is able to prevent neuronal apoptosis by modulating KCC2 expression in a Sprague Dawley rat controlled cortical impact model of TBI. The time course study showed decreased mRNA and protein expression of KCC2 in the ipsilateral peri-core parietal cortex after TBI. Double immunofluorescence staining demonstrated that KCC2 is located in the plasma membrane of neurons. In addition, melatonin (10mg/kg) was injected intraperitoneally at 5minutes and repeated at 1, 2, 3, and 4hours after brain trauma, and brain samples were extracted 24hours after TBI. Compared to the vehicle group, melatonin treatment altered the down-regulation of KCC2 expression in both mRNA and protein levels after TBI. Also, melatonin treatment increased the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI. In conclusion, our findings suggested that melatonin restores KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.