Intense exercise can cause excessive apoptosis and synapse plasticity damage in rat hippocampus through Ca²⁺ overload and endoplasmic reticulum stress-induced apoptosis pathway.
Intense exercise can cause excessive apoptosis and synapse plasticity damage in rat hippocampus through Ca²⁺ overload and endoplasmic reticulum stress-induced apoptosis pathway.
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DOI：
10.1097/00029330-201409200-00014
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发表时间：
2014
影响因子：
6.1
通讯作者：
Yi Ding;Cunqing Chang;Lan Xie;Zhi-min Chen;Hua Ai
中科院分区：
文献类型：
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作者：
Yi Ding;Cunqing Chang;Lan Xie;Zhi-min Chen;Hua Ai
背景剧烈运动可引起机体损伤和细胞凋亡，但对中枢神经系统的影响研究较少。海马损伤的最初原因是谷氨酸的兴奋毒性和钙超载。细胞内游离Ca（2+）（[Ca（2+）]i）超负荷可触发细胞凋亡途径，导致神经元损伤。本研究的目的是探讨剧烈运动是否会引起海马神经元凋亡和损伤，并确定这种凋亡激活了哪条通路。方法采用一次性游泳力竭大鼠模型。力竭后即刻测定细胞内[Ca（2+）]i，评价Fura-2/AM引起的钙超载;力竭后24 h采用胶质细胞酸性蛋白（GFAP）和突触素（SYP）免疫荧光法检测星形胶质细胞活化和突触可塑性。采用dUTP缺口末端标记法（TUNEL）显示凋亡细胞; Western blotting法同步检测内质网（ER）应激诱导的凋亡途径和线粒体凋亡途径。结果力竭后即刻海马细胞内[Ca（2+）]i显著升高（P < 0.01）; GFAP和SYP免疫荧光显示，力竭后24 h星形胶质细胞被激活，突触可塑性明显下降。TUNEL染色显示凋亡细胞明显增多Western blotting检测凋亡信号通路显示caspase-3裂解水平升高（P < 0.01）（P < 0.01），Bax caspase-12酶切（P < 0.01）C/EBP同源蛋白（CHOP）（P <0.01）、磷酸化JNK（P <0.01）和Bcl-2水平降低（P <0.01）。结果表明，力竭运动可通过[Ca（2+）]i超载引起海马神经元损伤和凋亡，损伤模式为突触可塑性崩溃，激活途径为内质网应激诱导的凋亡。结论剧烈运动可导致海马细胞过度凋亡和突触可塑性损伤，[Ca（2+）]i超负荷是其最初原因，从而为运动员脑健康的治疗干预提供了线索。
BACKGROUND Intense exercise can cause injury and apoptosis, but few studies have reported its effect on the central nervous system (CNS). The initial reason for hippocampus injury is the excitotoxicity of glutamate and calcium overload. Intracellular free Ca(2+) ([Ca(2+)]i) overload may trigger the apoptosis pathway and neuron damage. The aim of this study was to investigate whether intense exercise could cause hippocampus apoptosis and neuron damage and then to determine which pathway was activated by this apoptosis. METHODS We used one bout of swimming exhaustion rats as models. Intracellular [Ca(2+)]i was measured to estimate the calcium overload by Fura-2/AM immediately after exhaustion; glial fibrillary acidic protein (GFAP) and synaptophysin (SYP) immunofluorescence were performed for estimating astrocyte activation and synapse plasticity 24 hours after exhaustion. Apoptosis cells were displayed using dUTP nick end labelling (TUNEL) stain; endoplasmic reticulum (ER) stress-induced apoptosis pathway and mitochondrial apoptosis pathway were synchronously detected by Western blotting. RESULTS An increasing level of intracellular [Ca(2+)]i (P < 0.01) was found in the hippocampus immediately after exhaustion. GFAP and SYP immunofluorescence showed that the astrocytes are activated, and the synapse plasticity collapsed significantly 24 hours after exhaustion. TUNEL stain showed that the number of apoptosis cells were notably raised (P < 0.01); Western blotting of the apoptosis pathway showed increasing levels of caspase-3 cleavage (P < 0.01), Bax (P < 0.01), caspase-12 cleavage (P < 0.01), C/EBP-homologous protein (CHOP) (P < 0.01), and phospho-Junaminoterminal kinases (p-JNK; P < 0.01) and decreasing level of Bcl-2 (P < 0.01). Our results proved that exhaustion can induce hippocampus injury and apoptosis by [Ca(2+)]i overload, with collapsed synaptic plasticity as the injury pattern and ER stress-induced apoptosis as the activated pathway. CONCLUSION Intense exercise can cause excessive apoptosis and synapse plasticity damage in the hippocampus with [Ca(2+)]i overload as the initial reason, and thus provides leads for therapeutic interventions in the brain health of athletes.