He Zhen, Crook Julia E, Meschia James F, Brott Thomas G, Dickson Dennis W, McKinney Michael
Department of Pharmacology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Curr Neurovasc Res. 2005 Dec;2(5):365-74. doi: 10.2174/156720205774962674.
The present study examines the hypothesis that aging defined by the 50% survival age compromises neuroprotection afforded by ischemic preconditioning (IPC). Sixty-four male F344 rats aged 4- and 24-months, respectively, were subjected to IPC, (3-min ischemia) or sham-surgery followed by 10-min (full) ischemia or sham-surgery 2 days later. There were 4 groups at each age: sham-surgery-sham-surgery (SS), preconditioning-sham-surgery (PS), preconditioning-ischemia (PI) and sham-surgery-ischemia (SI) groups. Assessments of histology and immunoreactivities of N-methyl-D-aspartic acid receptor 1 (NMDAr1) and caspase-3 active peptide (C3AP) in the hippocampal CA1 region were performed 8 days after full ischemia. The CA1 "living cell ratio" was greater in the aged SI group than in the young SI group (32+/-6% vs. 17+/-5%, p<0.05), whereas the degree of protection against full ischemia afforded by IPC was reduced in the aged compared with the young (53+/-17% vs. 241+/-25%, P<0.0001). The basal level of NMDAr1 immunofluorescence was significantly higher in young animals, while the numbers of C3AP-positive cells were greater in all three aged ischemic groups as compared to respective young groups (p<0.01, p=0.055 and p<0.05). A fourth method of assessing cell damage using Fluoro Jade C labeled degenerating neurons that were also intensively eosinophilic. Counts of Fluoro Jade C-positive cells were higher in the young SI group than in the aged SI group (P<0.05), suggesting that mechanisms of ischemic cell death may change with aging. In conclusion, aging alters mechanisms of ischemic cell death in CA1 neurons and ischemic tolerance mechanisms are blunted by aging.
以50%存活年龄定义的衰老会损害缺血预处理（IPC）所提供的神经保护作用。分别选取64只4月龄和24月龄的雄性F344大鼠，对其进行IPC（3分钟缺血）或假手术，2天后再进行10分钟（完全）缺血或假手术。每个年龄组分为4组：假手术-假手术（SS）组、预处理-假手术（PS）组、预处理-缺血（PI）组和假手术-缺血（SI）组。在完全缺血8天后，对海马CA1区进行组织学评估以及N-甲基-D-天冬氨酸受体1（NMDAr1）和半胱天冬酶-3活性肽（C3AP）的免疫反应性评估。老年SI组的CA1“存活细胞比例”高于年轻SI组（32±6%对17±5%，p<0.05），而与年轻组相比，老年组中IPC对完全缺血的保护程度降低（53±17%对241±25%，P<0.0001）。年轻动物中NMDAr1免疫荧光的基础水平显著更高，而与各自的年轻组相比，所有三个老年缺血组中C3AP阳性细胞的数量更多（p<0.01、p = 0.055和p<0.05）。使用荧光玉C标记变性神经元（这些神经元也呈强嗜酸性）来评估细胞损伤的第四种方法。年轻SI组中荧光玉C阳性细胞的计数高于老年SI组（P<0.05），这表明缺血性细胞死亡机制可能随衰老而改变。总之，衰老改变了CA1神经元缺血性细胞死亡的机制，并且衰老使缺血耐受机制减弱。
