Yang Miyoung, Kim Juhwan, Kim Sung-Ho, Kim Joong-Sun, Shin Taekyun, Moon Changjong
Department of Veterinary Anatomy, College of Veterinary Medicine and Animal Medical Institute, Chonnam National University, Gwangju 500-757, South Korea.
Department of Experimental Radiation, Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 619-753, South Korea.
Neural Regen Res. 2012 Jul 25;7(21):1651-8. doi: 10.3969/j.issn.1673-5374.2012.21.008.
Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated during the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.
甲氨蝶呤用于治疗多种恶性肿瘤和自身免疫性疾病，会影响包括海马依赖性记忆功能在内的脑功能。然而，甲氨蝶呤诱导海马功能障碍的精确机制尚不清楚。为了评估突触可塑性相关信号的时间变化，在成年C57BL/6小鼠腹腔注射甲氨蝶呤（40mg/kg）后，检测其海马中N-甲基-D-天冬氨酸受体1、钙/钙调蛋白依赖性蛋白激酶II、细胞外信号调节激酶1/2、cAMP反应元件结合蛋白、谷氨酸受体1、脑源性神经营养因子和胶质细胞系源性神经营养因子的表达和活性。蛋白质印迹分析显示，甲氨蝶呤治疗后成年海马中突触可塑性相关信号出现双相变化。N-甲基-D-天冬氨酸受体1、钙/钙调蛋白依赖性蛋白激酶II和谷氨酸受体1在早期（注射后1天）被急性激活，而细胞外信号调节激酶1/2和cAMP反应元件结合蛋白的激活在早期（注射后1天）和晚期（注射后7 - 14天）呈双相增加。脑源性神经营养因子和胶质细胞系源性神经营养因子的表达在晚期（注射后7 - 14天）显著增加。因此，甲氨蝶呤治疗会影响成年小鼠海马中突触可塑性相关信号，提示突触可塑性相关信号的变化可能与神经元存活和可塑性相关的细胞重塑有关。
