Medical College of Shanghai Jiaotong University, Shanghai, China.
Neurosci Bull. 2009 Dec;25(6):367-75. doi: 10.1007/s12264-009-0608-x.
NMDA receptor channel plays an important role in the pathophysiological process of traumatic brain injury (TBI). The present study aims to study the pathological mechanism of TBI and the impairment of learning and memory after TBI, and to investigate the mechanism of the protective effect of NMDA receptor antagonist MK-801 on learning and memory disorder after TBI.
Forty Sprague-Dawley rats (weighing approximately 200 g) were randomized into 5 groups (n = 8 in each group): control group, model group, low-dose group (MK-801 0.5 mg/kg), middle-dose group (MK-801 2 mg/kg), and high-dose group (MK-801 10 mg/kg). TBI model was established using a weight-drop head injury mode. After 2-month drug treatment, learning and memory ability was evaluated by using Morris water maze test. Then the animals were sacrificed, and brain tissues were taken out for morphological and immunohistochemical assays.
The ability of learning and memory was significantly impaired in the TBI model animals. Besides, the neuronal caspase-3 expression, neuronal nitric oxide synthase (nNOS)-positive neurons and OX-42-positive microglia were all increased in TBI animals. Meanwhile, the number of neuron synapses was decreased, and vacuoles degeneration could be observed in mitochondria. After MK-801 treatment at 3 different dosages, the ability of learning and memory was markedly improved, as compared to that of the TBI model animals. Moreover, neuronal caspase-3 expression, OX-42-positive microglia and nNOS-positive neurons were all significantly decreased. Meanwhile, the mitochondria degeneration was greatly inhibited.
MK-801 could significantly inhibit the degeneration and apoptosis of neurons in damaged brain areas. It could also inhibit TBI-induced increase in nNOS-positive neurons and OX-42-positive microglia. Impairment in learning and memory in TBI animals could be repaired by treatment with MK-801.
N-甲基-D-天冬氨酸（NMDA）受体通道在创伤性脑损伤（TBI）的病理生理过程中发挥重要作用。本研究旨在探讨 TBI 的病理机制以及 TBI 后学习记忆损伤的机制，并研究 NMDA 受体拮抗剂 MK-801 对 TBI 后学习记忆障碍的保护作用机制。
40 只 Sprague-Dawley 大鼠（体重约 200 g）随机分为 5 组（每组 8 只）：对照组、模型组、低剂量组（MK-801 0.5 mg/kg）、中剂量组（MK-801 2 mg/kg）和高剂量组（MK-801 10 mg/kg）。采用落体式颅脑损伤模型建立 TBI 模型。药物治疗 2 个月后，采用 Morris 水迷宫试验评估学习记忆能力。然后处死动物，取出脑组织进行形态学和免疫组织化学检测。
TBI 模型动物的学习记忆能力明显受损。此外，TBI 动物神经元半胱氨酸天冬氨酸蛋白酶-3（caspase-3）表达、神经元型一氧化氮合酶（nNOS）阳性神经元和 OX-42 阳性小胶质细胞均增加，神经元突触数量减少，线粒体出现空泡变性。MK-801 以 3 种不同剂量治疗后，与 TBI 模型动物相比，学习记忆能力明显改善，神经元 caspase-3 表达、OX-42 阳性小胶质细胞和 nNOS 阳性神经元均显著减少，线粒体变性得到明显抑制。
MK-801 可显著抑制受损脑区神经元的变性和凋亡，抑制 TBI 诱导的 nNOS 阳性神经元和 OX-42 阳性小胶质细胞的增加，修复 TBI 动物的学习记忆损伤。
