NMDA receptor antagonist MK-801 reduces neuronal damage and preserves learning and memory in a rat model of traumatic brain injury

Neurosci Bull. 2009 Dec;25(6):367-75. doi: 10.1007/s12264-009-0608-x.


Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

目的: NMDA型谷氨酸受体通道在创伤性脑损伤(traumatic brain injury, TBI)的病理生理过程中具有重要的作用。 本研究探讨TBI后的学习记忆损伤及其病理特点, 并观察NMDA型谷氨酸受体拮抗剂MK-801对TBI引起的学习记忆障碍的保护机制。

方法: 体重200g左右的SD大鼠40只, 随机分为5组: 正常组(未创伤)、 模型组、 低剂量组(MK-801 0.5 mg/kg)、 中剂量组(MK-801 2 mg/kg)、 高剂量组(MK-801 10 mg/kg), 每组8只。 后4组经自由落体形成脑损伤模型。 经MK-801治疗2个月后, 进行Morris水迷宫测试学习记忆能力。 测试结束后处死, 取脑组织进行形态学及免疫组织化学检测。

结果: 在TBI后, 大鼠学习记忆力显著下降。 形态学和免疫组织化学研究表明, TBI大鼠神经细胞内caspase-3表达增加, 神经源性一氧化氮合酶(nNOS)阳性神经元增加, 并且OX-42 阳性小胶质细胞增加, 同时神经元突触减少, 线粒体空泡样变性。 经3种不同剂量的MK-801治疗后, TBI 模型动物学习记忆能力得到显著改善, 神经元caspase-3的表达量降低。 同时, nNOS阳性神经元和OX-42阳性小胶质细胞均显著减少, 线粒体空泡样变性减少。

结论: MK-801明显减少损伤脑区神经元变性死亡, 抑制nNOS阳性神经元和小胶质细胞增生活化等炎症反应, 改善TBI模型动物学习记忆力。

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiopathology
  • Brain Injuries / drug therapy*
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Dizocilpine Maleate / administration & dosage
  • Dizocilpine Maleate / pharmacology*
  • Learning / drug effects*
  • Learning / physiology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory / drug effects*
  • Memory / physiology
  • Microglia / drug effects
  • Microglia / pathology
  • Microglia / physiology
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Mitochondria / physiology
  • Neurons / drug effects
  • Neurons / pathology
  • Neurons / physiology
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology*
  • Neuropsychological Tests
  • Nitric Oxide Synthase Type I / metabolism
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / drug effects
  • Synapses / pathology
  • Synapses / physiology


  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate
  • Nitric Oxide Synthase Type I
  • Casp3 protein, rat
  • Caspase 3