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

作者：Han, Rui Zhang; Hu, Jin Jia^*; Weng, Yuan Chi; Li, Ding Feng; Huang, Yi

来源：Neuroscience Bulletin, 2009, 25(6): 367-375.

DOI：10.1007/s12264-009-0608-x

• traumatic brain injury
• MK-801
• learning and memory
• caspase-3
• microglia
• neuronal nitric oxide synthase

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.

• 出版日期2009-12
• 单位上海交通大学