Blaha G R, Raghupathi R, Saatman K E, McIntosh T K
Department of Neurosurgery, University of Pennsylvania, Hayden Hall, Philadelphia, PA 19104, USA.
Neuroscience. 2000;99(3):483-93. doi: 10.1016/s0306-4522(00)00214-1.
Brain-derived neurotrophic factor has been shown to be neuroprotective in models of excitotoxicity, axotomy and cerebral ischemia. The present study evaluated the therapeutic potential of brain-derived neurotrophic factor following traumatic brain injury in the rat. Male Sprague-Dawley rats (N=99) were anesthetized and subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.8 atm) or sham injury. Four hours after injury, the animals were reanesthetized, an indwelling, intraparenchymal cannula was implanted, and infusion of brain-derived neurotrophic factor or phosphate-buffered saline vehicle was initiated from a mini-osmotic pump and continued for two weeks. In Study 1 (N=48), vehicle or 12 microg/day of brain-derived neurotrophic factor was infused into the dorsal hippocampus. In Study 2 (N=51), vehicle or brain-derived neurotrophic factor at a high (12 microg/day) or low dose (1.2 microg/day) was infused into the injured parietal cortex. All animals were evaluated for neurological motor function at two days, one week and two weeks post-injury. Cognitive function (learning and memory) was assessed at two weeks post-injury using a Morris Water Maze. At two weeks post-injury, neuronal loss in the hippocampal CA3 and dentate hilus and in the injured cortex was evaluated. In Study 2, neuronal loss was also quantified in the thalamic medial geniculate nucleus. All of the above outcome measures demonstrated significant deleterious effects of brain injury (P<0.05 compared to sham). However, post-traumatic brain-derived neurotrophic factor infusion did not significantly affect neuromotor function, learning, memory or neuronal loss in the hippocampus, cortex or thalamus when compared to vehicle infusion in brain-injured animals, regardless of the infusion site or infusion dose (P>0.05 for each). In contrast to previous studies of axotomy, ischemia and excitotoxicity, our data indicate that brain-derived neurotrophic factor is not protective against behavioral or histological deficits caused by experimental traumatic brain injury using the delayed, post-traumatic infusion protocol examined in these studies.
脑源性神经营养因子已被证明在兴奋性毒性、轴突切断和脑缺血模型中具有神经保护作用。本研究评估了脑源性神经营养因子对大鼠创伤性脑损伤后的治疗潜力。将雄性Sprague-Dawley大鼠（N = 99）麻醉，使其遭受中度严重程度（2.4 - 2.8大气压）的侧方液体冲击性脑损伤或假损伤。损伤后4小时，再次麻醉动物，植入一个留置的脑实质内插管，并通过微型渗透泵开始输注脑源性神经营养因子或磷酸盐缓冲盐水载体，持续两周。在研究1（N = 48）中，将载体或每天12微克的脑源性神经营养因子输注到背侧海马体中。在研究2（N = 51）中，将载体或高剂量（每天12微克）或低剂量（每天1.2微克）的脑源性神经营养因子输注到受伤的顶叶皮质中。在损伤后两天、一周和两周对所有动物进行神经运动功能评估。在损伤后两周使用莫里斯水迷宫评估认知功能（学习和记忆）。在损伤后两周，评估海马体CA3和齿状回以及受伤皮质中的神经元损失。在研究2中，还对丘脑内侧膝状体核中的神经元损失进行了量化。所有上述结果指标均显示脑损伤具有显著的有害影响（与假损伤相比，P < 0.05）。然而，与在脑损伤动物中输注载体相比，创伤后脑源性神经营养因子输注对海马体、皮质或丘脑中的神经运动功能、学习、记忆或神经元损失没有显著影响，无论输注部位或输注剂量如何（每项P > 0.05）。与先前关于轴突切断、缺血和兴奋性毒性的研究不同，我们的数据表明，使用本研究中所检测的延迟创伤后输注方案，脑源性神经营养因子对实验性创伤性脑损伤引起的行为或组织学缺陷没有保护作用。
