Continuous low-dose treatment with brain-derived neurotrophic factor or neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia/ischemia: A stereological study
Continuous low-dose treatment with brain-derived neurotrophic factor or neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia/ischemia: A stereological study
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DOI：
10.1016/s0306-4522(03)00066-6
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发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Oorschot, DE
中科院分区：
文献类型：
--
作者：
Galvin, KA;Oorschot, DE
本研究旨在探讨持续、低剂量脑内输注脑源性神经营养因子（BDNF）或神经营养因子-3 （NT-3）是否能保护轻度新生儿缺氧/缺血性脑损伤的纹状体神经元丢失。持续的、低剂量的脑内治疗可能最大限度地减少单次高剂量的不良副作用，并延长神经保护的时间窗口。由于这种情况可能产生最高的存活率，因此使用了一种较轻的，尽管会引起脑损伤的缺氧/缺血性损伤模式。每只出生后第7天麻醉的大鼠立体定向植入连接微渗透泵的脑输液器。从出生后第7天开始，泵连续向右侧纹状体注入BDNF（4.5马克杯/天）、NT-3（12马克杯/天）或载药溶液3天。用免疫组织化学方法证实了BDNF或NT-3的存在。在出生后第8天，对大鼠进行右颈总动脉结扎，然后缺氧暴露1.5 h。此后每天称重，并在出生后第14天1周后处死。用光学定向器/卡瓦列里组合体视学方法测定右侧纹状体中棘神经元总数。其他神经保护措施，如脑重量和纹状体梗死体积也进行了。BDNF和NT-3分别使中棘神经元存活总数显著增加43%和33%。当比较脑重量、纹状体体积、纹状体梗死体积和NT-3的神经元密度测量时，这种显著的神经保护作用并不明显。因此，这些措施错过了神经元总数所显示的保护作用。这表明，在低剂量连续输注神经营养素治疗和轻度缺氧/缺血损伤后1周，需要通过体视学测量神经元总数来检测神经保护作用。结果还表明，较低的治疗剂量可能比以前认为的更有用。BDNF可能特别有用，因为它促进了神经保护和正常体重的增加。纹状体神经元免于死亡的能力可能有助于短期低剂量神经营养蛋白治疗人类轻度围产期缺氧/缺血性脑损伤。(c) 2003年。Elsevier Science Ltd.出版。版权所有。
This study aimed to investigate whether continuous, low-dose, intracerebral infusion of either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) could protect against striatal neuronal loss in mild neonatal hypoxic/ischaemic brain injury. Continuous, low-dose, intracerebral treatment is likely to minimise unwanted side effects of a single high dose and lengthen the time window for neuroprotection. A milder, albeit brain damage-inducing, hypoxic/ ischaemic injury paradigm was used since this situation is likely to produce the highest survival rates and thus the greatest prevalence.Anaesthetised postnatal day 7 rats were each stereotaxically implanted with a brain infusion kit connected to a micro-osmotic pump. The pump continuously infused either BDNF (4.5 mug/day), NT-3 (12 mug/day), or vehicle solution into the right striatum for 3 days from postnatal day 7. The intrastriatal presence of BDNF or NT-3 was verified immunohistochemically. On postnatal day 8, the rats underwent right common carotid artery ligation followed by hypoxic exposure for 1.5 h. Animals were weighed daily thereafter and killed 1 week later on postnatal day 14. The total number of medium spiny neurons within the right striatum was stereologically determined using an optical disector/Cavalieri combination. Other measures of neuroprotection such as brain weight and striatal infarct volume were also undertaken.BDNF or NT-3 significantly increased the total number of surviving medium spiny neurons by 43% and 33% respectively. This significant neuroprotection was not evident when brain weight, striatal volume, striatal infarct volume, and neuronal density measures for NT-3, were compared. These measures therefore missed the protective effect demonstrated by the total neuronal count. This suggests that stereological measurement of total neuronal number is needed to detect neuroprotection at 1 week after low-dose, continuously infused, neurotrophin treatment and mild hypoxic/ischaemic injury. The results also suggest that lower treatment doses may be more useful than previously thought. BDNF may be particularly useful since it fostered both neuroprotection and normal weight gain. The ability to rescue striatal neurons from death may contribute toward a potential short-term, low-dose neurotrophin treatment for mild perinatal hypoxic/ischaemic brain injury in humans. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.