Decrease of glial cell-derived neurotrophic factor contributes to anesthesia- and surgery-induced learning and memory dysfunction in neonatal rats
Decrease of glial cell-derived neurotrophic factor contributes to anesthesia- and surgery-induced learning and memory dysfunction in neonatal rats
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DOI：
10.1007/s00109-017-1521-9
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发表时间：
2017-04-01
影响因子：
4.7
通讯作者：
Zuo, Zhiyi
中科院分区：
文献类型：
--
作者：
Gui, Lingli;Lei, Xi;Zuo, Zhiyi
长时间的麻醉可能会对发育中的大脑产生毒性。然而，人们对手术和麻醉相结合对大脑发育的影响知之甚少。其影响机制尚不清楚。为了确定这些影响，出生后第 7 天的雄性和雌性 Sprague-Dawley 大鼠暴露于 3% 七氟醚 2 小时，有或没有右颈总动脉暴露。吡咯烷二硫代氨基甲酸酯 (PDTC) 是一种抗炎剂，在颈动脉暴露前 30 分钟和后 6 小时给予。在七氟醚暴露结束时给予抗神经胶质细胞源性神经营养因子（GDNF）抗体或GDNF。我们发现麻醉手术会引起学习和记忆障碍，通过巴恩斯迷宫和恐惧调节进行评估。麻醉手术还诱导神经炎症，降低神经胶质细胞源性神经营养因子的水平（GDNF，对照大鼠的蛋白质为 10.6 +/- 0.6 pg/mg，麻醉手术大鼠的蛋白质为 7.7 +/- 0.4 pg/mg，n = 17，p = 0.007）和海马神经发生。 PDTC 抑制这些手术效果（麻醉手术加 PDTC 大鼠的 GDNF 水平为 9.7 +/- 0.6 pg/mg 蛋白，n = 17，与对照大鼠相比，p = 0.763）。脑室内注射抗 GDNF 抗体（而非其热灭活形式）可诱导对照大鼠的学习和记忆障碍。脑室内注射 GDNF 可减轻麻醉手术后的学习和记忆障碍。我们得出的结论是，新生大鼠的麻醉手术会诱发神经炎症，从而导致 GDNF 水平下降、海马神经发生和认知障碍。 GDNF 减少在麻醉手术引起的认知障碍中起着重要作用。
Long duration of anesthesia may induce toxicity in the developing brain. However, little is known about the effects of the combination of surgery and anesthesia on the developing brain. The mechanisms for the effects are not clear. To determine these effects, postnatal day 7 male and female Sprague-Dawley rats were exposed to 3% sevoflurane for 2 h with or without right common carotid exposure. Pyrrolidine dithiocarbamate (PDTC), an anti-inflammatory agent, was given 30 min before and 6 h after the carotid exposure. Anti-glial cell-derived neurotrophic factor (GDNF) antibody or GDNF was given at the end of sevoflurane exposure. We found that anesthesia-surgery induced learning and memory impairment assessed by Barnes maze and fear conditioning. Anesthesia-surgery also induced neuroinflammation and reduced the level of glial cell-derived neurotrophic factor (GDNF, 10.6 +/- 0.6 pg/mg protein of control rats vs. 7.7 +/- 0.4 pg/mg protein of anesthesia-surgery rats, n = 17, p = 0.007) and neurogenesis in the hippocampus. PDTC inhibited these surgical effects (GDNF level 9.7 +/- 0.6 pg/mg protein of anesthesia-surgery plus PDTC rats, n = 17, p = 0.763 vs. control rats). Intracerebroventricular injection of an anti-GDNF antibody but not its heat-inactivated form induced learning and memory impairment in control rats. Intracerebroventricular injection of GDNF attenuated learning and memory impairment after anesthesia-surgery. We conclude that anesthesia-surgery in neonatal rats induces neuroinflammation, which then leads to a decreased level of GDNF and neurogenesis in the hippocampus and cognitive impairment. GDNF decrease plays an important role in anesthesia-surgery-induced cognitive impairment.