Jiang Tao, Wang Xiu-Qin, Ding Chuan, Du Xue-Lian
Department of Anesthesiology, Shandong Cancer Hospital, Jinan 250117, Shandong Province, China.
Department of Gynecology, Shandong Cancer Hospital, Jinan 250117, Shandong Province, China.
Korean J Physiol Pharmacol. 2017 Nov;21(6):579-589. doi: 10.4196/kjpp.2017.21.6.579. Epub 2017 Oct 30.
Anesthetics are used extensively in surgeries and related procedures to prevent pain. However, there is some concern regarding neuronal degeneration and cognitive deficits arising from regular anesthetic exposure. Recent studies have indicated that brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB) are involved in learning and memory processes. Genistein, a plant-derived isoflavone, has been shown to exhibit neuroprotective effects. The present study was performed to examine the protective effect of genistein against isoflurane-induced neurotoxicity in rats. Neonatal rats were exposed to isoflurane (0.75%, 6 hours) on postnatal day 7 (P7). Separate groups of rat pups were orally administered genistein at doses of 20, 40, or 80 mg/kg body weight from P3 to P15 and then exposed to isoflurane anesthesia on P7. Neuronal apoptosis was detected by TUNEL assay and FluoroJade B staining following isoflurane exposure. Genistein significantly reduced apoptosis in the hippocampus, reduced the expression of proapoptotic factors (Bad, Bax, and cleaved caspase-3), and increased the expression of Bcl-2 and Bcl-xL. RT-PCR analysis revealed enhanced BDNF and TrkB mRNA levels. Genistein effectively upregulated cAMP levels and phosphorylation of CREB and TrkB, leading to activation of cAMP/CREB-BDNF-TrkB signaling. PI3K/Akt signaling was also significantly activated. Genistein administration improved general behavior and enhanced learning and memory in the rats. These observations suggest that genistein exerts neuroprotective effects by suppressing isoflurane-induced neuronal apoptosis and by activating cAMP/CREB-BDNF-TrkB-PI3/Akt signaling.
麻醉剂在手术及相关操作中被广泛用于预防疼痛。然而，人们对长期接触麻醉剂引起的神经元退化和认知缺陷存在一些担忧。最近的研究表明，脑源性神经营养因子（BDNF）和环磷腺苷反应元件结合蛋白（CREB）参与学习和记忆过程。染料木黄酮是一种植物来源的异黄酮，已被证明具有神经保护作用。本研究旨在探讨染料木黄酮对异氟烷诱导的大鼠神经毒性的保护作用。新生大鼠在出生后第7天（P7）暴露于异氟烷（0.75%，6小时）。从出生后第3天（P3）到第15天，将不同组的幼鼠分别口服给予20、40或80 mg/kg体重的染料木黄酮，然后在P7接受异氟烷麻醉。异氟烷暴露后，通过TUNEL法和FluoroJade B染色检测神经元凋亡。染料木黄酮显著减少海马体中的细胞凋亡，降低促凋亡因子（Bad、Bax和裂解的半胱天冬酶-3）的表达，并增加Bcl-2和Bcl-xL的表达。RT-PCR分析显示BDNF和TrkB mRNA水平升高。染料木黄酮有效地上调了cAMP水平以及CREB和TrkB的磷酸化，导致cAMP/CREB-BDNF-TrkB信号通路的激活。PI3K/Akt信号通路也被显著激活。给予染料木黄酮改善了大鼠的一般行为，并增强了其学习和记忆能力。这些观察结果表明，染料木黄酮通过抑制异氟烷诱导的神经元凋亡以及激活cAMP/CREB-BDNF-TrkB-PI3/Akt信号通路发挥神经保护作用。
