PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure
PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure
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DOI：
10.1021/acschemneuro.0c00106
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发表时间：
2020-05-06
影响因子：
5
通讯作者：
Chen, Rulei
中科院分区：
文献类型：
--
作者：
Chen, Yingle;Li, Shunyuan;Chen, Rulei
七氟烷是最常用的麻醉剂之一，已被证明可在发育中的大脑中诱导广泛的神经变性。我们旨在评价PDE-7抑制剂（BRL-50481）对七氟烷对发育中神经系统的神经毒性作用的保护作用。使用Morris水迷宫试验检查七氟烷处理小鼠的空间学习和记忆，并评价PDE-7抑制剂（BRL-50481）对七氟烷诱导的损伤的神经保护作用。我们的研究结果表明，七氟烷治疗显着诱导神经退行性变和损害的长期记忆的新生小鼠。值得注意的是，BRL-50481联合给药可显著减轻七氟烷诱导的学习和记忆缺陷，防止识别记忆的恶化，并防止神经元凋亡。从机制上讲，BRL-50481给药通过恢复海马中的cAMP和激活cAMP/CREB信号传导抑制七氟烷诱导的神经退行性疾病。PDE 7抑制剂可能是七氟醚诱导的神经退行性变和长期记忆缺陷的潜在治疗剂。
[GRAPHICS]Sevoflurane, one of the most commonly used anesthetic agents, has been demonstrated to induce widespread neurodegeneration in the developing brain. We aimed to evaluate the protective effects of a PDE-7 inhibitor (BRL-50481) against the neurotoxic effects of sevoflurane on the developing nervous system. Spatial learning and memory in sevoflurane-treated mice were examined using the Morris water maze test, and neuroprotective effects of PDE-7 inhibitor (BRL-50481) against sevoflurane-induced impairments were evaluated. Our results showed that sevoflurane treatment markedly induced neurodegeneration and impaired long-term memory in neonatal mice. Notably, BRL-50481 coadministration could significantly attenuate sevofluraneinduced learning and memory defects, prevent deterioration of recognition memory, and protect against neuron apoptosis. Mechanistically, BRL-50481 administration suppressed sevoflurane-induced neurodegenerative disorders through restoring cAMP and activating cAMP/CREB signaling in the hippocampus. PDE7 inhibitor may be a potential therapeutic agent for sevoflurane-induced neurodegeneration and long-term memory deficits.