Department of Anesthesiology, Chongqing Cancer Institute, Chongqing, 40030, People's Republic of China.
Institute of Life Science, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Neurotox Res. 2017 Oct;32(3):409-419. doi: 10.1007/s12640-017-9751-8. Epub 2017 May 24.
Propofol can cause developing neuronal apoptosis in both in vivo and in vitro studies, and the mechanism is unclear till now. Our previous study has demonstrated that propofol can increase the TNF-α expression in the prefrontal cortex in rat developing brain, the TNF-α antagonist, etanercept, can inhibit propofol-induced neuronal apoptosis, but little is known about how TNF-α mediates that process. This study reveals that propofol at clinically relevant concentrations increases the TNF-α synthesis and release in neurons, and induces neuronal apoptosis; etanercept significantly reduces neuronal apoptosis, the elevation of cleaved caspase-8 and cleaved caspase-9, or the Akt phosphorylation induced by propofol, while the selective PI3K antagonist blocks the neuroprotection of etanercept. Propofol does not change the expression of P2X7 receptor in neurons, and the P2X7 receptor antagonist cannot affect the TNF-α synthesis or release after propofol treatment. These results suggest that propofol can increase the synthesis and release of TNF-α in the primary cultured prefrontal cortical neurons, TNF-α contributes to the intrinsic and extrinsic pathway in propofol-induced neuronal apoptosis via PI3K/Akt signaling pathway, and P2X7R is not involved in the synthesis and release of TNF-α induced by propofol.
丙泊酚在体内和体外研究中均可引起发育中的神经元凋亡，其机制目前尚不清楚。我们之前的研究表明，丙泊酚可增加大鼠发育脑前额叶皮质中的 TNF-α表达，TNF-α拮抗剂依那西普可抑制丙泊酚诱导的神经元凋亡，但关于 TNF-α如何介导该过程知之甚少。本研究揭示，丙泊酚在临床相关浓度下可增加神经元中 TNF-α的合成和释放，并诱导神经元凋亡；依那西普可显著减少神经元凋亡、caspase-8 和 caspase-9 的裂解或丙泊酚诱导的 Akt 磷酸化的升高，而选择性 PI3K 拮抗剂可阻断依那西普的神经保护作用。丙泊酚不改变神经元中 P2X7 受体的表达，且 P2X7 受体拮抗剂不能影响丙泊酚处理后 TNF-α的合成或释放。这些结果表明，丙泊酚可增加原代培养的前额叶皮质神经元中 TNF-α的合成和释放，TNF-α通过 PI3K/Akt 信号通路参与丙泊酚诱导的神经元凋亡的内在和外在途径，而 P2X7R 不参与丙泊酚诱导的 TNF-α的合成和释放。
