Zhang Yiying, Dong Yuanlin, Xu Zhipeng, Xie Zhongcong
Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St, Room 4310, Charlestown, MA, 02129-2060, USA.
Med Gas Res. 2012 Aug 17;2(1):20. doi: 10.1186/2045-9912-2-20.
The inhalation anesthetic isoflurane has been shown to open the mitochondrial permeability transition pore (mPTP) and induce caspase activation and apoptosis, which may lead to learning and memory impairment. Cyclosporine A, a blocker of mPTP opening might attenuate the isoflurane-induced mPTP opening, lessening its ripple effects. Magnesium and anesthetic propofol are also mPTP blockers. We therefore set out to determine whether propofol and magnesium can attenuate the isoflurane-induced caspase activation and mPTP opening.
We investigated the effects of magnesium sulfate (Mg2+), propofol, and isoflurane on the opening of mPTP and caspase activation in H4 human neuroglioma cells stably transfected to express full-length human amyloid precursor protein (APP) (H4 APP cells) and in six day-old wild-type mice, employing Western blot analysis and flowcytometry.
Here we show that Mg2+ and propofol attenuated the isoflurane-induced caspase-3 activation in H4-APP cells and mouse brain tissue. Moreover, Mg2+ and propofol, the blockers of mPTP opening, mitigated the isoflurane-induced mPTP opening in the H4-APP cells.
These data illustrate that Mg2+ and propofol may ameliorate the isoflurane-induced neurotoxicity by inhibiting its mitochondrial dysfunction. Pending further studies, these findings may suggest the use of Mg2+ and propofol in preventing and treating anesthesia neurotoxicity.
吸入性麻醉剂异氟烷已被证明可打开线粒体通透性转换孔(mPTP),并诱导半胱天冬酶激活和细胞凋亡,这可能导致学习和记忆障碍。环孢素A作为mPTP开放的阻滞剂,可能会减弱异氟烷诱导的mPTP开放,减轻其连锁反应。镁和麻醉剂丙泊酚也是mPTP阻滞剂。因此,我们着手确定丙泊酚和镁是否能减弱异氟烷诱导的半胱天冬酶激活和mPTP开放。
我们采用蛋白质印迹分析和流式细胞术,研究了硫酸镁(Mg2+)、丙泊酚和异氟烷对稳定转染以表达全长人淀粉样前体蛋白(APP)的H4人神经胶质瘤细胞(H4 APP细胞)和6日龄野生型小鼠中mPTP开放和半胱天冬酶激活的影响。
我们发现Mg2+和丙泊酚减弱了异氟烷诱导的H4-APP细胞和小鼠脑组织中半胱天冬酶-3激活。此外,mPTP开放的阻滞剂Mg2+和丙泊酚减轻了异氟烷诱导的H4-APP细胞中mPTP开放。
这些数据表明,Mg2+和丙泊酚可能通过抑制异氟烷诱导的线粒体功能障碍来改善其神经毒性。在进一步研究之前,这些发现可能提示Mg2+和丙泊酚可用于预防和治疗麻醉神经毒性。