麦芽酚铝染毒致雄性大鼠神经元铁死亡及其机制研究

Effect and Mechanism of Aluminum-maltolate Exposure on Neuron Ferroptosis in Rats

目的探讨亚慢性麦芽酚铝[aluminum-maltolate, Al(mal)_3]染毒致大鼠神经元铁死亡作用及其可能机制。方法选取18只健康雄性SPF级SD大鼠按体重随机分成3组:对照(生理盐水)组,9和18μmol/kg Al(mal)_3染毒组,每组6只。对大鼠进行Al(mal)_3腹腔注射染毒,1次/d,连续染毒90 d。通过Morris水迷宫实验和旷场实验测试大鼠学习记忆能力和自主活动能力;采用透射电子显微镜观察大鼠神经元线粒体超微结构变化;分别采用谷胱甘肽(glutathione, GSH)测试盒和组织铁(ferrum, Fe)测试盒测定大鼠脑组织GSH含量和Fe含量。结果水迷宫实验中,与对照组相比,各染毒组大鼠找到原平台位置时间逐渐延长,差异具有统计学意义(P<0.05)。旷场实验中,与对照组相比,各染毒组大鼠中央格停留时间明显延长,竖起次数明显减少,差异具有统计学意义(P<0.05)。电镜观察发现:染毒组大鼠神经元出现线粒体皱缩、线粒体膜密度增加及线粒体嵴消失等铁死亡特异性改变。与对照组相比,随染毒剂量增加,大鼠脑组织GSH含量逐渐降低,Fe含量逐渐升高,差异具有统计学意义(P<0.05)。结论亚慢性Al(mal)_3染毒可导致大鼠神经元铁死亡,脑组织GSH含量减少和Fe含量增加可能是铝致神经元铁死亡的机制之一。

Objectives To investigate the effect of Subchronic Aluminum-Maltolate[Al(mal)3] exposure on neuron ferroptosis in rats and its possible mechanism. Methods 18 healthy male Specific Pathogen Free(SPF) Sprague-Dawley(SD) rats were chosen and randomly divided into three groups according to their body weights: the control(saline) group and the 9 and 18 μmol/kg Al(mal)3 treated groups with 6 rats in each group. Rats in the control group received intraperitoneal(ip.) injections of 0.9 % normal saline and rats in 9 and 18 μmol/kg Al(mal)3 treated groups received ip. administrations of these two doses respectively once a day for 90 days. The learning and memory abilities as well as the general activities of rats were tested with Morris Watermaze(MWM) and Open Field Test(OFT). The changes of mitochondria ultrastructure in neurons of rats were observed by Transmission Electron Microscopy(TEM). The contents of GSH and Fe in animal brain tissue were detected using glutathione(GSH) test kit and tissue iron test kit. Results Compared with the control group, the time of finding platform site of each exposed group was significantly and gradually prolonged. In the OFT, compared with the control group, the retention time in the center of the arena in the exposed groups was significantly prolonged and the number of erect times decreased obviously(P<0.05).The neuron of rats in the exposed groups showed specific characteristic changes of ferroptosis with shrinkage of mitochondria, increase of mitochondrial membrane density and disappearance of mitochondrial ridge under the TEM. With the increase of dose, the content of GSH in neurons decreased gradually, while the content of Fe increased gradually compared with the control group(P<0.05). Conclusions Subchronic exposure to Al(mal)3 can lead to ferroptosis in neurons of rats, and the decrease of GSH content and the increase of Fe content in brain tissue maybe important mechanisms of neuron ferroptosis induced by exposure to aluminum.