氨基糖苷类抗生素耳毒性研究

Experiences in ototoxic investigations in aminoglycoside antibiotics

由于抗菌谱广和价格便宜等原因,氨基糖苷类抗生素被广泛应用于临床。然而氨基糖苷类抗生素的耳毒性和肾毒性却使其在临床应用中受到一定限制。氨基糖苷类抗生素在耳蜗毛细胞中的主要积聚部位是线粒体和溶酶体。氨基糖苷类抗生素引起的细胞内氧自由基活动增强是毛细胞损害的重要因素之一,因此局部或者全身应用氧自由基清除剂可以保护耳蜗免受氨基糖苷类抗生素的损害。钙激活的蛋白酶在氨基糖苷类抗生素引起的毛细胞破坏过程中同样扮演了重要的角色,因此抑制钙激活蛋白酶的活性也能有效保护耳蜗毛细胞。急性氨基糖苷类抗生素耳中毒引起的毛细胞破坏大都死于细胞凋亡,其凋亡原因主要是因为线粒体被药物特异性结合并破坏后,其内部的细胞色素C被释放到细胞质中,因而刺激了Caspase-9并激发其下游的Caspase-3,从而导致毛细胞的程序化死亡。与此不同的是,慢性氨基糖苷类抗生素耳中毒引起的毛细胞破坏不仅包括细胞凋亡而且涉及细胞坏死。在氨基糖苷类抗生素引起的毛细胞坏死过程中,溶酶体的超载破裂最终造成毛细胞自溶性坏死是其典型特征。氨基糖苷类抗生素对螺旋神经节没有直接的毒性作用,但是在耳蜗毛细胞被破坏之后,螺旋神经节往往由于缺乏神经营养因子而发生延迟性神经元死亡,应用转基因技术将神经营养因子基因片段转染到耳蜗支持细胞使之产生分泌神经营养因子的功能,可以有效减轻延迟性神经元死亡的发生率。

Aminoglycoside antibiotics （AmAn） are commonly used extensively throughout the world because of their low cost and capability to kill a broad spectrum of bacteria. However, the ototoxic and nephrotoxic effects of AmAn become main adverse reaction. The mechanisms involved in AmAn accumulation in the cochlear hair cells mainly in the mltochondria and lysosome. The toxic effects of AmAn appear to be mediated in part by the generation of reactive oxygen species that can disrupt membranes and biochemical processes within the hair cell. Local or systemic delivery of drugs that scavenge reactive oxygen species may provide a clinically viable approach for preventing AmAn ototoxicity. Calcim-activated proteinase is also play a role in AmAn induced hair cell degeneration which can be suppressed by calpain inhibitors. Acute AmAn induced hair cell death occurs mainly by apoptosis, which bind and damage mitochondria, lead to the release of cytochrome c into the cytoplasm, then turn on activates initiator caspase-9 followed by executioner caspase- 3. In contrast, long term systemic treatment of AmAn induced cochlear hair cell lesion involved in either apoptosis or necrosis. In AmAn induced hair cell necrosis, the overIoading and rupture of lysosome result in cell autolysis. AmAn does not damage spiral ganglion neurons directly, but a delayed neuron death frequently occurs after hair cell missing due to lacking neurotrophins. Neurotrophic gene transfections were efficaciously for spiral ganglion survival.