卡铂及其耳毒性

Carboplatin and its ototoxicity

卡铂作为一种铂制剂广泛应用于临床抗肿瘤的化学治疗,其毒副作用主要包括耳毒性,肾毒性,神经毒性,和抑制骨髓造血系统等等。卡铂可以选择性破坏灰鼠的耳蜗内毛细胞和前庭I型毛细胞以及与之相联系的传入神经元。在卡铂引起的灰鼠单纯内毛细胞部分损害动物模型,动物具有正常的耳声发射和微音器电位以及听神经动作电位阈值,但总和电位和听神经动作电位的振幅却明显减小。在卡铂造成60%-90%的内毛细胞缺损的动物模型中,灰鼠在安静条件下对纯音的听觉条件反射阈可以保持正常,但在宽带或窄带噪声的掩蔽作用下,其纯音听觉反射阈值却明显提高,同时对听觉瞬时清晰度的辨别能力也明显降低。卡铂引起的内毛细胞和前庭I型毛细胞及其传入数据元的破坏过程往往伴随着钙激活蛋白酶的活动和Caspase-8的启动以及p53的过度调控从而引起细胞凋亡,同时可见琥珀酸脱氢酶,钠钾ATP酶,碱性磷酸酶和葡萄糖-6-磷酸酶活性的减弱以及钙激活ATP酶活性的增强。无论在灰鼠的活体动物实验还是离体培养条件下,卡铂都对灰鼠耳蜗内毛细胞和前庭I型毛细胞具有特殊的选择性破坏作用。卡铂对灰鼠听觉系统的损害除了导致内毛细胞和I型螺旋神经节凋亡之外,还会破坏耳蜗核神经元,但对下丘和听皮层的神经元却不造成致命性损坏。在耳蜗内毛细胞和I型螺旋神经节以及耳蜗核神经元被卡铂破坏之后,下丘和听皮层神经元对微弱的输入声刺激信号却表现出超乎寻常的敏感性提高,提示中枢神经元可能通过降低其某些抑制性神经递质的释放使神经元的活动代偿性增强,亦可能通过加强兴奋性神经递质的释放,或者通过神经元新长出的轴突和末梢而接受到更多的刺激信号,从而弥补了因周边听觉输入信号减弱而引起的听功能障碍,因此,卡铂耳中毒灰鼠模型还可成为一个研究听觉中枢重组现象或听神经病的理想实验动物模型。

Carboplatin is a platinum-based drug that widely used for treatment of solid tumors. However, its clinic application is restricted by various side effects of nephrotoxicity, ototoxicity, neurotoxicity, and bone marrow depression, etc. In experimental animals, carboplatin preferentially damages inner hair cells and type I spiral ganglion neurons in the cochlea, and vestibular type I hair cells and their afferent neurons in chinchillas. In carboplatin induced inner hair cell lesions, chinchillas have normal distortion product otoacoustic emissions, normal cochlear microphonics, and near normal threshold of compound action potentials. However, the amplitude of summating potential and compound action potential were reduced. When carboplatin induce a 60-90% inner hair cell missing in chinchilla cochlea, animals still have normal hearing response to tone in quiet with shock-avoidance conditioning procedure, however the threshold of hearing response were greatly elevated when a broad band noise or a narrowband noise were given. In addition, the discrimination to auditory temporal resolution was also significantly depressed. Carboplatin induced degeneration in hair cells and afferent neurons are associated with activities in calcium-activated proteinase, initiator caspase-8, and over administration of p53, which lead to cell apoptosis. In the early stage of inner hair cell degeneration, activity depression were also found in succinate dehydrogenase, sodium and potassium activated ATPase, alkaline phosphatase, and glucose- 6-phosphatase, but in contrast, calcium activated ATPase was greatly increased. Carboplatin also selectively destroys cochlear inner hair cells and vestibular type I hair cells in oganotypic cultures in chinchillas, whereas damages the outer hair cells in vitro in rats. Besides the selective destruction of inner hair cells and type I spiral ganglion neurons in chinchillas, carboplatin also damages the auditory neurons in cochlear nucleus, but never destroy the auditory neurons in inferior colliculus and auditory cortex. After a permanent damage to the inner hair cells, the type I spiral ganglion neurons, and the neurons of cochlear nucleus, although the central auditory pathway is deprived of much of its sensory inputs, the amplitude of the local field potentials in the inferior colliculus and auditory cortex were near normal or enhanced. A number of different mechanisms could conceivably increase the gain of central auditory system： （1） The system gain could increase due to a reduction of inhibition. （2） The system could become more responsive to the remaining inputs because of greater release of excitatory neurotransmitter, reduced uptake and inactivation of excitatory neurotransmitter or an increase in the number of receptors. （3） The neurons could sprout new axons and form additional synapses. Therefore, chinchillas can be deprived of a significant portion of the neural inputs to the central auditory system by administering carboplatin, which can be considered with the clinical disorder known as auditory neuropathy.