title: Reversible neurotoxicity of kanamycin on dorsal cochlear nucleus.
abstract: The time course of aminoglycoside neurotoxic effect on cochlear nucleus is still obscure. We examined dynamic pathological changes of dorsal cochlear nucleus (DCN) and investigated whether apoptosis or autophagy was upregulated in the neurotoxic course of kanamycin on DCN after kanamycin treatment. Rats were treated with kanamycin sulfate/kg/day at a dose of 500mg by subcutaneous injection for 10 days. Dynamic pathological changes, neuron density and neuron apoptosis of the DCN were examined at 1, 7, 14, 28, 56, 70 and 140 days after kanamycin treatment. The expressions of JNK1, DAPK2, Bcl-2, p-Bcl-2, Caspase-3, LC3B and Beclin-1 were also detected. Under transmission electron microscopy, the mitochondrial swelling and focal vacuoles as well as endoplasmic reticulum dilation were progressively aggravated from 1 day to 14 days, and gradually recovered from 28 days to 140 days. Meanwhile, both autophagosomes and autolysosomes were increased from 1 day to 56 days. Only few neurons were positive to the TUNEL staining. Moreover, neither the expressions of caspase-3 and DAPK2 nor neurons density of DCN changed significantly. LC3-II was drastically increased at 7 days. Beclin-1 was upgraded at 1 and 7 days. P-Bcl-2 increased at 1, 7, 14 and 28 days. JNK1 increased at 7 days, and Bcl-2 was downgraded at 140 days. LC3-B positive neurons were increased at 1, 7 and 14 days. These data demonstrated that the neurons damage of the DCN caused by kanamycin was reversible and autophagy was upregulated in the neurotoxic course of kanamycin on DCN through JNK1-mediated phosphorylation of Bcl-2 pathway.
authors: Department of Otorhinolaryngology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, PR China.
authors: Guo-Run
authors: GR
authors: Fan
authors: Ze-Deng
authors: ZD
authors: Yin
authors: Yu
authors: Y
authors: Sun
authors: Sen
authors: S
authors: Chen
authors: Wen-Juan
authors: WJ
authors: Zhang
authors: Xiang
authors: X
authors: Huang
authors: Wei-Jia
authors: WJ
authors: Kong
authors: Hong-Lian
authors: HL
authors: Zhang
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000071186:Beclin-1; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D017626:Cochlear Nucleus / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D003404:Creatinine / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007612:Kanamycin / Q000633:toxicity*; D007668:Kidney / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000209:etiology* / Q000473:pathology*; D009584:Nitrogen / Q000097:blood / Q000652:urine; D011500:Protein Synthesis Inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D009419:Nerve Tissue Proteins; D011500:Protein Synthesis Inhibitors; D007612:Kanamycin; D003404:Creatinine; D048055:Mitogen-Activated Protein Kinase 8; D009584:Nitrogen