Docetaxel-induced neurotoxicity in rat dorsal root ganglia
| Autor: | Min-Li Huang, 黃敏莉 |
|---|---|
| Rok vydání: | 2008 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 96 Docetaxel is an anticancer agent targeting microtubules. It is widely used for treating a number of cancers, including breast cancer, ovary cancer, non small cell lung cancer, prostate cancer and neck cancer. One of the major side effects is o is peripheral neuropathy (neuropathic pain) including numbness, tingling and burning pain. The discomfort of pain peripheral neuropathy reduces the quality of life and there is no effective medicine to relieve the pain. So far, limited studies have focused on docetaxel-induced neuropathic pain. In my thesis, the neurotoxicity of docetaxel was studied using in vitro and in vivo approaches. In vitro study, dorsal root ganglion (DRG) explants were employed to investigate docetaxel-induced neurotoxicity. DNA fragmentation was observed 24 h after docetaxel incubation. Docetaxel time- and concentration-dependently increased ��-synuclein aggregation, Bcl-2 level and caspase 3 activation. Furthermore, Docetaxel elevated nuclear ATF(activating transcription factor)-4 and CHOP levels as well as caspase 12 activation, an endoplasmic reticulum-specific enzyme. Salubrinal, an ER stress inhibitor attenuated docetaxel-induced activation of caspase 12 level. Moreover, chronic administration of docetaxel (6 mg/kg/mL) was intravenously injected once a week in SD rats. Docetaxel-induced mechano-allodynia by Von Frey filaments was performed. Docetaxel induced allodynia 1-2 weeks and the allodynia was most evident 4-5 weeks and maintained 7 weeks after docetaxel treatment. Western blot was employed to analyze the time-effect of docetaxel on DRG. Elevations in ��-synuclein aggregation, Bcl-2 level, ATF4, CHOP and activation of caspase 12 were observed in DRG of docetaxel-treated rats. Taken together, my thesis established an animal model of docetaxel-induced neuropathic pain. Furthermore, Docetaxel increased ��-synuclein aggregation in DRG. Moreover, Docetaxel induced apoptosis via mitochondria and ER stress. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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