神经营养因子受体与顺铂诱导的耳蜗细胞毒性的相关性研究
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摘要
本研究通过顺铂耳毒性动物模型的建立,分别观察了顺铂在活体和离体培养中对耳蜗毛细胞及螺旋神经节神经元细胞的毒性作用;应用RT-PCR、免疫组化及Western blot检测TrkB、TrkC、p75及caspase-3在耳蜗的表达情况,从分子和蛋白水平明确在顺铂对耳蜗的毒性作用中它们的动态表达规律;并对caspase-3的表达与听力水平的关系、p75的表达与caspase-3表达之间的关系进行直线回归分析。在国内外首次提出,TrkB、TrkC和p75表达参与顺铂耳毒性耳蜗损伤的病理过程;而且p75参与顺铂中毒性耳聋的螺旋神经节神经元细胞凋亡;在p75介导的顺铂对螺旋神经节神经元的神经毒性作用中,caspase-3参与了下游激活信号。为药物性耳聋的病因学及治疗和预防方面的进一步研究提供理论依据和参照数据。
Introduction
Cisplatin (CDDP) is a highly effective chemotherapeutic agent but withsignificant ototoxic side effects. Now the exact mechanism of cisplatin-inducedototoxicity is not known, especially its neurotoxicity. It is well known thatneurotrophins play multiple crucial roles in the neurons cell differentiation,survival, cellular regeneration and repair through combined with their receptorslocated on the surface of neurons. However, NTs could result in neurotoxicity byinduced neuron apoptosis were found when P75 neruotrophin receptor wasworked as target in recent studies. In the auditory, the expression and distributionof Trks and P75 during development in inner ear has been reported. It is essentialfor promoting inner ear cells growth during development and maintaining survivalin the adult. Neurotrophins also affected on the synapse formation and neuraldistribution in organ of coti.
Hearing impairment that resulted from hair cells and spiral ganglion deathwith ototoxicity drug treatment is irreversible and related with apoptosis. Therewere not yet reported on concerning the relation between drug-induced deafnessand neurotrophin receptors. In this study, the role of neurotrophin receptors willbe investigated during hearing loss from ototoxocity drug. Some data can beprovided for study of mechanism of drug-induced deafness and its prevention or
therapy.Material and methodsThe postnatal day 3 Wistar rats were used for in vitro and adult for in vivostudies. In vivtro experiments, Cochlear cultures were treated with 0.25mMcisplatin for 12h or 24h and then hair cells and spiral ganglion neurons death wereobserved by immunolabelling. In vivo experiments, the 75 adult rats were dividedrandomly into 5 groups: Group I is saline control that received equivalent volumesof saline. Group II is that fifteen rats received a daily intraperitoneal injection ofcisplatin at a dose of 5mg/Kg for 1 day and killed at next day. Group III iscisplatin treated for 3 days at same dose daily and then killed at next day. GroupIV is cisplatin treated for 5 days killed at next day and Group V is cisplatin treatedfor 5 days and then were sacrificed after 7 days. Auditory thresholds weremeasured by evoked auditory brainstem responses (ABR). Thresholds were takenfor each animal prior to the beginning of the study and before decapitationat. Haircells and spiral ganglion neurons lesion were evaluated using cochlear surfacepreparations and cochlear section. The change of mRNA level of neurotrophinreceptors in cochlear tissue were examined by RT-PCR. The expressing pattern ofTrkB, TrkC, P75 in damaged cochleas were study by immunochemistry usingantibodies against TrkB, TrkC, P75 protein. The time pattern of expression P75and caspase-3 in cochleas were analyzed with western blot. Meanwhile, weprobed the relation between Caspase -3 and thresholds, expression of P75 andCaspase -3 with linear regression.Resultsin vitro experiment, CDDP resulted in all of rows of outer hair cells and innerhair cells lesion, and no significant different in impairment at all turn ofcochleas.SGNs in cochlear cultures after cisplatin treatment 12 hours appeared acharacter with cell body smaller and unshaped. These cells displayed an apoptotic
characteristic morphology that presented condensation of nucleus, nuclearfragmentation and intact cell membrane etc. CNQX, an inhibitor of glutaminereceptor also did not inhibit cochlear SGNs death according to morphologicanalysis.Auditory thresholds were comparable for all animals at the beginning of thestudy. Saline-injected control animals maintained stable thresholds for theduration of the experiments. The thresholds enhanced after CDDP treated at day 3and there were significant changes in ABR thresholds at day 7 after CDDPtreatment.RT-PCR data showed that mRNA level of all of trk B, trk C, P75 exhibitedin normal cochlear tissues.mRNA level of trk B increased to peak at day 1-3 afterCDDP treatment and decreased at day 5 early and following week. mRNA levelof trk C went up to peak at day 1 after CDDP treatment and went down duringsubsequently time. P75 kept a trend of continuance increase during the drugtreatment and decrease at drug stopped. Immunocytochemistry analysis resultsindicated that Trk B, Trk C and P75 protein were mainly located on cochlearspiral ganglion neurons, less on supporting cells, stria vascularis and hair cells,and that the expressing pattern were coincident with mRNA level. Both of P75and caspase-3 protein level enhanced in a similar regulation at the CDDP treatedgroups by western blot analysis. Linear regression indicated that there are a closecorrelation between expression of caspase-3 protein and threshold, expression ofp75 and caspase-3 protein during CDDP insults.Conclusion1. Hair cells and spiral ganglion neurons impairment were comparedbetween in vitro and in vivo with CDDP treatment. These results showed therewere different lesion pattern in cochlear culture model. These results indicatedthat cochlear SGNs damaged by cisplatin-indued were independent on glutamine
ototoxicity.2. The mechanism of cochlear hair cells and neurons damage by cisplatinhave been widely reported, however the change of neurotrophin receptor duringthe ototoxicity of cisplatin have rarely been observed. Our experimental resultssuggest that Trk B, Trk C and P75 may be involved in cochlear insult withCDDP-induced. Trk B and trk C played an important role in the reparative processof cochlear, especially at early stage of the damage.3. P75 could promoted SGNs apoptosis by cooperation with activatedcaspase-3 in CDDP-induced neurotoxicity. To reinforce the expression of TrkBand TrkC protein may protect cochlear SGNs from ototoxicity of cisplatin.Inhibitor of p75 may diminish the CDDP-induced apoptosis.
Introduction
Cisplatin (CDDP) is a highly effective chemotherapeutic agent but withsignificant ototoxic side effects. Now the exact mechanism of cisplatin-inducedototoxicity is not known, especially its neurotoxicity. It is well known thatneurotrophins play multiple crucial roles in the neurons cell differentiation,survival, cellular regeneration and repair through combined with their receptorslocated on the surface of neurons. However, NTs could result in neurotoxicity byinduced neuron apoptosis were found when P75 neruotrophin receptor wasworked as target in recent studies. In the auditory, the expression and distributionof Trks and P75 during development in inner ear has been reported. It is essentialfor promoting inner ear cells growth during development and maintaining survivalin the adult. Neurotrophins also affected on the synapse formation and neuraldistribution in organ of coti.
Hearing impairment that resulted from hair cells and spiral ganglion deathwith ototoxicity drug treatment is irreversible and related with apoptosis. Therewere not yet reported on concerning the relation between drug-induced deafnessand neurotrophin receptors. In this study, the role of neurotrophin receptors willbe investigated during hearing loss from ototoxocity drug. Some data can beprovided for study of mechanism of drug-induced deafness and its prevention or
therapy.Material and methodsThe postnatal day 3 Wistar rats were used for in vitro and adult for in vivostudies. In vivtro experiments, Cochlear cultures were treated with 0.25mMcisplatin for 12h or 24h and then hair cells and spiral ganglion neurons death wereobserved by immunolabelling. In vivo experiments, the 75 adult rats were dividedrandomly into 5 groups: Group I is saline control that received equivalent volumesof saline. Group II is that fifteen rats received a daily intraperitoneal injection ofcisplatin at a dose of 5mg/Kg for 1 day and killed at next day. Group III iscisplatin treated for 3 days at same dose daily and then killed at next day. GroupIV is cisplatin treated for 5 days killed at next day and Group V is cisplatin treatedfor 5 days and then were sacrificed after 7 days. Auditory thresholds weremeasured by evoked auditory brainstem responses (ABR). Thresholds were takenfor each animal prior to the beginning of the study and before decapitationat. Haircells and spiral ganglion neurons lesion were evaluated using cochlear surfacepreparations and cochlear section. The change of mRNA level of neurotrophinreceptors in cochlear tissue were examined by RT-PCR. The expressing pattern ofTrkB, TrkC, P75 in damaged cochleas were study by immunochemistry usingantibodies against TrkB, TrkC, P75 protein. The time pattern of expression P75and caspase-3 in cochleas were analyzed with western blot. Meanwhile, weprobed the relation between Caspase -3 and thresholds, expression of P75 andCaspase -3 with linear regression.Resultsin vitro experiment, CDDP resulted in all of rows of outer hair cells and innerhair cells lesion, and no significant different in impairment at all turn ofcochleas.SGNs in cochlear cultures after cisplatin treatment 12 hours appeared acharacter with cell body smaller and unshaped. These cells displayed an apoptotic
characteristic morphology that presented condensation of nucleus, nuclearfragmentation and intact cell membrane etc. CNQX, an inhibitor of glutaminereceptor also did not inhibit cochlear SGNs death according to morphologicanalysis.Auditory thresholds were comparable for all animals at the beginning of thestudy. Saline-injected control animals maintained stable thresholds for theduration of the experiments. The thresholds enhanced after CDDP treated at day 3and there were significant changes in ABR thresholds at day 7 after CDDPtreatment.RT-PCR data showed that mRNA level of all of trk B, trk C, P75 exhibitedin normal cochlear tissues.mRNA level of trk B increased to peak at day 1-3 afterCDDP treatment and decreased at day 5 early and following week. mRNA levelof trk C went up to peak at day 1 after CDDP treatment and went down duringsubsequently time. P75 kept a trend of continuance increase during the drugtreatment and decrease at drug stopped. Immunocytochemistry analysis resultsindicated that Trk B, Trk C and P75 protein were mainly located on cochlearspiral ganglion neurons, less on supporting cells, stria vascularis and hair cells,and that the expressing pattern were coincident with mRNA level. Both of P75and caspase-3 protein level enhanced in a similar regulation at the CDDP treatedgroups by western blot analysis. Linear regression indicated that there are a closecorrelation between expression of caspase-3 protein and threshold, expression ofp75 and caspase-3 protein during CDDP insults.Conclusion1. Hair cells and spiral ganglion neurons impairment were comparedbetween in vitro and in vivo with CDDP treatment. These results showed therewere different lesion pattern in cochlear culture model. These results indicatedthat cochlear SGNs damaged by cisplatin-indued were independent on glutamine
ototoxicity.2. The mechanism of cochlear hair cells and neurons damage by cisplatinhave been widely reported, however the change of neurotrophin receptor duringthe ototoxicity of cisplatin have rarely been observed. Our experimental resultssuggest that Trk B, Trk C and P75 may be involved in cochlear insult withCDDP-induced. Trk B and trk C played an important role in the reparative processof cochlear, especially at early stage of the damage.3. P75 could promoted SGNs apoptosis by cooperation with activatedcaspase-3 in CDDP-induced neurotoxicity. To reinforce the expression of TrkBand TrkC protein may protect cochlear SGNs from ototoxicity of cisplatin.Inhibitor of p75 may diminish the CDDP-induced apoptosis.
引文
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