摘要
Mefloquineisawidelyusedanti-malarialdrug.Someclinicalreportssuggestthatmefloquinemaybeototoxicandneurotoxic,butthereislittlescientificevidencefromwhichtodrawanyfirmconclusion.Toevaluatetheototoxicandneurotoxicpotentialofmefloquine,wetreatedcochlearorganotypicculturesandspiralganglioncultureswithvariousconcentrationsofmefloquine.Mefloquinecausedadose-dependentlossofcochlearhaircellsatdosesexceeding0.01mM.Haircelllossprogressedfrombasetoapexandfromoutertoinnerhaircellswithincreasingdose.Spiralganglionneuronsandauditorynervefiberswerealsorapidlydestroyedbymefloquineinadose-dependentmanner.Toinvestigatethemechanismsunderlyingmefloquine-inducedcelldeath,cochlearcultureswerestainedwithTO-Pro-3toidentifymorphologicalchangesinthenucleus,andwithcarboxyfluoresceinFAM-labeledcaspaseinhibitor8,9or3todeterminecaspase-mediatedcelldeath.TO-Pro-3-labelednucleiinhaircells,spiralganglionneuronsandsupportingcellswereshrunkenorfragmented,morphologicalfeaturescharacteristicofcellsundergoingapoptosis.Bothinitiatorcaspase8(membranedamage)andcaspase9(mitochondrialdamage),alongwithexecutionercaspase3,wereheavilyexpressedincochlearhaircellsandspiralganglionsaftermefloquinetreatment.Thesethreecaspaseswerealsoexpressedinsupportcells,althoughlabelingwaslesswidespreadandlessintense.Theseresultsindicatethatmefloquinedamagesboththesensoryandneuralelementsinthepostnatalratcochleabyinitiallyactivatingcelldeathsignalingpathwaysonthecellmembraneandinmitochondria.
出版日期
2009年02月12日（中国期刊网平台首次上网日期，不代表论文的发表时间）
