Amiodarone-Induced Retinal Neuronal Cell Apoptosis Attenuated by IGF-1 via Counter Regulation of the PI3k/Akt/FoxO3a Pathway.
Amiodarone (AM) is the most effective antiarrhythmic agent currently available. However, clinical application of AM is limited by its serious toxic adverse effects including optic neuropathy. The purpose of this study was to explore the effects of AM and to assess if insulin-like growth factor-1 (IGF-1) could protect retinal neuronal cells from AM-induced apoptosis, and to determine the molecular mechanisms underlying the effects. Accordingly, the phosphorylation/activation of Akt and FoxO3a were analyzed by Western blot while the possible pathways involved in the protection of IGF-1 were investigated by application of various pathway inhibitors. The full electroretinogram (FERG) was used to evaluate in vivo effect of AM and IGF-1 on rat retinal physiological functions. Our results showed that AM concentration dependently caused an apoptosis of RGC-5 cells, while IGF-1 protected RGC-5 cells against this effect by AM. The protective effect of IGF-1 was reversed by PI3K inhibitors LY294002 and wortmannin as well as the Akt inhibitor VIII. AM decreased p-Akt and p-FoxO3a while increased the nuclear localization of FoxO3a in the RGC-5 cells. IGF-1 reversed the effect of AM on the p-Akt and p-FoxO3a and the nuclear translocation of FoxO3a. Similar results were obtained in primary cultured retinal ganglia cells. Furthermore, FERG in vivo recording in rats showed that AM decreased a-wave and b-wave of FERG while IGF-1 reversed the effects of AM. These data show that AM induced apoptosis of retinal neuronal cells via inhibiting the PI3K/Akt/FoxO3a pathway while IGF-1 protected RGC-5 cells against AM-induced cell apoptosis by stimulating this pathway.
['Liao|Rifang|R|', 'Yan|Fengxia|F|', 'Zeng|Zhuanping|Z|', 'Farhan|Mohd|M|', 'Little|Peter|P|', 'Quirion|Remi|R|', 'Srivastava|Lalit K|LK|', 'Zheng|Wenhua|W|']
D000638:Amiodarone D000818:Animals D000831:Animals, Newborn D017209:Apoptosis D002460:Cell Line D002867:Chromones D004596:Electroretinography D000071316:Forkhead Box Protein O3 D007334:Insulin-Like Growth Factor I D008954:Models, Biological D009025:Morpholines D019869:Phosphatidylinositol 3-Kinases D010766:Phosphorylation D020011:Protective Agents D047428:Protein Kinase Inhibitors D051057:Proto-Oncogene Proteins c-akt D017207:Rats, Sprague-Dawley D055351:Retinal Neurons D015398:Signal Transduction
Apoptosis Akt FoxO3a Amiodarone Antiarrhythmic Neuroprotection