title: Amiodarone-Induced Retinal Neuronal Cell Apoptosis Attenuated by IGF-1 via Counter Regulation of the PI3k/Akt/FoxO3a Pathway.
abstract: 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.
authors: Neuropharmacology, School of Pharmaceutical Sciences, and Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Faculty of Health Sciences, University of Macau, Room 4021, Building E12, Avenida de Universidade, Taipa, Macau, China.
authors: Rifang
authors: R
authors: Liao
authors: Neuropharmacology, School of Pharmaceutical Sciences, and Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.|Faculty of Health Sciences, University of Macau, Room 4021, Building E12, Avenida de Universidade, Taipa, Macau, China.
authors: Fengxia
authors: F
authors: Yan
authors: School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
authors: Zhuanping
authors: Z
authors: Zeng
authors: Faculty of Health Sciences, University of Macau, Room 4021, Building E12, Avenida de Universidade, Taipa, Macau, China.
authors: Mohd
authors: M
authors: Farhan
authors: School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, 20 Cornwall St, Woolloongabba, QLD, 4102, Australia.
authors: Peter
authors: P
authors: Little
authors: Douglas Hospital Research Center, McGill University, Montreal, QC, Canada.
authors: Remi
authors: R
authors: Quirion
authors: Douglas Hospital Research Center, McGill University, Montreal, QC, Canada.
authors: Lalit K
authors: LK
authors: Srivastava
authors: Neuropharmacology, School of Pharmaceutical Sciences, and Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. wenhuazheng@umac.mo.|Faculty of Health Sciences, University of Macau, Room 4021, Building E12, Avenida de Universidade, Taipa, Macau, China. wenhuazheng@umac.mo.
authors: Wenhua
authors: W
authors: Zheng
mesh_terms: D000638:Amiodarone / Q000009:adverse effects* / Q000737:chemistry; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004596:Electroretinography; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D055351:Retinal Neurons / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000638:Amiodarone; D002867:Chromones; D000071316:Forkhead Box Protein O3; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C499515:FOXO3 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Akt; Amiodarone; Antiarrhythmic; Apoptosis; FoxO3a; Neuroprotection