title: Insulin attenuates arsenic-induced neurite outgrowth impairments by activating the PI3K/Akt/SIRT1 signaling pathway.
abstract: Arsenic neurotoxicity has a broad range of adverse effects on human health, which are induced in part by inhibition of neurite outgrowth. Insulin has been reported to promote neurite extension. The present study investigated whether insulin can protect neurons from impaired neurite outgrowth induced by arsenic, and examined the signaling pathway involved in this action. The study demonstrated that NaAsO2 caused inhibition of neurite outgrowth in differentiated SH-SY5Y cells indicating its neurotoxicity. This inhibitory effect of NaAsO2 was attenuated by insulin. It was found that blocking PI3K or Akt by selective inhibitors canceled the protective effect of insulin against NaAsO2-induced neurite outgrowth impairment suggesting the essential role of active PI3K and Akt in insulin's protective action. Inhibition of GSK3, which mimics an effect of insulin stimulation, had no effect on the impairment of neurite outgrowth by NaAsO2 implying that the insulin protective action is probably not due to its mediation of GSK3 inhibition ability. Moreover, NaAsO2 decreased the Akt activity, as it caused reduction in Akt phosphorylation, and downregulated expression of SIRT1. Additionally, the reduction of these signals by NaAsO2 was attenuated by insulin. Taken together, these results show that insulin attenuates arsenic-induced neurite outgrowth impairment possibly via activation of PI3K/Akt/SIRT1 signaling, and arsenic may exert neurite outgrowth inhibition through a mechanism involving reduction of signaling molecules downstream from insulin, PI3K/Akt/SIRT1. Our findings raise the possibility of using insulin to combat arsenic neurotoxicity.
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok 10210, Thailand.
authors.forename: Apichaya
authors.initials: A
authors.lastname: Niyomchan
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Office of the Higher Education Commission, Thailand. Electronic address: Piyajit@cri.or.th.
authors.forename: Piyajit
authors.initials: P
authors.lastname: Watcharasit
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand.
authors.forename: Daranee
authors.initials: D
authors.lastname: Visitnonthachai
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand.
authors.forename: Benjaporn
authors.initials: B
authors.lastname: Homkajorn
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Office of the Higher Education Commission, Thailand.
authors.forename: Apinya
authors.initials: A
authors.lastname: Thiantanawat
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Office of the Higher Education Commission, Thailand.
authors.forename: Jutamaad
authors.initials: J
authors.lastname: Satayavivad
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009447:Neuroblastoma; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D017670:Sodium Compounds / Q000633:toxicity*
chemical_list: D018053:Arsenites; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D056564:Sirtuin 1; D017670:Sodium Compounds; C017947:sodium arsenite; C447939:SIRT1 protein, human
keywords: Akt; Arsenic; Insulin; Neurite outgrowth; PI3K; SIRT1