title: Bone marrow mesenchymal stem cells attenuate 2,5-hexanedione-induced neuronal apoptosis through a NGF/AKT-dependent pathway.
abstract: Growing evidence suggests that the increased neuronal apoptosis is involved in n-hexane-induced neuropathy. We have recently reported that bone marrow-mesenchymal stem cells-derived conditioned medium (BMSC-CM) attenuated 2,5-hexanedione (HD, the active metabolite of n-hexane)-induced apoptosis in PC12 cells. Here, we explored the anti-apoptotic efficacy of BMSC in vivo. HD-treated rats received BMSC by tail vein injection 5 weeks after HD intoxication. We found that in grafted rats, BMSC significantly attenuated HD-induced neuronal apoptosis in the spinal cord, which was associated with elevation of nerve growth factor (NGF). Neutralization of NGF in BMSC-CM blocked the protection against HD-induced apoptosis in VSC4.1 cells, suggesting that NGF is essential for BMSC-afforded anti-apoptosis. Mechanistically, we found that the decreased activation of Akt induced by HD was significantly recovered in the spinal cord by BMSC and in VSC4.1 cells by BMSC-CM in a TrkA-dependent manner, leading to dissociation of Bad/Bcl-xL complex in mitochondria and release of anti-apoptotic Bcl-xL. The importance of Akt was further corroborated by showing the reduced anti-apoptotic potency of BMSC in HD-intoxicated VSC4.1 cells in the presence of Akt inhibitor, MK-2206. Thus, our findings show that BMSC attenuated HD-induced neuronal apoptosis in vivo through a NGF/Akt-dependent manner, providing a novel solution against n-hexane-induced neurotoxicity.
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, the First Affiliated Hospital of Dalian Medical University, Liaoning 116011, China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Chenxue
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hao
authors.affiliation: College of Stomatology, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Enjun
authors.initials: E
authors.lastname: Zuo
authors.affiliation: Department of Nutrition and Food Safety, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Shuangyue
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Piao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006588:Hexanones / Q000009:adverse effects*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009498:Neurotoxins / Q000009:adverse effects*; D016716:PC12 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000628:therapy*
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D006588:Hexanones; C548887:MK 2206; D009498:Neurotoxins; D020932:Nerve Growth Factor; C011269:2,5-hexanedione; D051057:Proto-Oncogene Proteins c-akt