Nicotine inhibits the proliferation by upregulation of nitric oxide and increased HDAC1 in mouse neural stem cells.
Cigarette smoking (CS) is considered one of the major risk factors to cause neurodegenerative disorders. Nicotine is the main chemical in CS which is responsible for dysfunction of the brain as a neuroteratogen. Also, nicotine dependency is a real mental illness and disease. Recently, chronic nicotine exposure has been shown to cause oxidative/nitrosative stress leading to a deleterious condition to cellular death in different brain regions. However, little is known about the effects of nicotine on mouse neural stem cells (mNSCs). The aim of this study is to investigate the effects of nicotine on mNSCs and elucidate underlying mechanisms involved in expression of a diversity of genes regulated by nicotine. When mNSCs were isolated from the whole brain of embryonic day 16 mice treated with nicotine at vehicle, 100, 400, and 800 μM for 5 d, nicotine significantly decreased the number and size of neurospheres. In immunocytochemistry, nicotine-exposed mNSCs expressing nestin showed the shortened filaments and condensed nuclei. In RT-PCR, messenger RNA (mRNA) levels of proliferating cell nuclear antigen (PCNA) and sirtuin1 (SIRT1) were significantly decreased, while the production of nitric oxide and mRNA levels of cyclooxygenase2 (COX-2), tumor necrosis factor-alpha TNF-α, and histone deacetylase 1 (HDAC1) were increased in a dose-dependent manner. In addition, sodium butyrate and valproic acid, HDAC inhibitors, partially rescue proliferation of mNSCs via inhibition of HDAC1 expression and NO production. Taken together, these data demonstrate that prolonged exposure of nicotine decreased proliferation of mNSCs by increased NO and inflammatory cytokine through increased HDAC1. Furthermore, this study could help in the development of a therapy for nicotine-induced neurodegenerative disorder and drug abuse.
Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, Gangwon, Republic of Korea.
Hanbyeol
H
Lee
Jeong-Ran
JR
Park
Jungwon
J
Yang
Eunjeong
E
Kim
Seok-Ho
SH
Hong
Heung-Myong
HM
Woo
Se-Min
SM
Ryu
Sung-Joon
SJ
Cho
Sung-Min
SM
Park
Se-Ran
SR
Yang
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000032:analysis / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D058953:Neural Stem Cells / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009538:Nicotine; D051546:Cyclooxygenase 2; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005980:Glutathione Reductase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1