Neurotoxic effect of 2,5-hexanedione on neural progenitor cells and hippocampal neurogenesis.
2,5-Hexanedione (HD), a metabolite of n-hexane, causes central and peripheral neuropathy leading to motor neuron deficits. Although chronic exposure to n-hexane is known to cause gradual sensorimotor neuropathy, there are no reports on the effects of low doses of HD on neurogenesis in the central nervous system. In the current study, we explored HD toxicity in murine neural progenitor cells (NPC), primary neuronal culture and young adult mice. HD (500 nM approximately 50 microM) dose-dependently suppressed NPC proliferation and cell viability, and also increased the production of reactive oxygen species (ROS). HD (10 or 50 mg/kg for 2 weeks) inhibited hippocampal neuronal and NPC proliferation in 6-week-old male ICR mice, as measured by BrdU incorporation in the dentate gyrus, indicating HD impaired hippocampal neurogenesis. In addition, elevated microglial activation was observed in the hippocampal CA3 region and lateral ventricles of HD-treated mice. Lastly, HD dose-dependently decreased the viability of primary cultured neurons. Based on biochemical and histochemical evidence from both cell culture and HD-treated animals, the neurotoxic mechanisms by which HD inhibits NPC proliferation and hippocampal neurogenesis may relate to its ability to elicit an increased generation of deleterious ROS.
Kim
Min-Sun
MS
Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
Park
Hee Ra
HR
Park
Mikyung
M
Kim
So Jung
SJ
Kwon
Mugil
M
Yu
Byung Pal
BP
Chung
Hae Young
HY
Kim
Hyung Sik
HS
Kwack
Seung Jun
SJ
Kang
Tae Seok
TS
Kim
Seung Hee
SH
Lee
Jaewon
J
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006588:Hexanones / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D006588:Hexanones; D017382:Reactive Oxygen Species; D019344:Lactic Acid; C011269:2,5-hexanedione