title: Suppression of neurite outgrowth of primary cultured hippocampal neurons is involved in impairment of glutamate metabolism and NMDA receptor function caused by nanoparticulate TiO2.
abstract: Numerous studies have indicated that nano-titanium dioxide (TiO2) can induce neurotoxicity in vitro and in vivo, however, it is unclear whether nano-TiO2 affects neurite outgrowth of hippocampal neurons. In order to investigate the mechanism of neurotoxicity, rat primary cultured hippocampal neurons on the fourth day of culture were exposed to 5, 15, and 30 μg/mL nano-TiO2 for 24 h, and nano-TiO2 internalization, dendritic growth, glutamate metabolism, expression of N-methyl-D-aspartate (NMDA) receptor subunits (NR1, NR2A and NR2B), calcium homeostasis, sodium current (INa) and potassium current (IK) were examined. Our findings demonstrated that nano-TiO2 crossed the membrane into the cytoplasm or nucleus, and significantly suppressed dendritic growth of primary cultured hippocampal neurons in a concentration-dependent manner. Furthermore, nano-TiO2 induced a marked release of glutamate to the extracellular region, decreased glutamine synthetase activity and increased phosphate-activated glutaminase activity, elevated intracellular calcium ([Ca(2+)]i), down-regulated protein expression of NR1, NR2A and NR2B, and increased the amplitudes of the INa and IK. In addition, nano-TiO2 increased nitric oxide and nitrice synthase, attenuated the activities of Ca(2+)-ATPase and Na(+)/K(+)-ATPase, and increased the ADP/ATP ratio in the primary neurons. Taken together, these findings indicate that nano-TiO2 inhibits neurite outgrowth of hippocampal neurons by interfering with glutamate metabolism and impairing NMDA receptor function.
authors.affiliation: School of Life Science, Huaiyin Normal University, Huaian 223300, China. Electronic address: hfshui666@126.com.
authors.forename: Fashui
authors.initials: F
authors.lastname: Hong
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Yuguan
authors.initials: Y
authors.lastname: Ze
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.affiliation: School of Life Science, Huaiyin Normal University, Huaian 223300, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Library of Soochow University, Suzhou 215123, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Xu
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ze
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles; D016501:Neurites; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014025:Titanium / Q000494:pharmacology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; C009495:titanium dioxide; D009569:Nitric Oxide; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D014025:Titanium; D019001:Nitric Oxide Synthase
keywords: Glutamate metabolism; NMDA receptor function; Neurite outgrowth; Primary hippocampal neurons; Titanium dioxide nanoparticles