TY - JOUR
T1 - Nox4 Promotes Neural Stem/Precursor Cell Proliferation and Neurogenesis in the Hippocampus and Restores Memory Function Following Trimethyltin-Induced Injury
AU - Yoshikawa, Yoji
AU - Ago, Tetsuro
AU - Kuroda, Junya
AU - Wakisaka, Yoshinobu
AU - Tachibana, Masaki
AU - Komori, Motohiro
AU - Shibahara, Tomoya
AU - Nakashima, Hideyuki
AU - Nakashima, Kinichi
AU - Kitazono, Takanari
N1 - Funding Information:
We thank Dr. Mayumi Yamato (Kyushu University) for technical instruction and support in the RAWM test. We also thank Hideko Noguchi (Kyushu University) and Naoko Kasahara (Hisayama Research Institute for Lifestyle Diseases) for technical support, and Maya Kanazawa (Kyushu University) for secretarial assistance. The work was supported in part by a Grant-in-Aid for Scientific Research (B) (16H05439) (T.K. and T.A.) and (C) (26462163) (Y.W.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan ; a grant from SENSHIN Medical Research Foundation , Japan (T.A.); and research grants from Eisai and Daiichi-Sankyo (T.K. and T.A.). We thank Barry Patel, PhD, from Edanz Group ( www.edanzediting.com/ac ) for editing a draft of this manuscript.
Publisher Copyright:
© 2018 IBRO
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H 2 O 2 , the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4 − / − mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4 − / − mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4 − / − animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4 − / − mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function.
AB - Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H 2 O 2 , the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4 − / − mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4 − / − mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4 − / − animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4 − / − mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function.
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U2 - 10.1016/j.neuroscience.2018.11.046
DO - 10.1016/j.neuroscience.2018.11.046
M3 - Article
C2 - 30528855
AN - SCOPUS:85058841710
VL - 398
SP - 193
EP - 205
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
ER -