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The Journal of Neuroscience, December 24, 2008, 28(52):14259-14270; doi:10.1523/JNEUROSCI.4258-08.2008

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Neurobiology of Disease
Hypoxia-Inducible Factor-1 Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

Shiu-Hwa Yeh,^1,3 Jan-Jong Hung,^1,2,3 Po-Wu Gean,^1,3 and Wen-Chang Chang^1,2,3

¹Department of Pharmacology, College of Medicine, ²Institute of Biosignal Transduction, College of Bioscience and Biotechnology, and ³Center for Gene Regulation and Signal Transduction, National Cheng-Kung University, Tainan 701, Taiwan

Correspondence should be addressed to either of the following: Jan-Jong Hung, Institute of Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan 701, Taiwan, Email: petehung{at}mail.ncku.edu.tw; or Wen-Chang Chang, Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan, Email: wcchang{at}mail.ncku.edu.tw

Inflammation is involved in some neurodegenerative disorders. NMDA glutamate receptors play an important role in neuronal development. Here, we show that NR1 expression in the cerebral cortex and primary neurons of rats was upregulated after lipopolysaccharide (LPS) treatment. This increase in NR1 expression was considered to be strongly associated with hypoxia-inducible factor-1 (HIF-1) activation because the treatment of primary neurons with either echinomycin or small interfering RNA (siRNA) targeting HIF-1 could block NR1 expression. HIF-1 could be induced by an increase in the translational efficiency of the cells. After this, it was transported into the nucleus where it bound to the NR1 promoter and regulated the induction of NR1 transcriptional activity by LPS. LPS injection into the prefrontal cortex caused neuronal death, and this condition was aggravated by intracerebroventricular injection of echinomycin. Furthermore, knockdown of HIF-1 and NR1 by the appropriate siRNAs reduced the neurite outgrowth and viability of the primary neurons. These results suggest that NR1 expression is regulated by HIF-1 and plays a protective role in neurons during LPS challenge.

Key words: LPS; HIF-1; NR1; echinomycin; rpS6; cultured cortical neurons

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Received Sept. 6, 2008; revised Nov. 11, 2008; accepted Nov. 12, 2008.

Correspondence should be addressed to either of the following: Jan-Jong Hung, Institute of Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan 701, Taiwan, Email: petehung{at}mail.ncku.edu.tw; or Wen-Chang Chang, Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan, Email: wcchang{at}mail.ncku.edu.tw

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