Theophylline potentiates lipopolysaccharide-induced NO production in cultured astrocytes

Mizue Ogawa, Katsura Takano, Kenji Kawabe, Mitsuaki Moriyama, Hideshi Ihara, Yoichi Nakamura

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Elucidation of the functions of astrocytes is important for understanding of the pathogenic mechanism of various neurodegenerative diseases. Theophylline is a common drug for bronchial asthma and occasionally develops side-effects, such as acute encephalopathy; although the pathogenic mechanism of the side-effects is unknown. The lipopolysaccharide (LPS)-induced nitric oxide (NO) production is generally used for an index of the activation of astrocyte in vitro. In this study, in order to elucidate the effect of theophylline on the astrocytic functions, we examined the LPS-induced NO production and the expression of iNOS in cultured rat cortex astrocytes. Theophylline alone could not induce the NO production; however, NO production induced by LPS was enhanced by theophylline in a dose-dependent manner; and by isobutylmethylxanthine, a phosphodiesterase inhibitor. The theophylline enhancement of LPS-induced NO production was further increased by dibutyryl cyclic AMP, a membrane-permeable cAMP analog; and by forskolin, an adenylate cyclase activator. When the cells were preincubated with Rp-8-Br-cAMP, an inhibitor of protein kinase A, the theophylline enhancement of LPS-induced NO production was decreased. The extent of iNOS protein expression induced by LPS was also enhanced by theophylline. It is likely that phosphodiesterase inhibition is a major action mechanism for the theophylline enhancement of LPS-induced NO production in astrocytes. Theophylline-induced acute encephalopathy might be due to the hyper-activation of astrocytes via cAMP signaling to produce excess amount of NO.

Original languageEnglish
Pages (from-to)107-116
Number of pages10
JournalNeurochemical Research
Issue number1
Publication statusPublished - Jan 2014


  • Astrocyte
  • NO
  • Theophylline

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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