期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 273, 期 1, 页码 159-171出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2013.08.028
关键词
Aldose reductase; Protein kinase C; Nuclear factor-kappa B (NF-kappa B); Neuroinflammation; Microglia
资金
- National Key Technology R & D Program New Drug Innovation of China [2012ZX09301002-002-002]
- Natural Science Foundation of China [81303253, 30873072]
- China Postdoctoral Science Foundation [2012M510294, 2013T60045]
- Postdoctoral Fellowship of Peking-Tsinghua Center for Life Sciences
Aldose reductase (AR) has a key role in several inflammatory diseases: diabetes, cancer and cardiovascular diseases. Therefore, AR inhibition seems to be a useful strategy for anti-inflammation therapy. In the central nervous system (CNS), microglial over-activation is considered to be a central event in neuroinflammation. However, the effects of AR inhibition in CNS inflammation and its underlying mechanism of action remain unknown. In the present study, we found that FMHM (a naturally derived AR inhibitor from the roots of Polygala tricornis Gagnep.) showed potent anti-neuroinflammatory effects in vivo and in vitro by inhibiting microglial activation and expression of inflammatory mediators. Mechanistic studies showed that FMHM suppressed the activity of AR-dependent phospholipase C/protein kinase C signaling, which further resulted in downstream inactivation of the I kappa B kinase/I kappa B/nuclear factor-kappa B (NF-kappa B) inflammatory pathway. Therefore, AR inhibition-dependent NF-kappa B inactivation negatively regulated the transcription and expression of various inflammatory genes. AR inhibition by FMHM exerted neuroprotective effects in lipopolysaccharide-induced neuron-microglia co-cultures. These findings suggested that AR is a potential target for neuroinflammation inhibition and that FMHM could be an effective agent for treating or preventing neuroinflammatory diseases. (C) 2013 Elsevier Inc. All rights reserved.
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