title: Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways.
abstract: 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 IκB kinase/IκB/nuclear factor-kappa B (NF-κB) inflammatory pathway. Therefore, AR inhibition-dependent NF-κB 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
authors.forename: Ke-Wu
authors.initials: KW
authors.lastname: Zeng
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Zhi-Zhong
authors.initials: ZZ
authors.lastname: Ma
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Jin
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Tu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D000449:Aldehyde Reductase; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases
keywords: (5-formylfuran-2-yl) methyl 4-hydroxy-2-methylenebutanoate; AR; Aldose reductase; FMHM; I kappa B kinase; IKK; IκB; LPS; MAPKs; Microglia; NF-κB; Neuroinflammation; Nuclear factor-kappa B (NF-κB); PKC; PLC; Protein kinase C; aldose reductase; inhibitor of kappa B; lipopolysaccharide; mitogen-activated protein kinases; nuclear factor kappa B; phospholipase C; protein kinase C