Anti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanism.
Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia contributes to human neurodegenerative disorders. Our previous study demonstrated the potent inhibition of lipopolysaccharide (LPS)-induced NO production in rat primary microglial cells by rhynchophylline (RIN) and isorhynchophylline (IRN), a pair of isomeric alkaloids of Uncaria rhynchophylla (Miq.) Jacks. that has been used in China for centuries as a "cognitive enhancer" as well as to treat strokes. We further investigated whether RIN and IRN effectively suppress release of proinflammatory cytokines in LPS-activated microglial cells and the underling molecular mechanism for the inhibition of microglial activation. RIN and IRN concentration-dependently attenuated LPS-induced production of proinflammatory cytokines such as TNF-alpha and IL-1beta as well as NO in mouse N9 microglial cells, with IRN showing more potent inhibition of microglial activation. The western blotting analysis indicated that the potential molecular mechanism for RIN or IRN-mediated attenuation was implicated in suppressions of iNOS protein level, phosphorylation of ERK and p38 MAPKs, and degradation of IkappaBalpha. In addition, the differential regulation of the three signaling pathways by two isomers was shown. Our results suggest that RIN and IRN may be effective therapeutic candidates for use in the treatment of neurodegenerative diseases accompanied by microglial activation.
Yuan
Dan
D
Department of Traditional Chinese Medicines, Shenyang Pharmaceutical University, 103 Wenhua Rd., Shenyang, 110016, China.
Ma
Bin
B
Yang
Jing-yu
JY
Xie
Yuan-yuan
YY
Wang
Li
L
Zhang
Li-jia
LJ
Kano
Yoshihiro
Y
Wu
Chun-fu
CF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D007536:Isomerism; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000078183:Oxindoles; D008517:Phytotherapy; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020521:Stroke / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D032070:Uncaria; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D020672:I-kappa B Proteins; D026121:Indole Alkaloids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000078183:Oxindoles; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C052714:rhyncophylline; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases