Neuroprotective effect of methyl lucidone against microglia-mediated neurotoxicity.

Abstract

Excessive microglial activation-mediated neurotoxicity has been implicated in playing a crucial role in the pathogenesis of stroke and neurodegenerative diseases. Therefore, much attention has been paid to therapeutic strategies aimed at suppressing neurotoxic microglial activation. The microglial regulatory mechanism of methyl lucidone, a cyclopentenedione isolated from the stem bark of Lindera erythrocarpa Makino, was investigated in the present study. Methyl lucidone treatment (0.1-10 μM) significantly inhibited lipopolysaccharide (LPS, 100 ng/ml, 24 h)-stimulated nitric oxide (NO) production in a dose-dependent manner in both primary cortical microglia and BV-2 cell line. Moreover, it strongly inhibited LPS-stimulated secretion of pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). Methyl lucidone treatment markedly induced down-regulation of LPS-induced nuclear translocation of nuclear factor κB (NF-κB) through preventing the degradation of the inhibitory protein IκBα. In addition, phosphorylation of Akt and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK) and p38 kinases were also suppressed by methyl lucidone. The cell viabilities of HT-22 neurons were significantly attenuated by treatment of the conditioned media containing neurotoxic secretary molecules from LPS-stimulated microglia. However, methyl lucidone significantly blocked neuronal cell death induced by microglial conditioned media. These neuroprotective effects of methyl lucidone were also confirmed in a neuron-microglia co-culture system using EGFP-transfected B35 neuroblastoma cell line. Taken together, these results suggest that methyl lucidone may have a neuroprotective potential via inhibition of neurotoxic microglial activation implicated in neurodegeneration.

• Authors: Yanji Cui, Jinji Wu, Sung-Cherl Jung, Gi-Ok Kim, Ryeo Kyeong Ko, Hye-Ja Lee, Eun-Sook Yoo, Hee-Kyoung Kang, Kyoungho Suk, Su-Yong Eun
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 690 Issue 1-3 Pg. 4-12 (Sep 05 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 22683871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Culture Media, Conditioned
• Cyclopentanes
• Cytokines
• Lipopolysaccharides
• NF-kappa B
• Neuroprotective Agents
• methyllucidone
• Nitric Oxide
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Cell Death (drug effects)
• Cerebral Cortex (cytology)
• Coculture Techniques
• Culture Media, Conditioned (metabolism)
• Cyclopentanes (pharmacology)
• Cytokines (metabolism)
• Lindera (chemistry)
• Lipopolysaccharides (pharmacology)
• Microglia (cytology, drug effects, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Neurons (cytology, drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide (biosynthesis)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Signal Transduction (drug effects)