Neoechinulin A suppresses amyloid-β oligomer-induced microglia activation and thereby protects PC-12 cells from inflammation-mediated toxicity.

Abstract

A pathological hallmark of Alzheimer's disease (AD), aggregation and deposition of amyloid-β peptides, has been recognized as a potent activator of microglia-mediated neuroinflammation and neuronal dysfunction. Therefore, downregulation of microglial activation has a significant therapeutic demand. In this study, focus was given to evaluate the ability of neoechinulin A, an indole alkaloid isolated from marine-derived Microsporum sp., to attenuate microglial activation by oligomeric amyloid-β 1-42 (Aβ42). Neoechinulin A treatment significantly inhibited the generation of reactive oxygen and nitrogen species in Aβ42-activated BV-2 microglia cells. In addition, we found that neoechinulin A significantly suppressed the production of neurotoxic inflammatory mediator tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in activated BV-2 cells. Moreover, the treatment downregulated the protein and gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-1β and IL-6. Further, activated microglia-mediated apoptosis of PC-12 pheochromocytoma cells was significantly repressed by neoechinulin A. The molecular mechanism studies suggested that neoechinulin A may block the phosphorylation of mitogen-activated protein kinase (MAPK) molecule p38, apoptosis signal-regulating kinase 1 (ASK-1) and nuclear translocation of nuclear factor-κB (NF-κB) p65 and p50 subunits. Regulation of these signalling pathways have most probably contributed to the anti-inflammatory activity of neoechinulin A. Collectively, these results suggest that with further studies neoechinulin A have a potential to be developed as a modulator of neuroinflammatory process in AD.

• Authors: Pradeep Dewapriya, Yong-Xin Li, S W A Himaya, Ratih Pangestuti, Se-Kwon Kim
• Journal: Neurotoxicology (Neurotoxicology) Vol. 35 Pg. 30-40 (Mar 2013) ISSN: 1872-9711 [Electronic] Netherlands
• PMID: 23261590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Anti-Inflammatory Agents
• Indole Alkaloids
• Inflammation Mediators
• Interleukin-1beta
• Interleukin-6
• NF-kappa B
• Neuroprotective Agents
• Peptide Fragments
• Piperazines
• Reactive Nitrogen Species
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• amyloid beta-protein (1-42)
• neoechinulin A
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• Map3k5 protein, mouse
• Dinoprostone

Topics

• Amyloid beta-Peptides (metabolism)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Communication (drug effects)
• Cyclooxygenase 2 (genetics, metabolism)
• Cytoprotection
• Dinoprostone (metabolism)
• Dose-Response Relationship, Drug
• Gene Expression Regulation
• Indole Alkaloids (pharmacology)
• Inflammation (genetics, metabolism, pathology, prevention & control)
• Inflammation Mediators (metabolism)
• Interleukin-1beta (genetics, metabolism)
• Interleukin-6 (genetics, metabolism)
• MAP Kinase Kinase Kinase 5 (metabolism)
• Mice
• Microglia (drug effects, metabolism, pathology)
• NF-kappa B (metabolism)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Oxidative Stress (drug effects)
• PC12 Cells
• Peptide Fragments (metabolism)
• Phosphorylation
• Piperazines (pharmacology)
• Rats
• Reactive Nitrogen Species (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)