Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Despite a variety of anti-inflammatory or immunomodulation drugs including interferon-beta are effective to reduce relapse risk, most patients have progressive neurological deterioration due to axonal degeneration. Accumulation of activated microglia is a pathological hallmark of active MS lesion. Microglia can act as not only antigen-presenting cells but also effector cells to damage other cells in the central nervous system. Especially, glutamate released by activated microglia induces excito-neurotoxicity and may contribute to neurodegeneration in MS. Gap junction is a major cell-to-cell channel and is composed of paired hemichannels on coupled cells. Recent studies showed that cells release various small molecules (including ions, ATP, and amino acids) from unpaired hemichannel of gap junction that is openly exposed to the extracellular space. We have previously revealed that activated microglia produce glutamate via glutaminase and release it through hemichannels of gap junctions. Thus, in this study, we examined whether the glutaminase inhibitor and the gap junction blocker relieved experimental autoimmune encephalomyelitis (EAE) that is an animal model of MS. Here we show that the gap junction blocker carbenoxolone (CBX) and the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) decreased glutamate release from activated microglia and rescued neuronal death in a dose-dependent manner in vitro. In EAE mice, treatment with CBX or DON also attenuated EAE clinical symptoms. Thus, blockade of glutamate release from activated microglia with CBX or DON may be an effective therapeutic strategy against neurodegeneration in MS.

• Authors: Jin Shijie, Hideyuki Takeuchi, Izumi Yawata, Yohei Harada, Yoshifumi Sonobe, Yukiko Doi, Jianfeng Liang, Li Hua, Satoko Yasuoka, Yan Zhou, Mariko Noda, Jun Kawanokuchi, Tetsuya Mizuno, Akio Suzumura
• Journal: The Tohoku journal of experimental medicine (Tohoku J Exp Med) Vol. 217 Issue 2 Pg. 87-92 (Feb 2009) ISSN: 1349-3329 [Electronic] Japan
• PMID: 19212100 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Diazooxonorleucine
• Glutamic Acid
• Glutaminase
• Carbenoxolone

Topics

• Animals
• Carbenoxolone (pharmacology)
• Cell Death (drug effects)
• Diazooxonorleucine (pharmacology)
• Dose-Response Relationship, Drug
• Encephalomyelitis, Autoimmune, Experimental (enzymology, pathology, prevention & control)
• Enzyme Inhibitors (pharmacology)
• Gap Junctions (drug effects, metabolism)
• Glutamic Acid (metabolism)
• Glutaminase (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Microglia (metabolism)
• Neurons (drug effects, pathology)
• Spinal Cord (drug effects, pathology)