2004 Fiscal Year Final Research Report Summary
Mechanism underlying neuroprotection by activated microglia
| Project/Area Number |
15590229
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General pharmacology
|
|---|
| Research Institution | HIROSHIMA UNIVERSITY |
|---|
Principal Investigator |
HIDE Izumi Hiroshima University, Fuculty of medicine, Academic Administrator, 医学部, 教務員 (20253073)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
NAKATA Yoshihiro Hiroshima University, Graduate School of Medical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (40133152)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Keywords | microglia / ATP / P2X7 receptors / TNF / nicotine / neuroprotection |
|---|
| Research Abstract |
Microglia are the primary immune cells in the central nervous system. After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis factor(TNF). The release of TNF appears to be dependent on the P2X_7 receptor. The inhibitors U0126,SP600125 and SB203580, which target MEK,JNK, and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did not prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X7 receptor blocker, and by genistein and PP-2, which are general and src-family-specific tyrosine kinase inhibitors, respectively. Most important, the treatment of the microglia in neurone-microglia cocultures with the P2X_7 agonist BzATP led to significant resuction in glutamate-induced neuronal cell death, and that either TNF-α converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Recombinant TNF itself showed a significant neuroprotective effects. On the other hand, LPS caused massive TNF release, but did not exert any protective effects on glutamate neurotoxity. Furthermore we investigated whether microglia could exert this protective action in vivo [by collaboration with Dr.Taniguchi and Dr.Kitamura, Kyoto Pharmaceutical University]. The intracerebroventricular injection of microglia into ischemic model rats protected against focal ischemia-induced neurodegeneration, and BzATP pretreatment showed a tendency to strengthen such effects. Therefore, modulation of P2X_7 receptors of microglia might be amenable to therapeutic intervention for neurodegeneration.
|
