MCI-186 prevents brain tissue from neuronal damage in cerebral infarction through the activation of intracellular signaling.
The mechanism by which MCI-186 (3-methyl-1-phenyl-2-prazolin-5-one) exerts protective effects during cerebral infarction, other than its function as a radical scavenger, has not been fully elucidated. Here, we found that MCI-186 stimulates intracellular survival signaling in vivo and in vitro. In a rat infarction model, the infarct area was significantly smaller and the degree of edema was reduced in MCI-186-treated animals. In the MCI-186-treated rats, the number of single stranded (ss) DNA-positive damaged cells in the peri-infarct area was decreased compared with the control, suggesting that MCI-186 protects cerebral tissues from cell damage. To clarify the mechanisms underlying the effect of MCI-186, we also examined the survival-promoting effect of this agent on cultured cortical neurons. In this in vitro system, MCI-186 blocked serum-free induced neuronal cell death. Interestingly, an increase in the activation of both Akt (a component of the PI3 kinase pathway) and ERK (a component of the MAP kinase pathway) was observed in the cortical cultures after MCI-186 exposure. Furthermore, the MCI-186-dependent survival effect in vitro was blocked by U0126, an MEK (an upstream of ERK) inhibitor, and also by LY294002, a PI3 kinase inhibitor. We also observed similar increases in the activation of Akt and ERK in the in vivo model, further suggesting that the antiapoptotic role of MCI-186 is mediated via the PI3 kinase and MAP kinase signaling pathways. We therefore conclude that, in addition to its role as a free radical scavenger, MCI-186 functions as an antiapoptotic factor by enhancing intracellular survival signaling.
Niyaz
Madinyet
M
Department of Pathology, Tokyo Medical University, Tokyo, Japan.
Numakawa
Tadahiro
T
Matsuki
Yoshinori
Y
Kumamaru
Emi
E
Adachi
Naoki
N
Kitazawa
Hiromi
H
Kunugi
Hiroshi
H
Kudo
Motoshige
M
D000818:Animals; D000831:Animals, Newborn; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology*; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000077553:Edaravone; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009025:Morpholines; D009419:Nerve Tissue Proteins; D009570:Nitriles; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D000077553:Edaravone; D000983:Antipyrine