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.