MCI‐186 prevents brain tissue from neuronal damage in cerebral infarction through the activation of intracellular signaling

Abstract

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.

The Novel Free Radical Scavenger, Edaravone, Increases Neural Stem Cell Number Around the Area of Damage Following Rat Traumatic Brain Injury

“…Meanwhile, a recent study demonstrated that phosphatidylinositol 3-kinase (PI3K), a component of the PI3K-Akt pathway activated by free radicals, inhibited apoptotic cell death in cultured rat NSCs (Lin et al 2004). Edaravone activated and increased PI3K-Akt signaling significantly, and inhibited neuronal cell death induced by brain injury (Niyaz et al 2007). Furthermore, edaravone protected cultured human NSCs from apoptotic cell death induced by radiation-induced free radicals (Ishii et al 2007).…”

“…Therefore, edaravone inhibits neural and glial cell degeneration and death in the cortex and hippocampus mediated by free radicals produced during ischemia (Yasuoka et al 2004). It has been reported that edaravone significantly inhibits JNK(c-Jun N-terminal kinase) (Wen et al 2006) and p38 (Niyaz et al 2007) activation after brain insult, and blocks induced free radical-mediated neural cell degeneration and death after brain injury. The present results suggested that edaravone absorbed free radicals generated by TBI and/or inhibited their function, thereby preventing free radical-mediated apoptosis and cell death subsequent to TBI.…”

Protective effects of MCI-186 on transplantation of bone marrow stromal cells in rat ischemic stroke model

“…MCI-186, a strong free radical scavenger, was reported to protect dopaminergic neurons (Yuan et al, 2008), hippocampal cells (Wu et al, 2006) and islet cells (Rao et al, 2005) from injury in cultured cell systems. In addition, its ability to attenuate ischemia-reperfusion (I/R) injury to the brain was highlighted in a number of reports (Amemiya et al, 2005;Niyaz et al, 2007;Kikuchi et al, 2009). However, there are no reports to evaluate whether MCI-186 can produce additional functional improvement when combined with BMSCs transplantation in ischemic stroke models.…”

Edaravone Protects Against Apoptotic Neuronal Cell Death and Improves Cerebral Function After Traumatic Brain Injury in Rats

“…Furthermore, c-Jun N-terminal kinase (JNK) activation is involved in free radical-mediated apoptotic cell death [31], and a spintrapped a-butylnitrone was shown to protect the hippocampal CA1 region after induction of global ischemia in the gerbil, a protective effect associated with the inhibition of JNK and p38 activity [31]. Edaravone can inhibit JNK [32] and p38 [33] activation and block free radical-mediated apoptotic neural cell degeneration and death after brain injury. Thus, in the present study, it is likely that edaravone absorbed free radicals generated by TBI and/or inhibited their function, thereby preventing free radical-mediated apoptotic neural and glial cell degeneration and death following TBI.…”