Edaravone neuroprotection effected by suppressing the gene expression of the Fas signal pathway following transient focal ischemia in rats

Abstract

Preclinical and clinical studies have demonstrated that a free radical scavenger edaravone has neuroprotective effects on ischemic stroke but the underlying mechanism is not fully understood. The aim of this research is to explore the effect of edaravone on the apoptotic process involving the Fas/FasL signaling pathway. Transient focal ischemia in rats was induced for 2 hours by middle cerebral artery occlusion (MCAO). After reperfusion rats were treated i.v. with either edaravone or physiological saline. The expression of Fas-associated death domain protein (FADD), death-associated protein (Daxx) and caspase-8 was examined by immunohistochemistry. The mRNA levels for FADD and Daxx by reverse-transcriptase PCR (RT-PCR) and apoptosis was assessed by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL). Neurological scores and infarction volumes were also evaluated. Edaravone significantly improved the neurological outcome (p<0.05) and reduced the total infarct volumes (p<0.05), compared with saline control. In addition, edaravone-treatment significantly reduced the number of TUNEL-positive cells (p<0.01), reduced expression levels of FADD, Daxx and caspase-8 immunoreactivity (p <0.05 approximately 0.01), and decreased mRNA levels of FADD and Daxx (p<0.05 approximately 0.01) within the peri-infarct area. We conclude that edaravone may protect ischemic neurons from apoptosis via suppressing the gene expression of the Fas/FasL signaling pathway.

The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke

“…Similar outcomes have been reported for two other metalloporphyrins, with one of them AEOL 1050 reducing the infarction volumes by 43% when delivered with the delay of 7.5 h post initiation of ischemia [89]. Compared to tempol, edaravone was tested more extensively, and showed strong neuroprotective properties at the dosages of 3–10 mg/kg and with the therapeutic window of up to 6 h (see for example [90–92]). However, in clinical settings and in the majority of animal studies edaravone treatments involved multiple administrations, unlike what has been done by us.…”

Edaravone (MCI-186), a free radical scavenger, attenuates retinal ischemiareperfusion injury in rats1

“…Edaravone can interact with both peroxyl and hydroxyl radicals, producing a stable oxidation product (OPB, 2-oxo-3-[phenylhydrazono]-butanoic acid) [22] . Edaravone has previously been reported to protect organs, such as the brain [17,18] , heart [23,24] , kidney [25] , and liver [26,27] from free radical-mediated injury. However, the direct scavenging property of edaravone in retinal I/R injury in rats remains to be explored.…”

“…In vitro and in vivo studies have also shown that edaravone could effectively inhibit I/R-induced apoptosis [15,16] . Edaravone was also suggested to have neuroprotective effects on transient forebrain or focal ischemia in rodent models [17,18] . However, up to now, there are not many studies on the effect of edaravone against retinal neuronal damage caused by I/R.…”

Methodological study investigating long term laser Doppler measured cerebral blood flow changes in a permanently occluded rat stroke model

“…A modified intraluminal permanent occlusion stroke model adapted from the methods of Longa et al (1989), Newcomb et al (2006), Xiao et al (2007) and Rivera et al (2008) was used. Briefly, animals were anesthetized with isoflurane and CBF was monitored by laser Doppler (Moorlab, Moor Instruments Inc) via burr holes drilled at coordinates: Ant −1 mm, Lat 4 mm, corresponding to the right striatum and Ant 1 mm, Lat 4 mm; the equivalent on the left contralateral side.…”