Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain

Abstract

3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle + tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone (3 mg/kg, i.v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.

Effects of Edaravone on a Rat Model of Punch-Drunk Syndrome

“…On the other hand, experimental ischemia-reperfusion induced by temporary middle cerebral artery occlusion resulted in the production of the highly neurotoxic 4-HNE, thereby contributing to apoptosis, suggesting that, after severe ischemia-reperfusion, the effects of free radicals on the brain are marked. 20) Based on this report and another that the degree of brain damage by free radicals is determined by the amount of free radical production exceeding the existing antioxidant activity in vivo, 10) we speculate that the production of free radicals was very low in the present vibration experiment, as described above, and they caused minimal tissue injury.…”

Edaravone (Radicut), a free radical scavenger, is a potentially useful addition to thrombolytic therapy in patients with acute ischemic stroke

“…Certain research groups have reported that the administration of edaravone increased the survival rate, and inhibited alteplase-induced hemorrhagic transformation, blood-brain barrier damage and oxidative stress in the ischemic brains of rats, and hypothesized that edaravone may reduce the activity of matrix metalloproteinase-9 (MMP-9) (43)(44)(45)(46). In their study, Kano et al (47) reported that edaravone attenuated the extravasation of alteplase through the cerebral vessels in a rat model of AIS.…”

“…In their study, Kano et al (47) reported that edaravone attenuated the extravasation of alteplase through the cerebral vessels in a rat model of AIS. Combination treatment with edaravone is therefore expected to extend the TTW for the use of alteplase (46). Furthermore, Isahaya et al (48) reported that edaravone treatment was associated with lower MMP-9 serum levels in patients with AIS.…”

Therapeutic time window of YGY-E neuroprotection of cerebral ischemic injury in rats

“…Only tPA is approved by the US Food and Drug Administration (FDA) for intravenous delivery within 3 h of symptom onset in treating ischemic stroke (6). However, only a small portion of ischemic stroke patients receive effective thrombolytic therapy due to the narrow therapeutic time window and the threat of hemorrhage (7). The earlier the intervention involvement, the more benefit the patient receives.…”