Abstract
The aim of the current study was to explore the protective effects of sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (brand name: brozopine, BZP) in a rat model of global cerebral ischemia. The rat model was established using a modified Winocur’s method; close postoperative observation was conducted at all times. Neurological function was detected through prehensile traction and beam-walking test. BZP reduced mortality and prolonged the survival time of rats with global cerebral ischemia, within 24 h. There was a decreased survival rate (60%) in the Model group, while the survival rate of the BZP (3 and 12 mg/kg) remarkably increased the survival rate (to 80 and 90%, respectively), in a dose-dependent manner. Compared with the Model group (survival time: 18.50 h), the administration of BZP (0.75, 3, and 12 mg/kg) prolonged the survival time (to 20.38, 21.85, and 23.90 h, respectively), particularly in BZP 12 mg/kg group (P < 0.05). Additionally, the BZP (12 mg/kg) group exhibited an improvement in their motor function (P < 0.05). The BZP groups (0.75, 3, and 12 mg/kg) displayed significantly reduced necrosis and the percentage of apoptotic cells (P < 0.05 and P < 0.01, respectively). Compared with Model group, BZP (0.75, 3, and 12 mg/kg) increased the NeuN optical density values (P < 0.01). Rats with global ischemia had a high expression of Cyt-c, caspase-3, and the Bax/Bcl-2 ratio compared with sham group (P < 0.01). BZP (0.75, 3, and 12 mg/kg), however, reduced the expression of Cyt-c, caspase-3, and the Bax/Bcl-2 ratio, in a dose-dependent manner (P < 0.01). There was low expression of p-Akt and PI3K in Model group, compared with the sham group (P < 0.01). Meanwhile, BZP (0.75, 3, and 12 mg/kg) increased the expression of p-Akt and PI3K in a dose-dependent manner (P < 0.01). We also found the expression of Cyt-c, caspase-3, Bax/Bcl-2 ratio, PI3K, p-Akt, and comprehensive score were directly related. In conclusion, BZP had therapeutic potential and prevented stroke in rat model of global cerebral ischemia. The underlying mechanisms may be related to the inhibition of apoptosis and activation of the survival-signaling-pathway.
Highlights
Sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP), which is derived from 1-3-n-butylphthalide (NBP), has a chemical structure that is similar to aspirin
Compared with the model group, the administration of sodium-5-bromo-2-(α-hydroxypentyl) benzoate (BZP) (0.75, 3, and 12 mg/kg) prolonged the survival time, in BZP 12 mg/kg group (P < 0.05). These results demonstrated that BZP increased the survival rate and prolonged the survival time in rats with global ischemia
BZP was distributed in tissue from both the normal and global cerebral ischemia brains, it was highly concentrated in the latter, where it was mostly metabolized into Br-NBP
Summary
Sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP), which is derived from 1-3-n-butylphthalide (NBP), has a chemical structure that is similar to aspirin. NBP was developed as an anti-cerebral ischemic agent in 2002, in China. It was widely used, with good clinic results, increasing reports of adverse reactions such as coagulopathy, gastrointestinal irritation, and liver dysfunction, led to its discontinuation. Our previous studies demonstrated that 3-butyl-6-bromo-1(3H)-isobenzofuranone (Br-NBP) had anti-hydrogen peroxide-induced damage in PC12 cells and anti-platelet aggregation effect in vitro or in vivo on rats (Gao et al, 2010; Ma et al, 2012). Based on our previous findings, BZP played a neuroprotective role against focal cerebral ischemia-reperfusion injury in rats, via anti-apoptosis and anti-inflammation mechanisms, and the promotion of synaptic plasticity (unpublished data). The preventive and therapeutic effects of BZP on a rat model of global ischemia injury have not yet been studied. We investigated the modulatory effects of BZP on rats following global ischemia injury
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