2-(1-Hydroxypentyl)-benzoate Increases Cerebral Blood Flow and Reduces Infarct Volume in Rats Model of Transient Focal Cerebral Ischemia

Abstract

2-(1-Hydroxypentyl)-benzoate (dl-PHPB), a derivate of 3-n-butylphthalide (dl-NBP), is a novel drug candidate used for treatment of cerebral ischemia. The goal of the present study was to investigate the effects of dl-PHPB on infarct volume, neurological function, and cerebral blood flow (CBF) in transient focal cerebral ischemia. Therefore, an animal model of 2-h middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion was used. Rats received dl-PHPB (1.3, 3.9, or 12.9 mg/kg) intravenously 10 min after the onset of MCAO. Compared with the vehicle control group (37.4%), infarct volume in dl-PHPBtreated groups was reduced significantly and dose-dependently to 25.4, 17.4, and 13.7%, respectively. The changes in neurological deficient were also observed in neurobehavioral test in a dose-dependent manner, and the neuronal score was improved significantly from the vehicle control of 3.2 to 2.7, 2.1, and 1.8, respectively. At the highest dose, the potency of dl-PHPB was similar to those of dl-NBP. CBF was quantified by using laser-Doppler flowmetry. During the ischemia, the regional CBF values of dl-PHPB groups were significantly higher than that of vehicle group. In addition, our study showed that dl-PHPB converted into dl-NBP very quickly in blood in vitro. Approximately 70% of dl-PHPB converted into dl-NBP in 5 min when dl-PHPB was added into plasma at final concentrations of 6, 30, and 60 g/ml. This result demonstrated that the neuronal protection effects of dl-PHPB were mainly induced by dl-NBP, an active compound converted from its precursor, dl-PHPB. In conclusion, dl-PHPB can reduce infarct volume and improve neurobehavioral deficits in a rat model of transient MCAO. Those effects may partially be due to an increase in CBF by the active metabolite (dl-NBP) of dl-PHPB. Therefore, our results suggest that dl-PHPB may be useful for treatment of ischemia stroke.

3-N-Butylphthalide (NBP) Attenuates the Amyloid-�-Induced Inflammatory Responses in Cultured Astrocytes via the Nuclear Factor-κB Signaling Pathway

“…NBP exhibits protective effects against focal cerebral ischemia in animal models through the prevention of mitochondrial damage, the inhibition of neuronal apoptosis, the improvement of cerebral blood flow, and the reduction of infarct volume [21,22,23]. Our previous studies demonstrated that NBP could significantly inhibit caspase-3-mediated apoptosis after cerebral ischemia in diabetic rats [24]; and NBP administration could attenuate stroke-induced neuron loss and activation of astrocytes in diabetic rats [25].…”

Changes in Gene Expression in the Rat Hippocampus after Focal Cerebral Ischemia

“…The parietal cortical perfusion in the territory of MCA was measured. The laser Doppler probe was connected to a BLF21D laser Doppler flowmeter (Transonic systems Inc., Ithaca, NY, USA), and the values were obtained from 10 min before the ischemic event until 15 min after reperfusion 28) . The changes in rCBF are expressed as the percentage of the baseline values.…”

Synergistic effects of prostaglandin E1 and lithium in a rat model of cerebral ischemia1

“…Five minutes after the pMCAO operation, the probe was inserted again to monitor rCBF, showing a sharp drop of rCBF (approximately 5%-10% of the pre-ischemia value). Then the rCBF was measured again 15, 30 and 60 min after surgical operation [15] . Evaluation of infarct volume, brain water content and neurological deficit Twenty-four hours after ischemia, the neurological deficits in rats subjected to pMCAO were evaluated using a protocol previously described in a blinded manner [16] .…”