title: 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-PHPB-treated 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 mug/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.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
mesh_terms: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000517:prevention & control*; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010420:Pentanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C511222:2-(1-hydroxypentyl)-benzoate; D001565:Benzoates; D001572:Benzofurans; D018696:Neuroprotective Agents; D010420:Pentanes; D011355:Prodrugs; C027125:3-n-butylphthalide