title: (S)-ZJM-289, a nitric oxide-releasing derivative of 3-n-butylphthalide, protects against ischemic neuronal injury by attenuating mitochondrial dysfunction and associated cell death.
abstract: Pharmacological compounds that release nitric oxide (NO) have been recognized as the potential therapeutic agents for acute stroke. (S)-ZJM-289 is a novel NO-releasing derivative of 3-n-butylphthalide (NBP) with enhanced anti-platelet and anti-thrombotic actions. The present study was performed to investigate the neuroprotective effects and related mechanisms of (S)-ZJM-289 on ischemic neuronal injury in vitro and in vivo. Primary cortical neuronal cultures were exposured to oxygen-glucose deprivation followed by recovery (OGD/R), a model of ischemia-like injury, and treated with (S)-ZJM-289 before OGD. In vitro results showed that (S)-ZJM-289 attenuated OGD/R-induced neuronal injury, which was associated with the maintenance of mitochondrial integrity and function by alleviating intracellular calcium overload and reactive oxygen species (ROS) accumulation, preventing mitochondrial membrane depolarization and preserving respiratory chain complexes activities. Moreover, (S)-ZJM-289 treatment suppressed mitochondrial release of cytochrome c (cyt c) and nuclear translocation of apoptosis-inducing factor (AIF), thereby blocking mitochondria-mediated cell death, which may be partially mediated by up-regulation of Hsp70. The neuroprotection by (S)-ZJM-289 was also studied using a model of middle cerebral artery occlusion (MCAO). Oral administration of (S)-ZJM-289 at the onset of reperfusion for 3d significantly reduced the brain infarct size, improved neurological deficit and prevented neuronal loss and apoptosis. In current study, (S)-ZJM-289 appears to be more potent in ischemic neuroprotection than NBP, in particular at the lower doses, which may be due to the synergistic action of NBP and NO. These findings point to that (S)-ZJM-289 could be an attractive alternative to NBP in preventing the process of ischemia/reperfusion (I/R) injury.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Xuliang
authors.initials: X
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002934:Cinnamates / Q000138:chemical synthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D028361:Mitochondrial Diseases / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D009566:Nitrates / Q000138:chemical synthesis / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
chemical_list: C554089:(2-(1-diethylaminoacetoxy)pentyl)benzoic acid (2-methoxy-4-(2-(4-nitrooxybutoxycarbonyl)vinyl))phenyl ester; D001572:Benzofurans; D002934:Cinnamates; D018696:Neuroprotective Agents; D009566:Nitrates; C027125:3-n-butylphthalide