title: (S)-ZJM-289 preconditioning induces a late phase protection against nervous injury induced by transient cerebral ischemia and oxygen-glucose deprivation.
abstract: (S)-ZJM-289, a novel nitric oxide (NO)-releasing derivative of 3-n-butylphthalide, induces the neuroprotection in a rat model of focal cerebral ischemia/reperfusion (I/R). However, much is unknown about the late phase effect in the neuroprotection of (S)-ZJM-289 preconditioning. The purpose of this study is to explore the late phase neuroprotection of (S)-ZJM-289 preconditioning, as well as underlying mechanisms involved. Preconditioning with 40-160 mg/kg, (S)-ZJM-289 significantly reduces brain damage after I/R. (S)-ZJM-289 preconditioning is effective when applied 1-3 days before I/R. Moreover, the degrees of neuroprotection offered by (S)-ZJM-289 preconditioning and ischemic preconditioning are virtually identical. (S)-ZJM-289 preconditioning also protects primary cultured cortical neurons against oxygen-glucose deprivation and recovery-induced cytotoxicity in vitro. (S)-ZJM-289 preconditioning significantly increases the generation of NO, but has no effect on the nitric oxide synthase activities. Additionally, (S)-ZJM-289 preconditioning promotes the dissociation between nuclear-factor-E2-related factor (Nrf2) and kelch-like ECH-associated protein 1, and induces Nrf2 nuclear localization. The neuroprotection of (S)-ZJM-289 preconditioning is blocked by Nrf2-siRNA in vitro. (S)-ZJM-289 preconditioning up-regulates antioxidant enzymes against nervous injury. (S)-ZJM-289 preconditioning significantly activates extracellular regulated protein kinases (ERK) and inhibits c-Jun N-terminal kinases signaling cascade. The neuroprotection is abolished by the ERK inhibitor PD98059 in vitro. Subsequently, (S)-ZJM-289 preconditioning increases the levels of anti-apoptotic protein B cell lymphoma 2 (Bcl-2) and inhibited the translocation of Bcl-2 associated X to the mitochondria, thus attenuating the release of cytochrome c from the mitochondria and the activation of downstream caspase. These results suggest that (S)-ZJM-289 preconditioning exerts the late phase protection against nervous injury induced by transient cerebral ischemia and oxygen-glucose deprivation.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Xuliang
authors.initials: X
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002478:Cells, Cultured; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009566:Nitrates / Q000737:chemistry / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley
chemical_list: C554089:(2-(1-diethylaminoacetoxy)pentyl)benzoic acid (2-methoxy-4-(2-(4-nitrooxybutoxycarbonyl)vinyl))phenyl ester; D002934:Cinnamates; D005419:Flavonoids; D018696:Neuroprotective Agents; D009566:Nitrates; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one