(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: Chao Zhang, Zhenzhen Zhang, Qian Zhao, Xuliang Wang, Hui Ji, Yihua Zhang
• Journal: Neurotoxicity research (Neurotox Res) Vol. 26 Issue 1 Pg. 16-31 (Jul 2014) ISSN: 1476-3524 [Electronic] United States
• PMID: 24277159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (2-(1-diethylaminoacetoxy)pentyl)benzoic acid (2-methoxy-4-(2-(4-nitrooxybutoxycarbonyl)vinyl))phenyl ester
• Cinnamates
• Flavonoids
• Neuroprotective Agents
• Nitrates
• Protein Kinase Inhibitors
• Nitric Oxide
• Nitric Oxide Synthase
• Glucose
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Brain (drug effects, physiopathology)
• Cells, Cultured
• Cinnamates (chemistry, pharmacology)
• Flavonoids (pharmacology)
• Glucose (deficiency)
• Hypoxia-Ischemia, Brain (drug therapy, physiopathology)
• Infarction, Middle Cerebral Artery (drug therapy, physiopathology)
• Ischemic Attack, Transient (drug therapy, physiopathology)
• MAP Kinase Signaling System (drug effects)
• Male
• Mitochondria (drug effects, physiology)
• Neurons (drug effects, physiology)
• Neuroprotective Agents (chemistry, pharmacology)
• Nitrates (chemistry, pharmacology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rats, Sprague-Dawley