(S)-ZJM-289 preconditioning induces a late phase protection against nervous injury induced by transient cerebral ischemia and oxygen-glucose deprivation

Neurotox Res. 2014 Jul;26(1):16-31. doi: 10.1007/s12640-013-9444-x. Epub 2013 Nov 26.


(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • (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