Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia

Neuroscience. 2015 Apr 16;291:250-259. doi: 10.1016/j.neuroscience.2015.02.001. Epub 2015 Feb 10.


(1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) is a precursor to key flavor ingredients in leaves of Nicotiana species. The present study shows 4R decreased brain damage in rodent ischemic stroke models. The 4R-pretreated mice had lower infarct volumes (26.2±9.7 mm3) than those in control groups (untreated: 63.4±4.2 mm3, DMSO: 60.2±14.2 mm3). The 4R-posttreated rats also had less infarct volumes (120±65 mm3) than those in the rats of the DMSO group (291±95 mm3). The results from in vitro experiments indicate that 4R decreased neuro2a cell (neuroblastoma cells) apoptosis induced by oxygen-glucose deprivation (OGD), and improved the population spikes' (PSs) recovery in rat acute hippocampal slices under OGD; a phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, abolished the effect of 4R on PSs recovery. Furthermore, 4R also inhibited monocyte adhesion to murine brain-derived endothelial (bEND5) cells and upregulation of intercellular adhesion molecule-1(ICAM-1) induced by OGD/reoxygenation (OGD/R), and restored the p-Akt level to pre-OGD/R values in bEND5 cells. In conclusion, the present study indicates that 4R has a protective effect in rodent ischemic stroke models. Inhibition of ICAM-1 expression and restoration of Akt phosphorylation are the possible mechanisms involved in cellular protection by 4R.

Keywords: 4R cembranoid; inflammation; intercellular adhesion molecule-1; ischemia; neuroprotection; oxygen–glucose deprivation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / pathology
  • Brain / physiopathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / physiology
  • Cell Line
  • Cell Line, Tumor
  • Disease Models, Animal
  • Diterpenes / pharmacology*
  • Female
  • Glucose / deficiency
  • Male
  • Mice
  • Neuroprotective Agents / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Stroke / drug therapy*
  • Stroke / pathology
  • Stroke / physiopathology


  • (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol
  • Diterpenes
  • Neuroprotective Agents
  • Glucose