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

- Treatment with 4R reduces infarct volume in rodent ischemic stroke models.
- 4R decreases apoptosis of neuroblastoma cells induced by OGD.
- 4R improves the population spikes recovery in rat acute hippocampal slices in OGD.
- 4R inhibits ICAM-1 expression in murine brain-derived endothelial cells.
- 4R restores Akt phosphorylation in murine brain-derived endothelial cells in OGD.

(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.