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. (16th April 2015)

• Record Type: Journal Article
• Authors: Martins, A.H.; Hu, J.; Xu, Z.; Mu, C.; Alvarez, P.; Ford, B.D.; El Sayed, K.; Eterovic, V.A.; Ferchmin, P.A.; Hao, J.
• Is Part Of: Neuroscience. Volume 291(2015)
• Page Start: 250
• Page End: 259
• Publication Date: 2015-04-16
• Subjects: 4R (1S, 2E, 4R, 6R, -7E, 11E)-2, 7, 11-cembratriene-4, 6-diol -- ACSF artificial cerebrospinal fluid -- BBB blood–brain barrier -- bEND5 murine brain-derived endothelial -- CBF cerebral blood flow -- CREB cAMP-responsive element binding protein -- F fluorescence -- ICAM-1 intercellular adhesion molecule-1 -- OGD oxygen–glucose deprivation -- OGD/R OGD/reoxygenation -- pAkt phosphorylated Akt -- PBS phosphate-buffered solution -- PI propidium iodide -- PI3K phosphatidylinositol 3-kinase -- pMCAO permanent middle cerebral artery occlusion -- PRAS proline-rich Akt substrate -- PSs population spikes -- tMCAO transient MCAO -- TTC 2, 3, 5-triphenyltetrazolium chloride -- VCAM-1 vascular cell adhesion molecule; 4R cembranoid -- oxygen–glucose deprivation -- inflammation -- intercellular adhesion molecule-1 -- ischemia -- neuroprotection; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.02.001
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: 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. Abstract: (1 S, 2 E, 4 R, 6 R, -7 E, 11 E )-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 mm 3 ) than those in control groups (untreated: 63.4 ± 4.2 mm 3, DMSO: 60.2 ± 14.2 mm 3 ). The 4R-posttreated rats also had less infarct volumes (120 ± 65 mm 3 ) than those in the rats of the DMSO group (291 ± 95 mm 3 ). 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.