In vivo neuroprotective effect of labdane diterpenes in a translational stroke model.


Stroke remains a major health problem worldwide, and is the leading cause of long-lasting disability in humans. However, currently there are still no effective treatments available. This is the motivation that has led us to study the in vivo neuroprotective effect of the labdane diterpene dehydroisohispanolone (DT1) in a translational stroke model.

A physiological model of ischemic stroke induced by endovascular occlusion of the middle cerebral artery (MCAo) was used to analyze the infarct size and signaling pathways by magnetic resonance imaging (MRI), 2,3,5-triphenyltetrazolium chloride (TTC) staining and immunohistochemistry. We have demonstrated that DT1 is able to cross the blood-brain barrier (BBB), thus becoming a potential therapeutic agent for ischemic stroke. Regarding the signaling pathways triggered by the compound, after DT1 treatment there is an increased expression of p-Akt and, at the same time, there are lower caspase-3 levels. Therefore, the mechanism of action of DT1 seems to involve the activation of specific survival signals (PI3K/Akt) and inhibition of death pathways, such as apoptosis. Cell population changes were also observed. After DT1 treatment lower levels of SOX-2, a neural stem cell (NSC) marker, were found, suggesting that some NSCs start the differentiation to repair the damage from stroke. By other side, there is a large increase in the formation of new blood vessels due to angiogenesis is one of the neurorepair mechanisms after stroke.

The main advantage is that studies have been performed on an in vivo translational model so it would have a huge impact on clinical since it would allow to find an effective treatment for a disorder that now has no cure.

L Martos Blasco
MV Gómez-Gaviro
Universidad Autónoma de Madrid