Neuroprotective therapy for ischemic stroke
| Reference number | |
| Coordinator | GLUCOX BIOTECH AB |
| Funding from Vinnova | SEK 3 627 267 |
| Project duration | November 2013 - October 2016 |
| Status | Completed |
Purpose and goal
NADPH oxidas 4 (Nox4)-activity is part of normal physiological regulation of metabolic processes and is upregulated at need. Increased levels to high nonphysiological concentrations will instead be harmful as is the case when cerebral blood flow is restored at the treatment of ischemic stroke. A Nox4-inhibitor with a back-up has been developed in collaboration with UM to attenuate brain damage in stroke models with the goal to develop a human pharmaceutical to protect the brain.
Expected results and effects
GLX7013114 and GLX7013107 have been developed with the highest selectivity to Nox4 inhibition in relation to other Nox-isoforms. These inhibitors demonstrate neuroprotective effect in two different in vitro stroke models at UM:´Hippocampal Brain Slices´ (HBS) and ´Human Brain Micro vascular Endothelial Cells´ (HBMEC) that were subjected to oxygen and glucose deprivation. FTIA without adverse effects and PK results provided the foundation of on-going in vivo study in mice stroke models.
Planned approach and implementation
Selective inhibitors against Nox4 have been developed using membrane/whole-cell assays overexpressing Nox4. Initial ambition was to lower the IC50 to low microM levels to be efficient in vivo stroke models. Selected substances were then investigated of its selectivity towards other Nox-isoforms in cell bases assays and also towards Xanthine oxidase in enzyme based assay. Then pharmacologic evaluation of pre-CD + back-up before challenged in stroke models.