Involvement of Central Endothelin B Receptors in Focal Cerebral Ischemia

Endothelin has been implicated in numerous aspects of ischemic stroke, with a majority of studies focusing on the involvement of endothelin A receptors. Despite the high concentration of endothelin B receptors in the central nervous system, no study has been performed to determine the involvement of these receptors in ischemic stroke. The purpose of the current study was to determine the involvement of central endothelin B receptors using highly selective agonist, IRL-1620 and antagonist, BQ788 in a permanent model of middle cerebral artery occlusion in rats. Animals were assessed for neurological and motor function deficit, infarct volume, oxidative stress, and changes in neurons, astrocytes and vascular endothelial cells following the acute (24 hours) and sub-acute (1 week) phases of cerebral ischemia. Whereas animals subjected to cerebral ischemia displayed a marked decrease in motor function, animals treated with IRL-1620 demonstrated significant improvement in these parameters for up to one week following cerebral ischemia. Moreover, animals treated with IRL-1620 presented with a significant reduction in infarct volume at 24 hours and 1 week following ischemia as compared to the vehicle-treated group (24.27 ± 4.37 mm3 and 54.06 ± 14.12 mm3 versus 153.23 ± 32.18 mm3 and 177.06 ± 13.21 mm3, respectively). It was also found that animals treated with IRL-1620 showed a reduction in oxidative stress, as measured by levels of malondialdehyde, superoxide dismutase and reduced glutathione, as compared to vehicle-treated animals, indicating that endothelin B receptors are involved in neuroprotective effects following cerebral ischemia. Additionally, animals receiving treatment with IRL-1620 demonstrated an increase in numbers of neurons and new blood vessels as well as heightened levels of proliferating cells and nerve growth factor at 1 week following infarct, indicating endothelin B receptors may be involved in neurovascular repair and remodeling processes. All effects of IRL-1620 were blocked by pretreatment with BQ788, confirming the role of endothelin B receptors in neurovascular remodeling. The present study demonstrates that endothelin B receptors are involved in the neuroprotective and neurovascular repair stages of cerebral ischemia, and points to selective endothelin B receptor stimulation as a novel therapeutic target in the treatment of focal cerebral ischemia.