Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats

Neuroprotection afforded by antagonists of endothelin-1 receptors in experimental stroke

“…Nevertheless, we now reported a neuroprotective effect of ETR B antagonists (BQ-788) in combination with Clazosentan Ò (antagonists of receptor A of ET-1). In this regard, our results seem contradictory to those reporting that ETR B agonists reduce neurological damage following permanent middle cerebral artery occlusion in rats (Leonard et al, 2011). In fact, our results indicated that effects observed on BQ-788 group were not significantly different from controls.…”

“…Moreover, ETR A antagonists showed a protective effect on brain edema and injury after transient middle cerebral artery occlusion in rats (Matsuo et al, 2001;Dawson et al, 1999). It has been also reported in animal models of cerebral ischemia that the administration of antagonists or agonists for ETR B induces worsening of brain injury (Chuquet et al, 2002;Leonard et al, 2011). However, TAK-044, an ETR A /ETR B receptor antagonist, also showed neuroprotective effects in an animal model of cerebral ischemia (Gupta et al, 2005).…”

Stimulation of endothelin B receptors by IRL-1620 decreases the progression of Alzheimer’s disease

“…Complete deficiency or blockade of ET B receptors leads to exacerbation of ischemic brain damage (Ehrenreich et al, 1999;Chuquet et al, 2002). We have demonstrated that activation of ET B receptors with intravenous IRL-1620, a highly selective ET B agonist, results in a significant elevation in cerebral blood flow in normal rats and reduction in neurological deficit and infarct volume of stroked rats (Leonard and Gulati, 2009;Leonard et al, 2011). It was further found that the efficacy of IRL-1620 in a rat model of stroke was completely antagonized by BQ788 indicating involvement of ET B receptors (Leonard et al, 2011(Leonard et al, , 2012.…”

“…Previous studies in our lab have shown that intravenous (i.v.) administration of IRL-1620 provides neuroprotection and enhances neurovascular recovery following cerebral ischemia (Leonard et al, 2011(Leonard et al, , 2012Leonard and Gulati, 2013). In the current study, we examined the effect of selective stimulation of ET B receptors via intravenous administration of IRL-1620 on memory deficit following Ab injection.…”

Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism

“…ET-1 and its downstream effects are frequent targets of treatment for neurological diseases (Chang et al, 2004;Leonard et al, 2011;Wengenmayer et al, 2011). As such, the molecular mechanisms following ET-1 exposure in the brain are of great interest in developing strategies to address its specific consequences.…”