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AVE 0991

Lee et al. tested the efficacy of a selective MasR agonist, AVE0991, in in vitro and in vivo models of ischemic stroke.

AVE 0991 (AVE) was administered intranasally 1 h after SAH induction. A779, a selective inhibitor of Mas, and small interfering ribonucleic acid (siRNA) for UCP-2 were administered by intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Neurological tests, immunofluorescence, TUNEL, Fluoro-Jade C, DHE staining, and Western blot experiments were performed. We found that Mas activation with AVE significantly improved neurobehavioral scores and reduced oxidative stress and neuronal apoptosis in SAH+AVE group compared with SAH+vehicle group. Moreover, AVE treatment significantly promoted phosphorylation of CREB and the expression UCP-2, as well as upregulated expression of Bcl-2 and downregulation of Romo-1 and Bax. The protective effects of AVE were reversed by i.c.v injection of A779 and UCP-2 siRNA in SAH+AVE+A779 and SAH+AVE+UCP-2 siRNA groups, respectively. In conclusion, our data provides evidence that Mas activation with AVE reduces oxidative stress injury and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH. Furthermore, our study indicates that Mas may be a novel therapeutic treatment target in early brain injury of SAH 1).

Primary cortical neurons were cultured from E15-17 mouse embryos for 7-9 d, subjected to glucose deprivation for 24 h alone or with test drugs, and percentage cell death was determined using trypan blue exclusion assay. Additionally, adult male mice were subjected to 1 h middle cerebral artery occlusion and were administered either vehicle or AVE0991 (20 mg/kg i.p.) at the commencement of 23 h reperfusion. Some animals were also treated with the MasR antagonist, A779 (80 mg/kg i.p.) 1 h prior to surgery. Twenty-four h after MCAo, neurological deficits, locomotor activity and motor coordination were assessed in vivo, and infarct and edema volumes estimated from brain sections. Following glucose deprivation, application of AVE0991 (10-8 M to 10-6 M) reduced neuronal cell death by ~60% (P<0.05), an effect prevented by the MasR antagonist. By contrast, AVE0991 administration in vivo had no effect on functional or histological outcomes at 24 h following stroke. These findings indicate that the classical MasR agonist, AVE0991, can directly protect neurons from injury following glucose-deprivation. However, this effect does not translate into an improved outcome in vivo when administered systemically following stroke 2).

Mo J, Enkhjargal B, Travis ZD, Zhou K, Wu P, Zhang G, Zhu Q, Zhang T, Peng J, Xu W, Ocak U, Chen Y, Tang J, Zhang J, Zhang JH. AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats. Redox Biol. 2018 Sep 28;20:75-86. doi: 10.1016/j.redox.2018.09.022. [Epub ahead of print] PubMed PMID: 30296700.
Lee S, Evans MA, Chu HX, Kim HA, Widdop RE, Drummond GR, Sobey CG. Effect of a Selective Mas Receptor Agonist in Cerebral Ischemia In Vitro and In Vivo. PLoS One. 2015 Nov 5;10(11):e0142087. doi: 10.1371/journal.pone.0142087. eCollection 2015. PubMed PMID: 26540167; PubMed Central PMCID: PMC4634944.
ave_0991.txt · Last modified: 2018/10/09 22:06 by administrador