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Effect of a Selective Mas Receptor Agonist in Cerebral Ischemia In Vitro and In Vivo.

Lee S, Evans MA, Chu HX, Kim HA, Widdop RE, Drummond GR, Sobey CG - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.

ABSTRACT
Functional modulation of the non-AT1R arm of the renin-angiotensin system, such as via AT2R activation, is known to improve stroke outcome. However, the relevance of the Mas receptor, which along with the AT2R forms the protective arm of the renin-angiotensin system, as a target in stroke is unclear. Here we tested the efficacy of a selective MasR agonist, AVE0991, in in vitro and in vivo models of ischemic stroke. 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.

No MeSH data available.


Related in: MedlinePlus

The effect of AVE0991 on neuronal cell death following glucose deprivation.Data are shown for cells exposed to normal conditions (control) or glucose deprivation (vehicle) for 24 h or with (A) AVE0991 or (B) AVE0991+A779. Data are presented as mean ± S.E.M (*P<0.05, **P<0.01 vs. vehicle; n = 6).
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pone.0142087.g001: The effect of AVE0991 on neuronal cell death following glucose deprivation.Data are shown for cells exposed to normal conditions (control) or glucose deprivation (vehicle) for 24 h or with (A) AVE0991 or (B) AVE0991+A779. Data are presented as mean ± S.E.M (*P<0.05, **P<0.01 vs. vehicle; n = 6).

Mentions: To investigate whether MasR stimulation may be neuroprotective, cultured primary cortical neurons were exposed to glucose deprivation for 24 h in the presence of the classical MasR agonist, AVE0991. When cells were deprived of glucose for 24 h, there was ~30% cell death, compared to ~8% death in control cells (Fig 1). Treatment with AVE0991 resulted in reduced neuronal death during glucose deprivation, and at 1x10-7 M reached near-complete protection of neurons in comparison to control cells (Fig 1A; P<0.01). Likewise, when AVE0991 (1x10-7 M) was applied 1 h after the onset of GD the protection was maintained, whereas the protective effect was lost if application occurred at later time points (i.e., 4 h and 8 h after GD) (S1 Fig). Moreover, neuroprotection was prevented when cells were co-incubated with AVE0991 and the MasR antagonist, A779 (Fig 1B). Note, A779 had no effect on neuronal cell death when administered to glucose-deprived cells alone.


Effect of a Selective Mas Receptor Agonist in Cerebral Ischemia In Vitro and In Vivo.

Lee S, Evans MA, Chu HX, Kim HA, Widdop RE, Drummond GR, Sobey CG - PLoS ONE (2015)

The effect of AVE0991 on neuronal cell death following glucose deprivation.Data are shown for cells exposed to normal conditions (control) or glucose deprivation (vehicle) for 24 h or with (A) AVE0991 or (B) AVE0991+A779. Data are presented as mean ± S.E.M (*P<0.05, **P<0.01 vs. vehicle; n = 6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4634944&req=5

pone.0142087.g001: The effect of AVE0991 on neuronal cell death following glucose deprivation.Data are shown for cells exposed to normal conditions (control) or glucose deprivation (vehicle) for 24 h or with (A) AVE0991 or (B) AVE0991+A779. Data are presented as mean ± S.E.M (*P<0.05, **P<0.01 vs. vehicle; n = 6).
Mentions: To investigate whether MasR stimulation may be neuroprotective, cultured primary cortical neurons were exposed to glucose deprivation for 24 h in the presence of the classical MasR agonist, AVE0991. When cells were deprived of glucose for 24 h, there was ~30% cell death, compared to ~8% death in control cells (Fig 1). Treatment with AVE0991 resulted in reduced neuronal death during glucose deprivation, and at 1x10-7 M reached near-complete protection of neurons in comparison to control cells (Fig 1A; P<0.01). Likewise, when AVE0991 (1x10-7 M) was applied 1 h after the onset of GD the protection was maintained, whereas the protective effect was lost if application occurred at later time points (i.e., 4 h and 8 h after GD) (S1 Fig). Moreover, neuroprotection was prevented when cells were co-incubated with AVE0991 and the MasR antagonist, A779 (Fig 1B). Note, A779 had no effect on neuronal cell death when administered to glucose-deprived cells alone.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.

ABSTRACT
Functional modulation of the non-AT1R arm of the renin-angiotensin system, such as via AT2R activation, is known to improve stroke outcome. However, the relevance of the Mas receptor, which along with the AT2R forms the protective arm of the renin-angiotensin system, as a target in stroke is unclear. Here we tested the efficacy of a selective MasR agonist, AVE0991, in in vitro and in vivo models of ischemic stroke. 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.

No MeSH data available.


Related in: MedlinePlus