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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

Cerebral infarct and edema volumes.Infarct volumes taken 24 h post-transient middle cerebral artery occlusion in (A) total infarct and (B) edema volumes (vehicle, n = 12; AVE0991, n = 12; AVE0991+A779, n = 12). Data are presented as mean ± S.E.M.
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pone.0142087.g004: Cerebral infarct and edema volumes.Infarct volumes taken 24 h post-transient middle cerebral artery occlusion in (A) total infarct and (B) edema volumes (vehicle, n = 12; AVE0991, n = 12; AVE0991+A779, n = 12). Data are presented as mean ± S.E.M.

Mentions: Mice treated with AVE0991 exhibited similar levels of neurological impairment to vehicle-treated mice after cerebral ischemia (Fig 2B; median neurological deficit score: veh, 2.5 vs AVE0991, 3; n = 12). In the hanging wire test, there was no apparent effect of AVE0991 treatment (Fig 2C; n = 12). Locomotor activity data indicated a trend for greater impairment in AVE0991-treated mice after stroke with total distance travelled and total time mobile both reduced by >50% compared with vehicle-treated mice, although these differences did not reach statistical significance (Fig 3A and 3B; n = 11–12). The average speed of the animals while mobile was similar in all 3 groups (Fig 3C; n = 11–12). In addition, mice treated with AVE0991 made similar numbers of foot slips compared to vehicle-treated mice, when corrected for the distance travelled (Fig 3D; n = 11–12). A779 treatment in combination with AVE0991 had no significant effect on any of the functional outcome measures (Figs 2B, 3A and 3B). Consistent with these behavioural/functional data, infarct and edema volumes were also similar in all three groups (Fig 4A and 4B; all n = 12). An intermediate dose of AVE0991 (10 mg/kg) also did not affect stroke outcome (S2, S3 and S4 Figs).


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)

Cerebral infarct and edema volumes.Infarct volumes taken 24 h post-transient middle cerebral artery occlusion in (A) total infarct and (B) edema volumes (vehicle, n = 12; AVE0991, n = 12; AVE0991+A779, n = 12). Data are presented as mean ± S.E.M.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0142087.g004: Cerebral infarct and edema volumes.Infarct volumes taken 24 h post-transient middle cerebral artery occlusion in (A) total infarct and (B) edema volumes (vehicle, n = 12; AVE0991, n = 12; AVE0991+A779, n = 12). Data are presented as mean ± S.E.M.
Mentions: Mice treated with AVE0991 exhibited similar levels of neurological impairment to vehicle-treated mice after cerebral ischemia (Fig 2B; median neurological deficit score: veh, 2.5 vs AVE0991, 3; n = 12). In the hanging wire test, there was no apparent effect of AVE0991 treatment (Fig 2C; n = 12). Locomotor activity data indicated a trend for greater impairment in AVE0991-treated mice after stroke with total distance travelled and total time mobile both reduced by >50% compared with vehicle-treated mice, although these differences did not reach statistical significance (Fig 3A and 3B; n = 11–12). The average speed of the animals while mobile was similar in all 3 groups (Fig 3C; n = 11–12). In addition, mice treated with AVE0991 made similar numbers of foot slips compared to vehicle-treated mice, when corrected for the distance travelled (Fig 3D; n = 11–12). A779 treatment in combination with AVE0991 had no significant effect on any of the functional outcome measures (Figs 2B, 3A and 3B). Consistent with these behavioural/functional data, infarct and edema volumes were also similar in all three groups (Fig 4A and 4B; all n = 12). An intermediate dose of AVE0991 (10 mg/kg) also did not affect stroke outcome (S2, S3 and S4 Figs).

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