Angiotensin-(1–7) (Ang-[1–7]), a biologically active component of the renin-angiotensin system, regulates blood pressure by counteracting the vasoconstrictor and proliferative effects of Ang II. AVE 0991 is a novel nonpeptide compound that evoked effects similar to Ang-(1–7) on the endothelium. AVE 0991 competed for high-affinity binding of [125I]-Ang-(1–7) to bovine aortic endothelial cell membranes with IC50 values of 21 ± 35 nM (n=3). The released amount of bioactive NO was ≈5 times higher for AVE 0991 (10 μmol/L) in comparison to Ang-(1–7) (10 μmol/L)[3]. In water-loaded C57BL/6 mice, AVE 0991 (0.58 nmol/g body weight) produced a significant reduction in urinary volume (0.06+/-0.03 mL/60 min [n=9] versus 0.27+/-0.05 [n=9]; P<0.01), associated with an increase in urinary osmolality[4]. In infarcted male Wistar rats, AVE-0991 significantly attenuated the decrease in systolic tension (sham operated, 13.00 ± 1.02 g; infarction, 7.18 ± 0.66 g; AVE treated, 9.23 ± 1.05 g, n = 5), +dT/dt, -dT/dt, and heart rate induced by myocardial infarction. Furthermore, AVE-0991 significantly decreased the infarcted area (6.98 ± 1.01 vs. 3.94 ± 1.04 mm2 in AVE-treated rats)[5].
AVE 0991 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary astrocytes
0.01μM, 0.1μM, 1μM
24 h
To investigate the effects of AVE 0991 on Aβ-induced inflammation and autophagy in astrocytes. Results showed that AVE 0991 significantly inhibited the release of inflammatory cytokines (IL-1β, IL-6, TNF-α) and promoted autophagy by upregulating LC3 and Beclin-1 expression and downregulating P62 levels.
J Inflamm Res. 2023 Feb 1;16:391-406.
AVE 0991 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
CD2F1 mice
Cancer cachexia model
Oral gavage
1 mg/kg and 15 mg/kg
Low dose: 10 administrations over 13 days; High dose: 9 administrations over 10 days
To evaluate the effects of AVE 0991 on tumor growth and muscle wasting in mice with cancer cachexia, results showed that AVE 0991 slowed tumor development, reduced weight loss, improved locomotor activity, and attenuated muscle wasting.
Cancer Res. 2019 Feb 15;79(4):706-719
Rats
Subarachnoid hemorrhage model
Intranasal administration
0.9 mg/kg
Single dose, observed up to 28 days
To evaluate the protective effects of AVE 0991 on oxidative stress and neuronal apoptosis after subarachnoid hemorrhage. Results showed that AVE 0991 significantly improved neurobehavioral scores and reduced oxidative stress and neuronal apoptosis through the Mas/PKA/CREB/UCP-2 pathway.
Redox Biol. 2019 Jan;20:75-86
APP/PS1 transgenic mice
Alzheimer's disease model
Intraperitoneal injection
1, 3, 10 mg/kg
Once daily for 30 consecutive days
To evaluate the effects of AVE 0991 on cognitive function, neuronal damage, and inflammation in APP/PS1 mice. Results showed that AVE 0991 (3 and 10 mg/kg) significantly improved cognitive function, reduced neuronal death and synaptic damage, and suppressed astrocyte-mediated inflammation.
J Inflamm Res. 2023 Feb 1;16:391-406.
Aged male Sprague-Dawley rats
Laparotomy-induced delayed neurocognitive recovery model
Intranasal administration
0.9 mg/kg
Single dose
AVE 0991 significantly improved hippocampus-dependent learning and memory deficits induced by surgery, attenuated hippocampal neuroinflammation by reducing microglial activation marker CD11b and inflammatory molecules, and restored BBB integrity by modulating MMP-9/TIMP-3 balance and occludin expression.
Front Aging Neurosci. 2021 Feb 15;13:624387
Rats
Congestive heart failure model
Intraperitoneal injection
24 µg/kg/h
Continuous for 28 days
To evaluate the chronic effects of AVE 0991 on renal function and cardiac hypertrophy in rats with congestive heart failure. Results showed that chronic administration of AVE 0991 exerted significant diuretic, natriuretic, and kaliuretic effects in CHF rats, reduced serum creatinine and aldosterone levels, and attenuated cardiac hypertrophy.
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