Activation of angiotensin-converting enzyme 2 produces an antidepressant-like effect via MAS receptors in mice

Figures

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  Fig. 1. Effects of DIZE on the tail suspension test in mice. A: The immobility time was measured 60 min after the administration of vehicle or DIZE (0.01, 0.1, 1 nmol). B: Time courses of the DIZE (1 nmol)-induced antidepressant-like effect in mice. C: Effects of A779 on the DIZE-induced reduction in immobility time in mice. Vehicle, DIZE (1 nmol) or DIZE (1 nmol) in combination with A779 (0.3 or 3 nmol) were administered 60 min prior to measurements. One-way ANOVA: F (3, 42) = 21.24, p < 0.0001, Fig. 1(A), F (4, 52) = 15.96, p < 0.0001, Fig. 1(C). Two-way ANOVA: [time: F (4, 95) = 4.671, p = 0.0017; treatment: F (1, 95) = 51.07, p < 0.0001; time × treatment: F (4, 95) = 6.079, p = 0.0002, Fig. 1(B)]. Values represent the means ± SEM. Numbers in parentheses indicate the number of animals in each group. **p < 0.01 compared with vehicle-treated mice. ##p < 0.01 compared with DIZE (1 nmol)-treated mice

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  Fig. 2. Effects of Ang (1–7) on the tail suspension test in mice. A: The immobility time was measured 60 min after the administration of vehicle, Ang (1–7) (30 or 300 pmol) or Ang (1–7) (300 pmol) in combination with A779 (3 nmol). B: Time courses of the Ang (1–7) (300 pmol)-induced antidepressant-like effect in mice. One-way ANOVA: F (3, 37) = 5.265, p = 0.0040, Fig. 2(A). Two-way ANOVA: [time: F (2, 56) = 8.822, p = 0.0005; treatment: F (1, 56) = 26.82, p < 0.0001; time × treatment: F (2, 56) = 4.369, p = 0.0172, Fig. 2(B)]. Values represent the means ± SEM. Numbers in parentheses indicate the number of animals in each group. **p < 0.01 compared with vehicle-treated mice. #p < 0.05 compared with Ang (1–7) (300 pmol)-treated mice

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  Fig. 3. Changes in ACE2 activity in the brain of naïve mice following the i.c.v. administration of DIZE. Sixty min after the administration, samples of the cerebral cortex, prefrontal cortex, hippocampus, and amygdala were collected from the brain and homogenized to determine ACE2 activity. Student’s t-test: t = 0.1171, df = 10, p = 0.9091, Fig. 3(A); t = 0.2676, df = 10, p = 0.7945, Fig. 3(B); t = 3.137, df = 10, p = 0.0106, Fig. 3(C); t = 1.22, df = 10, p = 0.2505, Fig. 3(D). Values represent the means ± SEM. Numbers in parentheses indicate the number of animals in each group. *p < 0.05 compared with vehicle-treated mice

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  Fig. 4. Double immunofluorescence staining for ACE2 and cell specific markers for neuron (NeuN), microglia (Iba-1) or astrocyte (GFAP) in the hippocampus of naïve mice. Photomicrographs showing fluorescent labeling for ACE2 (red), NeuN (green), Iba-1 (green), GFAP (green) or nuclei with DAPI (blue) in the hippocampus of naïve mice

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  Fig. 5. Hypothesis for DIZE antidepressant mechanism