Impact of genetic deletion of MrgD or Mas receptors in depressive-like behaviour in mice.

OBJECTIVES: To evaluate the impact of genetic deletion of receptors of the counterregulatory arms of the renin-angiotensin system in depressive-like behaviours. METHODS: 8-12 weeks-old male mice wild type (WT, C57BL/6J) and mice with genetic deletion of MrgD (MrgD KO) or Mas receptors (Mas KO) were subjected to the Forced Swim Test (FST) and the Tail Suspension Test (TST). Brain-derived neurotrophic factor (BDNF) levels were measured by enzyme-linked immunosorbent assay (ELISA). Blockade of Mas was performed by acute intracerebroventricular (icv) injection of its selective antagonist, A779. RESULTS: No statistical difference in immobility time was observed between MrgD KO and WT male animals subjected to FST and TST. However, acute icv injection of A779 significantly increased the immobility time of MrgD KO male mice subjected to FST and TST, suggesting the involvement of Mas in preventing depressive-like behaviour. Indeed, Mas KO male animals showed increased immobility time in FST and TST, evidencing a depressive-like behaviour in these animals, in addition to a reduction in BDNF levels in the prefrontal cortex and hippocampus. No changes in BDNF levels were observed in MrgD KO male animals. CONCLUSION: Our data showed that Mas plays an important role in the neurobiology of depression probably by modulating BDNF expression. On the contrary, lack of MrgD did not alter depressive-like behaviour, which was supported by the lack of alterations in BDNF levels.

Alamandine through MrgD receptor induces antidepressant-like effect in transgenic rats with low brain angiotensinogen.

Alamandine (Ala1-Arg2-Val3-Tyr4-Ile5-His6-Pro7), a heptapeptide hormone of the renin-angiotensin system (RAS), exerts its effects through the Mas-related G-protein coupled receptor of the type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we tested the hypothesis that alamandine could attenuate the depression-like behavior observed in transgenic rats with low brain angiotensinogen, TGR (ASrAOGEN)680. Transgenic rats exhibited a significant increase in the immobility time in forced swim test, a phenotype reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro7-Ang-(1-7), a Mas/MrgD receptor antagonist, prevented the antidepressant-like effect induced by this peptide demonstrating, for the first time, that alamandine through MrgD receptor, can modulate depression-like behavior in TGR (ASrAOGEN)680. This result shows an action of alamandine which strengthens the importance of the counter-regulatory arms of the RAS in fight and treatment of neuropsychiatric diseases.

Alamandine Induces Neuroprotection in Ischemic Stroke Models.

BACKGROUND AND OBJECTIVE: Stroke, a leading cause of mortality and disability, characterized by neuronal death, can be induced by a reduction or interruption of blood flow. In this study, the role of Alamandine, a new peptide of the renin-angiotensin system, was evaluated in in-vitro and in-vivo brain ischemia models. METHODS: In the in-vitro model, hippocampal slices from male C57/Bl6 mice were placed in a glucose-free aCSF solution and bubbled with 95% N2 and 5% CO2 to mimic brain ischemia. An Alamandine concentration-response curve was generated to evaluate cell damage, glutamatergic excitotoxicity, and cell death. In the in-vivo model, cerebral ischemia/ reperfusion was induced by bilateral occlusion of common carotid arteries (BCCAo-untreated) in SD rats. An intracerebroventricular injection of Alamandine was given 20-30 min before BCCAo. Animals were subjected to neurological tests 24 h and 72 h after BCCAo. Cytokine levels, oxidative stress markers, and immunofluorescence were assessed in the brain 72 h after BCCAo. RESULTS: Alamandine was able to protect brain slices from cellular damage, excitotoxicity and cell death. When the Alamandine receptor was blocked, protective effects were lost. ICV injection of Alamandine attenuated neurological deficits of animals subjected to BCCAo and reduced the number of apoptotic neurons/cells. Furthermore, Alamandine induced anti-inflammatory effects in BCCAo animals as shown by reductions in TNFα, IL- 1ß, IL-6, and antioxidant effects through attenuation of the decreased SOD, catalase, and GSH activities in the brain. CONCLUSION: This study showed, for the first time, a neuroprotective role for Alamandine in different ischemic stroke models.