Transgenic rat with overproduction of ubiquitous angiotensin-(1-7) presents neuroprotection in a model of ischemia and reperfusion.

Recent studies showed that angiotensin-(1-7) has cerebroprotective actions in stroke. In the present study, we aim to test whether tissue overexpression of Angiotensin-(1-7), mainly in the brain provides neuroprotection in a model of ischemia/reperfusion by bilateral common carotid arteries occlusion/reperfusion (BCCAo/R). Evaluation of neurological deficit scores and bilateral asymmetry test (BAT) were performed seven days after transient BCCAo/R in transgenic rats (TG-7371) overexpressing Angiotensin-(1-7) and Sprague-Dawley (SD) rats. To assess blood-brain barrier (BBB) permeability Evans blue dye (EB) was intravenously injected. Cytokine levels were quantified in the whole brain through Elisa assay and oxidative stress was measured 7 days after ischemia. The expression of AT1 and Mas receptors and inducible nitric oxide synthase (iNOS) was evaluated by RT-PCR. Neurological deficits were observed in both SD-BCCAo/R and TG-BCCAo/R, contrasting to sham-operated groups. However, TG-BCCAo/R showed a significant lower neurological score and latency in BAT when compared with SD-BCCAo/R. BBB integrity in TG-BCCAo/R was improved, since these animals showed lower extravasation of EB than SD-BCCAo/R. Interestingly, TG-BCCAo/R presented lower levels of pro-inflammatory cytokines when compared to SD-BCCAo/R. Levels of IL-10 were higher in SD-BCCAo/R than in SD control and even higher in TG-BCCAo/R. TG-BCCAo/R animals presented decreased levels of TBARS and increase in SOD activity and GSH levels when compared to SD sham rats. RT-PCR results showed higher levels of AT1 receptor and iNOS in SD-BCCAo/R compared to TG-BCCAo/R, but no difference was observed for Mas receptor. The present study shows that lifetime increase in cerebral expression of an Ang-(1-7)-producing fusion protein induces neuroprotection in experimental global cerebral ischemia and reperfusion, reassuring that, pharmacological strategies leading to increase in Ang-(1-7) can be an additional tool for stroke therapy.

Renin-Angiotensin System in Huntington's Disease: Evidence from Animal Models and Human Patients.

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.

Neuropsychiatric Properties of the ACE2/Ang-(1-7)/Mas Pathway: A Brief Review.

The current pharmacological strategies for the management of anxiety disorders and depression, serious conditions which are gaining greater prevalence worldwide, depend on only two therapeutic classes of mood-stabilizing drugs: Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). Although first line agents with proven efficacy, their clinical success in the management of anxiety disorders and depression is still considered highly complex due to the multifaceted nature of such conditions. Several studies have shown a possible therapeutic target could be found in the form of the Angiotensin-Converting Enzyme [ACE] type 2 (ACE2), Angiotensin [Ang]-(1-7) and Mas receptor pathway of the Renin- Angiotensin System (RAS), which as will be discussed, has been described to exhibit promising therapeutic properties for the management of anxiety disorders and depression. In this article, the literature to describe recent findings related to the role of the RAS in anxiety and depression disorders was briefly revised. The literature used covers a time range from 1988 to 2019 and were acquired from the National Center for Biotechnology Information's (NCBI) PubMed search engine. The results demonstrated in this review are promising and encourage the development of new research for the treatment of anxiety and depression disorders focusing on the RAS. In conclusion, the ACE2/Ang-(1-7)/Mas pathway may exhibit anxiolytic and anti-depressive effects through many possible biochemical mechanisms both centrally and peripherally, and result in highly promising mental health benefits which justifies further investigation into this system as a possible new therapeutic target in the management of neuropsychiatric disorders, including any as of yet undescribed risk-benefit analysis compared to currently-implemented pharmacological strategies.

Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System.

BACKGROUND: Aripiprazole is an antipsychotic drug used to treat schizophrenia and related disorders. Our previous study showed that this compound also induces antinociceptive effects. The present study aimed to assess the participation of the opioid system in this effect. METHODS: Male Swiss mice were submitted to paw pressure test and hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2 µg). Aripiprazole was injected 10 min before the measurement. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine, and bestatin were given 30 min before aripiprazole. Nociceptive thresholds were measured in the 3rd hour after PGE2 injection. RESULTS: Aripiprazole (100 µg/paw) injected locally into the right hind paw induced an antinociceptive effect that was blocked by naloxone (50 µg/paw), a nonselective opioid receptor antagonist. The role of µ-, δ-, and κ-opioid receptors was investigated using the selective antagonists, clocinnamox (40 µg/paw), naltrindole (15, 30, and 60 µg/paw), and nor-binaltorphimine (200 µg/paw), respectively. The data indicated that only the δ-opioid receptor antagonist inhibited the peripheral antinociception induced by aripiprazole. Bestatin (400 µg), an aminopeptidase-N inhibitor, significantly enhanced low-dose (25 µg/paw) aripiprazole-induced peripheral antinociception. CONCLUSION: The results suggest the participation of the opioid system via δ-opioid receptor in the peripheral antinociceptive effect induced by aripiprazole.

The Renin-Angiotensin System and the Neurodegenerative Diseases: A Brief Review.

BACKGROUND: A large body of studies characterized the renal and cardiovascular effects of the peptides of the renin-angiotensin system (RAS). We now recognize that, in addition to angiotensin (Ang) II and Ang III, other peptides, such as, Ang-(1-7), Ang-(1-9), Ang IV and Alamandine can mediate actions of the RAS in different tissues, including the brain. Effects elicited by angiotensins in the brain are complex, site specific and dependent on the interaction with selective receptors, angiotensin type 1 receptor (AT1), AT2, Mas or MrgD, which present widespread distribution in the central nervous system. Although the majority of studies indicate a neuroprotective action for the inhibition of angiotensin converting enzyme or blockade of AT1 receptor, recent studies point to the participation of other angiotensin peptides in the pathophysiology of the neurodegenerative diseases. OBJECTIVES AND METHODS: In this article, we revised the literature to describe recent findings related to the role of RAS in neurodegenerative diseases such as, Parkinson, Alzheimer, Huntington and Multiple Sclerosis. RESULTS: The results obtained are promising and may stimulate the development of novel and more effective pharmacological tools to prevent and better control neurodegenerative diseases. In this brief review, we present results from studies showing the participation of the RAS with respect to neurodegenerative diseases, such as, Parkinson, Alzheimer, Huntington and Multiple Sclerosis. CONCLUSION: Increased RAS activity leading to increase in Ang II levels, may increase the risk of developing PD, AD, HD or MS. However, the alteration in the balance among angiotensin peptides resulting in increasing Ang-(1-7) or Alamandine may represent effective neuroprotective strategy in population groups at high risk or as coadjutant treatment to reduce the progression of these diseases. Although most studies suggest a neuroprotective action for ACE inhibition or AT1 receptor antagonism, many studies will still be needed to characterize the relative importance (and intracellular mechanisms) of each RAS peptide for the pathophysiology of neurodegenerative diseases. The results to date are promising and may lead to new and more effective pharmacological tools to prevent and better control neurodegenerative diseases.

Reduced anxiety-like behavior in transgenic rats with chronically overproduction of angiotensin-(1-7): Role of the Mas receptor.

Angiotensin-(1-7) [Ang-(1-7)], a counterregulatory peptide of the renin-angiotensin system (RAS), exerts its cardiovascular and renal functions through the G-protein-coupled receptor Mas. More recently, Ang-(1-7) has also been implicated in the control of emotional states related to fear and anxiety. Here, we tested the hypothesis that transgenic rats overexpressesing Ang-(1-7) (TGR) show reduced anxiety-like behavior in two distinct animals models, the Elevated Plus Maze (EPM) and Vogel Conflict Test (VCT). Sprague-Dawley rats (SDs) were used as controls. In addition, we also verified whether this phenotype depend on activation of the Mas receptor. In line with our hypothesis, TGR rats showed an increase in the percentage of time and entries in the open arms of the EPM. There was also an increase in the number of punished licks in VCT. These phenotypes were reversed by ICV injection of the Mas receptor antagonist, A779, but not by the AT2 and MrgD receptor antagonist, PD123319. These results suggest that chronic elevation of Ang-(1-7) levels results in a phenotype characterized by reduced anxiety-like behavior, possibly due to higher activation of the Mas receptor. Therefore, facilitation of the Ang-(1-7)/Mas receptor signaling may be further investigated as an additional strategy for the treatment of anxiety-related disorders.

Antidepressant-like effect of valproic acid-Possible involvement of PI3K/Akt/mTOR pathway.

RATIONALE: Few studies suggest that antidepressants exert their effects by activating some signaling pathways, including the phosphatidylinositol 3-kinase (PI3K). Moreover, valproic acid (VPA) activates the PI3K pathway. Thus, here we investigated the antidepressant-like effect of VPA and if its effect is related to PI3K/Akt/mTOR activation. METHODS: C57Bl/6 (WT) and PI3Kγ-/- mice received VPA injections (30, 100 or 300mg/kg, i.p.) and 30min after they were submitted to the forced swimming (FS), tail suspension (TS) and open field (OF) tests. Another group was pretreated with rapamycin (5mg/kg, i.p.) 150min before VPA administration. Akt phosphorylation levels were measured by Western blotting. RESULTS: In WT mice, VPA (30mg/kg) reduced the immobility time in both FS and TS tests. However, VPA (300mg/kg) increased the immobility time in FS test. All doses of VPA did not alter locomotor activity. In PI3Kγ-/- mice, none of the doses revealed antidepressant-like effect. However, in the OF test, the lower dose of VPA increased the travelled distance in comparison with vehicle group. An increase in Akt phosphorylation levels was observed in WT, but not in PI3Kγ-/- mice. Finally, the pretreatment of WT mice with rapamycin abolished the antidepressant-like effect of VPA (30mg/kg) in FS test. CONCLUSION: These data suggest that the antidepressant-like effects of VPA might depend on PI3K and mTOR activation. Thus, more studies are necessary to investigate the mechanisms involved in the antidepressant-like effect induced by VPA in order to investigate novel therapeutic targets for the treatment of depression.

Anxiolytic- and antidepressant-like effects of angiotensin-(1-7) in hypertensive transgenic (mRen2)27 rats.

Angiotensin-(1-7) [Ang-(1-7)], a counter-regulatory peptide of the renin-angiotensin system (RAS) exerts its effects through the G-protein-coupled receptor Mas, which is expressed in different tissues, including the brain. Ang-(1-7) has a broad range of effects beyond the well-described cardiovascular and renal actions, including the modulation of emotional and behavioural responses. In the present study we tested the hypothesis that Ang-(1-7) could attenuate the anxiety- and depression-like behaviours observed in transgenic hypertensive (mRen2)27 rats (TGRs). We also hypothesized that Ang-(1-7) could be involved in the anxiolytic-like effect induced by ACE (angiotensin-converting enzyme) treatment in these hypertensive rats. Therefore, TGRs and Sprague-Dawley rats were subjected to the Elevated Plus Maze (EPM) test, Forced Swimming Test (FST) and Novelty Suppressed Feeding (NSF). TGRs presented a decreased percentage of entries in the open arms of the EPM test, a phenotype reversed by systemic treatment with enalapril or intracerebroventricular infusion of Ang-(1-7). It is interesting that pre-treatment with A779, a selective Mas receptor antagonist, prevented the anxiolytic-like effect induced by the ACE inhibitor. In the NSF test, TGRs showed increased latency to eating, an indicative of a higher aversion in response to a new environment. These animals also showed increased immobility in the FST. Again, Ang-(1-7) reversed this phenotype. Thus, our data showed that Ang-(1-7) can modulate anxiety- and depression-like behaviours in TGRs and warrant further investigation as a new therapy for certain psychiatric disorders.