ACTIVATION OF ANGIOTENSIN-CONVERTING ENZYME 2 PRODUCES AN ANTIDEPRESSANT-LIKE EFFECT IN MICE

Abstract Background Angiotensin (Ang) -converting-enzyme (ACE) 2 converts Ang Ⅱ into Ang (1-7), which in turn acts on MAS receptors (ACE2/Ang (1-7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression [1]. Recent studies have reported that diminazene aceturate (DIZE) enhances the catalytic activity of ACE2 by direct binding [2]. Indeed, the administration of DIZE in a diabetic mouse model activated ACE2 and increased Ang (1-7) production [3]. Aims & Objectives In the present study, to investigate whether ACE2 activation in the brain could be a novel therapeutic target for depression, we examined the effects of DIZE on depressive-like behavior using behavioral, pharmacological, and biochemical assays. Methods We measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration to determine whether DIZE or Ang (1-7) produce antidepressant- like effects. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Results Administration of DIZE or Ang (1-7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. Discussion & Conclusion These results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1- 7)/MAS receptor pathway and resulting in antidepressant-like effects. References 1.J. Vian, C. Pereira, V. Chavarria, C. Kö hler, B. Stubbs, J. Quevedo, S.W. Kim, AF. Carvalho, M. Berk, BS. Fernandes, The renin-angiotensin system: a possible new target for depression. BMC Med 2017, 15:144 2.L. V. Kulemina, D.A. Ostrov. Prediction of off-target effects on angiotensin-converting enzyme 2. J Biomol Screen 2011, 16:878-885. 3.Y. Zhang, J. Liu, J.Y. Luo, X.Y. Tian, W.S. Cheang, J. Xu, C.W. Lau, L. Wang, W.T. Wong, C.M. Wong, et al. Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes. Antioxid Redox Signal 2015, 23:880-892