Captopril prevents depressive-like behavior in an animal model of depression by enhancing hippocampal neurogenesis via activation of the ACE2/Ang (1–7)/Mas receptor/AMPK/BDNF pathway

Abstract

The brain's Renin-Angiotensin System plays an important role in the modulation of mental state. Previously we demonstrated that activated angiotensin (Ang) converting enzyme (ACE) 2, which converts Ang II into Ang (1–7), or the intracerebroventricular administration of Ang (1–7) produced an antidepressant-like effect in mice via Mas receptors (MasR). Since the ACE inhibitor Captopril (Cap) increases Ang (1–7) in the brain, it remains unknown whether Cap affects the depressive-like behavior of olfactory bulbectomized (OBX) mice, an animal model of depression. We tested the effect of Cap on the depressive-like behavior of these mice in the tail-suspension test, quantified ACE2, p-AMP activated protein kinase (AMPK), and brain-derived neurotrophic factor (BDNF) using western blots, and examined the changes in Ang (1–7) level, neurogenesis, and in the expression of ACE2 and MasR on various cell types in the hippocampus using immunohistochemistry. While OBX mice exhibited a depressive-like behavior in the tail-suspension test, as well as a reduction in ACE2, Ang (1–7), p-AMPK, BDNF, and hippocampal neurogenesis, these changes were prevented by Cap administration. The intracerebroventricular administration of Ang (1–7) improved the OBX-induced depressive-like behavior. Except for the changes in ACE2 and Ang (1–7), the effects of Cap were inhibited by the coadministration of A779 (MasR inhibitor) or Compound-C (AMPK inhibitor). ACE2 localized to all cell types, while MasR localized to microglia and neurons. Our results suggest that Cap may act on ACE2-positive cells in the hippocampus to increase ACE2 expression level, thereby enhancing signaling in the ACE2/Ang (1–7)/MasR/AMPK/BDNF pathway and producing antidepressant-like effects.