Chronically infused angiotensin II induces depressive-like behavior via microglia activation

Abstract

Brain inflammation is one of hypotheses explaining complex pathomechanisms of depression. Angiotensin II (ANGII), which is associated with hypertension, also induces brain inflammation. However, there is no animal study showing the direct relationship between ANGII and depression. To address this issue, ANGII-containing osmotic pumps were implanted into adult male C57BL/6 mice subcutaneously for subacute (7 days) and chronic (at least 21 days) periods and behavioral and molecular analyses were conducted. Chronic infusion of ANGII into mice induced depressive-like behaviors, including the tail suspension test and forced swimming test, which were reversed by imipramine. Chronic infusion of ANGII also induced microglial activation in the hippocampus with increase of Il-1β mRNA and decrease of Arg1 mRNA. In addition, chronic ANGII infusion activated the hypothalamic–pituitary–adrenal axis (HPA axis) and resulted in decreased hippocampal glucocorticoid receptor level. However, subacute ANGII infusion did not induce significant molecular and behavioral changes in mice compared to that of control. The molecular and behavioral changes by chronic ANGII infusion were reversed by co-treatment of minocycline or telmisartan. In addition, ANGII treatment also induced the pro-inflammatory changes in BV-2 microglial cells. Our results indicate that ANGII can induce depressive-like behaviors via microglial activation in the hippocampus and HPA axis hyperactivation in mice. These might suggest possible mechanism on depressive symptom in chronic hypertensive state.

Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease

“…Centrally active blockers/inhibitors of RAS may, therefore, represent a promising treatment in addition to standard AD therapies such as cholinesterase inhibitors. In support of this view, inhibition of RAS was found to ameliorate cognitive disturbances by reducing microglia-related neuroinflammation also in other animal models of brain disorders, such as neuropsychiatric lupus and depression [ 79 , 80 , 81 ].…”

Microglia involvement in the schizophrenia occurrence in male offspring with maternal dexamethasone exposure

“…These data provide mounting evidence supporting the previous contention that cellular and molecular mechanisms may underly depression-like behavior. Hippocampal GR resistance (decreased GR expression) activates microglia, via decreased expression of ARG-1 and increased expression of pro-in ammatory genes, consequently aggravating HPA-axis imbalance (increased Crh and CORT) as well as depressive-like behavior [71]. Decreased hippocampal ARG-1 expression, in particular, may be associated with enhanced stress vulnerability [72].…”

Renin-angiotensin System: A New Promising Therapeutic and Mechanisms for Depression and Anxiety

“…Ang II was previously discovered as a pro-hypertensive factor present in areas of the brain associated with cardiovascular and recently has been found to be associated with motor activity, anxiety, learning, and memory (Saavedra et al, 2005). Additionally, increased Ang II levels were significantly associated with depression, anxiety, hyperactivity of the HPA axis, and stress (Tashev & Ivanova, 2018) (Park et al, 2020). For instance, adult C57 mice treated with Ang II for 14 consecutive days resulted in anxious-like behaviors and bidirectional synaptic plasticity impairment, and increased expression of GABA A R α1 (Gao et al, 2021).…”