Protective Effect of Irbesartan an Angiotensin (AT1) Receptor Antagonist in Unpredictable Chronic Mild Stress Induced Depression in Mice

Abstract

Oxidative stress and alternation of renin-angiotensin system has been implicated in the pathophysiology of various cardio vascular, endocrine including mood and anxiety disorders. The present study evaluated the role of irbesartan in stress induced different models of depression. Mice were treated with irbesartan (40 mg/kg), fluoxetine (25 mg/kg) alone in combination orally. Drugs treatment started after 2 weeks from the beginning of the unpredictable mild stress (UCMS) protocol. Behavioural tests were performed on week 6, at least 24 h after the last treatment. Modified forced swim test (MFST), tail suspension test (TST) and open field test (OFT) were used followed by antioxidant markers and 5-HT levels determination. Irbesartan increased swimming, climbing and decreased immobility times in MFST, decrease immobility time in TST. Irbesartan also increased no. of field crossings; rearings and also increased time spent in the centre of OFT. Thus, antidepressant like activity in UCMS mice was observed. Combination of irbesartan with fluoxetine showed potentiating effect of behavioural parameters in all animal models. Combination groups also showed antioxidant effects and elevated the 5-HT levels in UCMS mice. Chronic administration of Irbesartan exerted antidepressant like effect, reduced oxidative stress and elevated brain 5-HT levels.

Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder

“…Angiotensin II is a potent stimulator of NADPH oxidase 48 and, importantly, dysregulation of angiotensin II signaling has been described in depression 56 . Treatment with an angiotensin II receptor antagonist reduces oxidative stress and exerts antidepressant-like effects in rodent models 57 . In humans, most studies suggest that drugs targeting the renin-angiotensin-aldosterone system improve depressive symptoms 58 .…”

The renin–angiotensin system: a possible new target for depression

“…Blockage of Ang II also leads to antidepressant-like activity in the learned helplessness [ 169 ] and chronic mild stress paradigms [ 170 , 171 ], both more valid models than the forced swim test. Preclinical data also suggests a link between the antidepressant effect and a decrease in Ang II activity; AT1R antagonism by its specific blockers losartan [ 3 ], valsartan [ 171 ], irbesartan [ 170 ] and telmisartan [ 172 ] has similar actions to that caused by ACEIs. As with most antidepressants, use of these blockers also seems to have antianxiety properties.…”

“…Animal experiments also support the anti-inflammatory and oxidative stress-reducing effects of these drugs as part of their mechanisms of action. Both irbesartan and fluoxetine decreased levels of thiobarbituric-reactive substances – oxidative stress markers – while increasing catalase and glutathione (antioxidants) and serotonin (5-HT) levels in the brain [ 170 ]. Valsartan also increased neurogenesis in mice [ 171 ].…”

The AT1 Receptor Antagonist Losartan Does Not Affect Depressive-Like State and Memory Impairment Evoked by Chronic Stressors in Rats

“…Indeed, RAS components and Ang II receptors (i.e., AT 1 and AT 2 receptors) were identified in limbic structures controlling stress responses (Wright and Harding, 2011; Bali and Jaggi, 2013). In this sense, previous studies have documented an involvement of the Ang II acting via activation of the AT 1 receptor in the etiology of stress-evoked diseases (Watanabe et al, 1998; Saavedra et al, 2004; Saavedra et al, 2011; Bali and Jaggi, 2013; Ayyub et al, 2016; Fontes et al, 2016). The mechanisms related to involvement of Ang II/AT 1 receptor in complications evoked by stress are not completely understood, but neuroinflammation, dysregulated hormonal and sympathetic responses, and oxidative stress might be involved (Saavedra et al, 2011; Labandeira-Garcia et al, 2017; Saavedra, 2017).…”