Abstract
The incidence of depression doubles in diabetic patients and is associated with poor outcomes. Studies indicate that renin-angiotensin-aldosterone system inhibitors (RAASi) might relieve depression, however the mechanism of action is not well understood. We recently showed that angiotensin receptor blockers have antidepressant effects in experimental diabetes comorbid depression. Here we investigated whether all types of RAASi exhibit antidepressant and neuroprotective properties. Diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated per os with non-pressor doses of enalapril, ramipril, spironolactone or eplerenone for 2 weeks. Behavior was evaluated using forced swim test and open field test. Inflammatory response and brain-derived neurotrophic factor (BDNF) signaling were investigated in the hippocampus. Both ACEi and MR antagonists reversed diabetes-induced behavioral despair confirming their antidepressant-like effect. This may occur via alterations in hippocampal cytokine-mediated inflammatory response. Repressed BDNF production was restored by RAASi. Both ACEi and MR antagonists facilitated the BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein signaling pathway as part of their neuroprotective effect. These data highlight the important benefits of ACEi and MR antagonists in the treatment of diabetes-associated depressive symptoms. Our novel findings support the link between diabetes comorbid depression, inflammation and repressed BDNF signaling. RAASi could provide new therapeutic options to improve the outcomes of both disorders.
Highlights
Diabetes and depression are vast challenges for modern healthcare systems and generate a significant social and economic burden (Egede et al, 2002; van Dieren et al, 2010)
Sample lysates of 40 μg/lane were electrophoretically resolved on 4–20 % polyacrylamide gels, transferred to nitrocellulose membranes and immunoblotted with the appropriate primary antibodies: phosphorylated endothelial nitric oxide synthase (p-eNOS; Ser1177), phosphorylated neuronal nitric oxide synthase nuclear (p-nNOS; Ser 852), endothelin-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), brain-derived neurotrophic factor (BDNF), furin, matrix metalloproteinase-3 (MMP-3), p75 neurotrophin receptor (p75NTR), phosphorylated c-Jun N-terminal kinase (p-JNK; Thr183/Tyr185), tyrosine receptor kinase B (TrkB), phosphorylated extracellular-signal-regulated kinase (p-ERK; Tyr204), phosphorylated cAMP response element binding protein (p-CREB; Ser133)
renin-angiotensin-aldosterone system inhibitors (RAASi) are the cornerstones of the management of diabetes-related complications
Summary
Diabetes and depression are vast challenges for modern healthcare systems and generate a significant social and economic burden (Egede et al, 2002; van Dieren et al, 2010). All elements of classic RAAS are expressed in the brain, where they regulate blood pressure, cerebral circulation, central sympathetic activity, behavior and the brain’s innate immune response (Paul et al, 2006; Saavedra, 2012). Both systemic and local RAAS in the brain are over-activated in diabetes coupled with increased level of angiotensin II (Ang II) (RibeiroOliveira et al, 2008). In a streptozotocin-induced diabetes model angiotensin-converting enzyme inhibitors (ACEi) enalapril or ramipril, and mineralocorticoid-receptor (MR) antagonists spironolactone or eplerenone were applied to test their antidepressant-like effect and reveal their diverse mechanisms of action
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