Abstract
Aims/hypothesisDiabetes is a worldwide epidemic linked with diverse diseases of the nervous system, including depression. A few studies suggested a connection between renin–angiotensin–aldosterone system blockers and reduced depressive symptoms, although underlying mechanisms are unclear. Here we investigated the antidepressant effect and the mechanisms of action of the angiotensin receptor 1 blocker (ARB) losartan in an experiential model of diabetes-associated depression.MethodsExperimental diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated for 2 weeks with a non-pressor oral dose of losartan (20 mg/kg). In protocol 1, cerebrovascular perfusion and glial activation were evaluated by single-photon emission computed tomography–MRI and immunohistochemistry. In protocol 2, behaviour studies were performed (forced swim test and open field test). Hippocampal proinflammatory response and brain-derived neurotrophic factor (BDNF) signalling were also assessed.ResultsHere, we show that diabetic rats exhibit depression-like behaviour, which can be therapeutically reversed by losartan. This action of losartan occurs via changes in diabetes-induced neuroinflammatory responses rather than altered cerebral perfusion. We also show that as a part of its protective effect losartan restores BDNF production in astrocytes and facilitates BDNF–tropomyosin receptor kinase B–cAMP response element-binding protein signalling in the diabetic brain.Conclusions/interpretationWe identified a novel effect of losartan in the nervous system that may be implemented to alleviate symptoms of diabetes-associated depression. These findings explore a new therapeutic horizon for ARBs as possible antidepressants and suggest that BDNF could be a target of future drug development in diabetes-induced complications.
Highlights
Noncommunicable diseases represent a major challenge for health systems, further augmented by the co-occurrence of multiple chronic conditions
Losartan ameliorates depression-like behaviour in diabetic rats In the open field test (OFT), both vehicle- and losartan-treated diabetic rats performed fewer grid crossings, indicating that the general physical condition of these rats was worse than that of the non-diabetic control group (Fig. 1a)
When different movement variables were measured separately, the time spent struggling was significantly increased by losartan treatment (Fig. 1d–f). These results suggest that losartan has a strong antidepressant effect
Summary
Noncommunicable diseases represent a major challenge for health systems, further augmented by the co-occurrence of multiple chronic conditions. While both diabetes and depression present huge socioeconomic problems affecting millions of people worldwide, the role of diabetes in increasing the risk of depression is only beginning to emerge [1]. The link between the two diseases is unclear at present due to lack of appropriate mechanistic insight. The incidence of depression is markedly increased in individuals with diabetes [3]. Since diabetes is widely recognised as a state of chronic systemic inflammation [4], inflammatory actions could represent a plausible mechanism through which diabetes and depression interact [5]. There is insufficient experimental evidence to support this hypothesis and effective therapies are lacking
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
