Home Medizin Das Diabetesmedikament Dulaglutid kann die Symptome einer Depression lindern

Das Diabetesmedikament Dulaglutid kann die Symptome einer Depression lindern

von NFI Redaktion

A recent Brain and Behavior study investigated the antidepressant effect of Dulaglutide and the mechanism underlying this effect.


Study: Treatment with Dulaglutide reverses depression behavior and metabolic homeostasis of the hippocampus in mice exposed to chronic mild stress. Image credit: luchschenF/Shutterstock.com









Study: Treatment with Dulaglutide reverses depression behavior and metabolic homeostasis of the hippocampus in mice exposed to chronic mild stress. Image credit: luchschenF/Shutterstock.com

Background

Depression is a chronic mood disorder characterized by negative mood, insomnia, weight loss, anhedonia, aversion to activity, fatigue, and low self-esteem. According to the World Health Organization, depression has become one of the major health burdens worldwide.

This mental illness is usually treated with an antidepressant that takes about a month to alleviate symptoms. However, antidepressants have several side effects that can be toxic at high doses.

A combination of psychological, genetic, and neurological factors contributes to the manifestations of depression. Although the exact etiology of this mental health issue is not fully understood, research has shown that chronic stress can trigger depression.

The hippocampus is a brain region associated with depression and undergoes functional and morphological changes in response to stress. Animal model studies have demonstrated that a reduction in neuron and glial size, a decrease in synaptic markers, loss of dendrites, and an increase in apoptosis in the hippocampus lead to depression.

Many studies have uncovered the metabolic aspects of depression. Diabetes and obesity, for example, are two common metabolic disorders that increase the risk of depression. Given the high prevalence, novel therapies with high efficacy and fewer side effects are needed to combat depression. The Chronic Mild Stress (CMS) model is considered a reliable rodent model for studying depression.

Glucagon-like peptide-1 (GLP-1) and its receptor agonists are involved in anti-inflammatory effects and neuroprotective activities and can improve mental disorders, especially depression and cognitive impairments. GLP-1 is a peptide hormone that stimulates insulin secretion and restricts glucagon synthesis in a glucose-dependent manner in the pancreas. Liraglutide, a GLP-1 analog, has shown a positive effect in reducing anxiety and depression symptoms.

Dulaglutide is a novel long-acting GLP-1 receptor agonist that improves cognitive dysfunction and neuronal damage in rats with vascular dementia. Although many studies have highlighted the effectiveness of Dulaglutide in preventing depression behavior induced by Chronic Social Defeat Stress (CSDS), the underlying mechanism of this effect is not clearly understood.

About the Study

The current study employed a metabolomics approach to evaluate the effect of Dulaglutide in a CMS model. Additionally, the underlying mechanism of this effect was also investigated. Adult male ICR mice, an albino strain of mice, were selected for this study, all approximately seven weeks old, following a week of acclimatization.

After one week of acclimatization, 60 mice were randomly divided into four groups: the control group (CON), the CMS and vehicle group (CMS+Veh), the CMS and 0.3 mg/kg Dulaglutide group (Low Dula), and the CMS and 0.6 mg/kg Dulaglutide group (High Dula). Except for the CON group, all other groups were exposed to stressors.

To establish the CMS model of depression, selected mice were exposed to two or three different stressors continuously for 28 days. Stressors included 12 hours of food and water deprivation, 24 hours of being housed on wet bedding, 24 hours in a tilted cage, 1 minute in a skewer tube, and 5 minutes of cold water treatment. The body weight of each test mouse was measured weekly, and behavioral tests like the Tail Suspension Test (TST), Open Field Test (OFT), and Forced Swimming Test (FST) were conducted.

Study Findings

Mice exposed to CMS for four weeks exhibited depressive and anxiety-like symptoms. An LC-MS/MS metabolomics study was conducted to understand the potential pathophysiological mechanisms and investigate the efficacy of medications in alleviating depression symptoms.

A significant difference between the CON group, CMS+Veh group, and High Dula group was observed in line with the metabolic disorders induced by chronic stress, which were altered by Dulaglutide treatment. Several potential biomarkers related to purine metabolism, arginine and proline metabolism, glycerophospholipid metabolism, glutamate metabolism, sphingolipid metabolism, and bile secretion were identified.

Lipid metabolism pathways could be potential targets for alleviating depression with Dulaglutide. Lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), phosphatidylinositol (PI), sphingolipids, and phosphatidylcholine (PC) are involved in the therapeutic effect of Dulaglutide in alleviating depression. Consistent with previous study results, this study emphasized the association between lipid metabolism and the antidepressant effect of Dulaglutide.

The current study showed downregulation of N-acetyl-L-aspartic acid (NAA) in the CMS model group. NAA, one of the key metabolites of the vertebrate nervous system, was found in reduced amounts in rats exposed to chronic unpredictable mild stress. However, the current study showed that Dulaglutide therapy increased NAA levels by upregulating them in the hippocampus.

An upregulation of L-glutamic acid and L-arginine was observed in the CMS model group. Treatment with Dulaglutide led to a decrease in arginine and proline, indirectly indicating a neuroprotective effect.

Conclusions

The current study shed light on the antidepressant effect of Dulaglutide using the CMS depression model. Specifically, this study elucidated the potential metabolisms underlying the antidepressant effect of Dulaglutide.

Journal Reference:

  • Jin, M., Zhang, S., Huang, B., Li, L., Liang, H., Ni, A., Han, L., Liang, P., Liu, J., Shi, H., & Lv, P. (2024) Brain and Behavior 14(3). doi: 10.1002/brb3.3448. Link to Study

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