Alleviation of Depression by Glucagon-Like Peptide 1 Through the Regulation of Neuroinflammation, Neurotransmitters, Neurogenesis, and Synaptic Function

Abstract

Depression has emerged as a major cause of mortality globally. Many studies have reported risk factors and mechanisms associated with depression, but it is as yet unclear how these findings can be applied to the treatment and prevention of this disorder. The onset and recurrence of depression have been linked to diverse metabolic factors, including hyperglycemia, dyslipidemia, and insulin resistance. Recent studies have suggested that depression is accompanied by memory loss as well as depressive mood. Thus, many researchers have highlighted the relationship between depressive behavior and metabolic alterations from various perspectives. Glucagon-like peptide-1 (GLP-1), which is secreted from gut cells and hindbrain areas, has been studied in metabolic diseases such as obesity and diabetes, and was shown to control glucose metabolism and insulin resistance. Recently, GLP-1 was highlighted as a regulator of diverse pathways, but its potential as the therapeutic target of depressive disorder was not described comprehensively. Therefore, in this review, we focused on the potential of GLP-1 modulation in depression.

Keywords: depression; glucagon-like peptide-1 (GLP-1); neurogenesis; neuroinflammation; synaptic plasticity.

Figure 1

The function of glucagon-like peptide 1 (GLP-1) in humans. GLP-1, secreted from the intestinal L-cells, circulates the whole body through the blood. GLP-1 influences energy metabolism and glucose metabolism by regulating the insulin level. In the brain, GLP-1 secreted from intestinal cells can be absorbed into the brain, and the GLP-1 secreted from neurons remains in the cerebrospinal fluid. GLP-1 can control the secretion of various neurotransmitters and the progression of neuroinflammation, and can regulate insulin sensitivity in the brain.

Figure 2

Schematic diagram of physiological and molecular changes in the brain of patients with depression. We have summarized several physiological and molecular alterations in the brain of patients with depression. The depressive brain exhibits severe neuroinflammation involving higher pro-inflammatory cytokine production, neurotransmitter imbalance, and synaptic dysfunction through the dysregulation of ERK, Glycogen synthase kinase 3β (GSK-3β), and mammalian target of the rapamycin (mTOR) pathways, and these ultimately lead to the loss of hippocampal volume and cognitive decline.