Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide

Abstract

Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone’s regulation of some autonomic functions and liraglutide’s neuroprotective potential.

Keywords: Type 2 diabetes, Glucagon-like peptide-1, Gut, Brain, Insulin, Liraglutide, Alzheimer disease, Neuroprotection

Core tip: Glucagon-like peptide-1 (GLP-1) physiological responses are dependent on a gut-brain axis and receptor (GLP-1R) activation. GLP-1Rs are widely expressed throughout the body, including several brain areas. GLP-1 may readily diffuse across the blood-brain-barrier, activating neuroprotective pathways. Given the native GLP-1 short half-life, liraglutide has been developed with a highly increased half-life, allowing its use to treat type 2 diabetes (T2D). Given T2D patients increased risk for obesity and dementia [e.g., Alzheimer disease (AD)], and evidence from preclinical studies, whereby liraglutide showed impressive neuroprotective effects, clinical studies are underway to test the role of liraglutide on weigh control and AD.