摘要
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 T2 D 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-T2 D 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 T2 D, 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.
Long-acting glucagon-like peptide-1 （GLP-1） analoguesmarketed for type 2 diabetes （T2D） treatment havebeen showing positive and protective effects in severaldifferent tissues, including pancreas, heart or even brain.This gut secreted hormone plays a potent insulinotropicactivity and an important role in maintaining glucosehomeostasis. Furthermore, growing evidences suggestthe occurrence of several commonalities between T2Dand neurodegenerative diseases, insulin resistancebeing pointed as a main cause for cognitive decline andincreased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulinsignaling may have a protective role against cognitivedeficits. As GLP-1 receptors （GLP-1R） are expressedthroughout the central nervous system and GLP-1 maycross the blood-brain-barrier, an emerging hypothesissuggests that they may be promising therapeutic targetsagainst brain dysfunctional insulin signaling-relatedpathologies. Importantly, GLP-1 actions depend not onlyon the direct effect mediated by its receptor activation,but also on the gut-brain axis involving an exchangeof signals between both tissues via the vagal nerve,thereby regulating numerous physiological functions（e.g. , energy homeostasis, glucose-dependent insulinsecretion, as well as appetite and weight control）.Amongst the incretin/GLP-1 mimetics class of anti-T2Ddrugs with an increasingly described neuroprotectivepotential, the already marketed liraglutide emerged as aGLP-1R agonist highly resistant to dipeptidyl peptidase-4degradation （thereby having an increased half-life） andwhose systemic GLP-1R activity is comparable to thatof native GLP-1. Importantly, several preclinical studiesshowed anti-apoptotic, anti-inflammatory, anti-oxidantand neuroprotective effects of liraglutide against T2D,stroke and Alzheimer disease （AD）, whereas severalclinical trials, demonstrated some surprising benefits ofliraglutide on weight loss, microglia inhibition, behaviorand cognition, and in AD biomarkers. Herein, we discussthe GLP-1 action through the gut-brain axis, thehormone＇s regulation of some autonomic functions andliraglutide＇s neuroprotective potential.
基金
Supported by FEDER(Programa Operacional Factores de Competitividade-COMPETE)
Portuguese funds via Portuguese Science Foundation(FCT)(Projects:PTDC/SAUNMC/110990/2009,PTDC/SAU-TOX/117481/2010 and Pest/SAU/LA0001/2011
fellowships:SFRH/BD/90036/2012,PTDC/SAU-TOX/117481/2010,SFRH/BPD/95770/2013,SFRH/BPD/84163/2012,QREN Do IT,"DIAMARKER PROJECT",n.o 13853,SFRH/BD/73388/2010,SFRH/BPD/84473/2012)
