title: 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.
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Emanuel Monteiro
authors.initials: EM
authors.lastname: Candeias
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Inês Carolina
authors.initials: IC
authors.lastname: Sebastião
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Susana Maria
authors.initials: SM
authors.lastname: Cardoso
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Sónia Catarina
authors.initials: SC
authors.lastname: Correia
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Cristina Isabel
authors.initials: CI
authors.lastname: Carvalho
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Plácido
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Maria Sancha
authors.initials: MS
authors.lastname: Santos
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Catarina Resende
authors.initials: CR
authors.lastname: Oliveira
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Paula Isabel
authors.initials: PI
authors.lastname: Moreira
authors.affiliation: Emanuel Monteiro Candeias, Inês Carolina Sebastião, Susana Maria Cardoso, Sónia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Plácido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Duarte
keywords: Alzheimer disease; Brain; Glucagon-like peptide-1; Gut; Insulin; Liraglutide; Neuroprotection; Type 2 diabetes