The Neuroprotective Effect of Liraglutide is Mediated by Glucagon-Like Peptide 1 Receptor-Mediated Activation of cAMP/PKA/CREB Pathway.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1)-based drugs are being used to achieve better glucose control in patients with type 2 diabetes, and GLP-1 mimetics such as liraglutide have shown therapeutic potential in preventing diabetes-related microvascular and macrovascular complications as well as comorbidities such as neurodegenerative disorders. In the present study, we investigated the effects of liraglutide on primary rat cortical astrocytes treated with advanced glycation end-products (AGEs).


METHODS
Gene and protein expression was analyzed by quantitative real time PCR, western blots, and enzyme-linked immunosorbent assay. The caspase-3 activity was assessed using a caspase-3 colorimetric assay kit. The ROS production was measured with CM-H2DCFDA staining. The cell viability of rat astrocytes was determined using MTT assay.


RESULTS
Liraglutide ameliorated AGEs-induced oxidative stress, inflammatory cytokine secretion, caspase activation, and cell death in astrocytes, and reversed the AGEs mediated reduction in intracellular cyclic AMP (cAMP) levels, protein kinase A (PKA) activity, and the phosphorylation of the cAMP response element-binding (CREB) protein. The protective effects of liraglutide against AGEs-mediated toxicity were abolished by GLP-1 receptor (GLP-1R) knockdown or pretreatment of cells with the adenylyl cyclase inhibitor SQ22536 or the PKA inhibitor Rp-cAMP.


CONCLUSIONS
Liraglutide exerts its neuroprotective effects via the GLP-1R-mediated activation of the cAMP/PKA/CREB pathway. The results of the present study support the therapeutic potential of liraglutide for the treatment of neurodegenerative disorders.
Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Yi
Y
Bao
Lei
L
Jiang
Haiyan
H
Chen
Junjie
J
Zou
Zhimin
Z
Liu
Yongquan
Y
Shi
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D000069450:Liraglutide / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D018027:Receptors, Glucagon; D000069450:Liraglutide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases