Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress.

Abstract

Glucagon-like peptide 1 (GLP-1) is a growth factor that has demonstrated neuroprotective properties in a range of studies. In an APPswe/PS1ΔE9 mouse model of Alzheimer's disease (AD), we previously found protective effects on memory formation, synaptic plasticity, synapse survival and a reduction of amyloid synthesis and plaque load in the brain. Here, we analyse the neuroprotective properties of the GLP-1 analogue liraglutide in human neuroblastoma cell line SH-SY5Y during methyl glyoxal stress. We show for the first time that cell viability was enhanced by liraglutide (XTT assay) in a dose-dependent way, while cytotoxicity (LDH assay) and apoptosis were reduced. Expression of the pro-survival Mcl1 signaling protein was increased, as was activation of cell survival kinases Akt, MEK1/2 and the transcription factor p90RSK. Liraglutide also decreased pro-apoptotic Bax and Bik expression. In addition, the membrane potential and the influx of calcium into the cell were enhanced by liraglutide. GLP-1 receptor expression was also increased by the drug. The results demonstrate a range of growth factor-related cytoprotective processes induced by liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza®). It is also tested in clinical trials in patients with Alzheimer disease.

• Authors: Mohit K Sharma, Jaishree Jalewa, Christian Hölscher
• Journal: Journal of neurochemistry (J Neurochem) Vol. 128 Issue 3 Pg. 459-71 (Feb 2014) ISSN: 1471-4159 [Electronic] England
• PMID: 24112036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 International Society for Neurochemistry.

Chemical References

• Apoptosis Regulatory Proteins
• BIK protein, human
• GLP1R protein, human
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Membrane Proteins
• Mitochondrial Proteins
• Neuroprotective Agents
• Receptors, Glucagon
• bcl-2-Associated X Protein
• Pyruvaldehyde
• Liraglutide
• Glucagon-Like Peptide 1
• Oncogene Protein v-akt
• Mitogen-Activated Protein Kinases
• Caspase 3
• Calcium

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Blotting, Western
• Calcium (metabolism)
• Caspase 3 (metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Glucagon-Like Peptide 1 (analogs & derivatives, pharmacology)
• Glucagon-Like Peptide-1 Receptor
• Humans
• Hypoglycemic Agents (pharmacology)
• Immunohistochemistry
• Liraglutide
• Membrane Potentials
• Membrane Proteins (metabolism)
• Mitochondrial Proteins
• Mitogen-Activated Protein Kinases (metabolism)
• Neuroprotective Agents
• Oncogene Protein v-akt (metabolism)
• Pyruvaldehyde (toxicity)
• Receptors, Glucagon (biosynthesis, genetics)
• Stress, Physiological (drug effects)
• bcl-2-Associated X Protein (metabolism)