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

• Published in: Journal of neurochemistry 2014-02, Vol.128 (3), p.459-471
• Main Authors: Sharma, Mohit K., Jalewa, Jaishree, Hölscher, Christian
• Format: Article
• Language: English
• Subjects: AKT protein; Alzheimer's disease; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; bcl-2-Associated X Protein - metabolism; Blotting, Western; Brain; Calcium - metabolism; Caspase 3 - metabolism; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents - pharmacology; Immunohistochemistry; incretins; insulin; Liraglutide; Membrane Potentials; Membrane Proteins - metabolism; Mitogen-Activated Protein Kinases - metabolism; neurodegeneration; neuroprotection; Neuroprotective Agents; Oncogene Protein v-akt - metabolism; Peptides; Pyruvaldehyde - toxicity; Receptors, Glucagon - biosynthesis; Receptors, Glucagon - genetics; Stress analysis; Stress, Physiological - drug effects
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12469

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. We investigated the neuroprotective properties of the GLP‐1 analogue liraglutide in SH‐SY5Y cells during methyl glyoxal stress. Cell survival was enhanced, while cytotoxicity and apoptosis was reduced. Expression of the pro‐survival Mcl1 signaling protein, activation of Akt, MEK1/2 and the transcription factor p90RSK was increased. Pro‐apoptotic Bax and Bik expression was reduced, and the influx of calcium into the cell was normalised. The results demonstrate a range of growth factor related cytoprotective processes induced by the drug liraglutide. We investigated the neuroprotective properties of the GLP‐1 analogue liraglutide in SH‐SY5Y cells during methyl glyoxal stress. Cell survival was enhanced, while cytotoxicity and apoptosis was reduced. Expression of the pro‐survival Mcl1 signaling protein, activation of Akt, MEK1/2 and the transcription factor p90RSK was increased. Pro‐apoptotic Bax and Bik expression was reduced, and the influx of calcium into the cell was normalised. The results demonstrate a range of growth factor related cytoprotective processes induced by the drug liraglutide.