Incretins are growth factors that have demonstrated neuroprotective properties in a range of studies. Here, we analyse the neuroprotective properties of the Glucagon like peptide-l (GLP-l) analogues in human neuroblastoma SH-SY5Y cells against methyl glyoxal (MG) stress. The results demonstrate a range of growth factor-related cytoprotective processes induced by liraglutide (Victoza®), currently used to treat type 2 diabetes. FUl1her, we study the comparative long-term effects of three different GLP-l analogues on cell viability, proliferation and cytotoxicity and demonstrate the long-term exposure of liraglutide and lixisenatide (Lyxumia®) to be more protective when compared to the exendin-4 (Byetta~ . We also report the absence of any additive effect on cell viability and proliferation, when using GLP-l analogues in combination, but a 3-fold increase in cytoprotection observed when comparing 100 nM doses of liraglutide and lixisenatide to exendin-4 (p<0.001). In addition, we demonstrate that lixisenatide (10 and 50 nM) is neuroprotective when compared to 50 nM liraglutide (p<0.05) and 50 and 100 nM exendin-4 (p<0.001) against MG post stress. Further, the most effective doses for native Glucose dependent insulinotropic peptide (GIP), (D-Ala2)GIP and (Pro3)GIP were 200, 100 and 1 nM exhibiting a 43 ± 3% decrease in LDH levels (p<0.001). Lastly, we show a novel mechanism wherein blockade ofMEK1I2 leads to the activation of AktIPKB (p<0.001). A decrease in the survival (p<0.05) and an increase in the cytotoxicity (p<0.05) during inhibition of MEK1I2 followed by liraglutide treatment, suggest a role ofMEK1I2 in protecting the cells. Our studies show that the liraglutide pre-treatment confers neuroprotection by increasing the cell survival and decreasing cytotoxicity but inhibition of MEK1I2 withdraws this neuroprotective effect, suggesting the involvement of MAPKIERK pathway in the neuroprotection conferred by liraglutide. Overall, incretins confer protection and have potential to be developed as possible drugs to treat neurodegenerative disorders.