Stable apelin-13 analogues promote cell proliferation, differentiation and protect inflammation induced cell death

Emerging evidence indicates that apelin, an adipokine, plays a critical role in numerous biological functions and may hold potential for therapeutic applications; however, its efficacy is constrained by rapid plasma degradation. Thus, the search for novel apelin analogues with reduced susceptibility to plasma degradation is ongoing. We have previously shown novel modified apelin-13 analogues, providing exciting opportunities for potential therapeutic development against Alzheimer's disease. In this study we explored novel insights into the neuroprotective effects of stable fatty acid modified (Lys8GluPAL) apelin-13-amide and amidated apelin-13 amide in mitigating cellular damage in SH-SY5Y neuroblastoma cells exposed to palmitic acid (PA) and lipopolysaccharide-induced (LPS) stress. Both apelin-13 analogues were found to modulate ER stress response and reduce oxidative stress by suppressing PA- and LPS-induced ROS production (36 % and 42 % reductions in GSH/GSG (p < 0.005). The peptides attenuated apoptosis by reducing caspase 3/7 activity and restoring bcl2 expression (p < 0.05) in cells treated with PA and LPS. They also downregulated pro-apoptotic genes, protected neurites from stress-induced damage, and promoted neurite outgrowth. The observed protective effects could be due to activation of the AMPK pathway, a critical regulator of cellular energy homeostasis and survival. These findings provide insight into novel, enzymatically stable apelin-13 analogues and highlight their potential to be developed as therapeutic agents against neuroinflammation and neurodegenerative disease, including Alzheimer's disease.