Effects of linagliptin on glucose-induced neuronal damage on Caenorhabditis elegans

Introduction: C. elegans lacks a vascular system and is therefore an ideal model system to investigate the mechanisms of glucose-mediated damage to neurons. Experimental hyperglycaemia causes neuronal dysfunction in C. elegans and reduces lifespan by overproduction of ROS and MG-derived AGEs. A key regulator for longevity and stress response is DAF-16, which up-regulates MnSOD, an enzyme detoxifying ROS. Here we used wild-type and daf-16 strains to study the potential molecular mechanisms underlying the effects of linagliptin on C. elegans with relation to the diabetic retina.

Method: A total of 150 – 300 C. elegans were used per group. Linagliptin was administered to C. elegans by feeding 13µmol/L linagliptin daily for 12days, resulting in an intracellular linagliptin concentration of around 8nmol/L.

Results: In wild-type C. elegans linagliptin normalised the reduced lifespan and improved relative head motility (a parameter for neuronal activity) by 10% (p< 0.01), and 36% (p< 0.05), respectively. These positive effects were blunted in daf-16 knock-out worms. Importantly, linagliptin significantly decreased ROS (by 19% (p< 0.05) and 12% (p< 0.05)) and MG-derived AGEs (by 15% (p< 0.05) and 8% (p< 0.05)) in both wild-type and daf-16 knock-out worms, respectively.

Conclusion: Linagliptin exhibits anti-MG-derived AGEs and antioxidative properties in a daf-16 independent manner. In contrast, the neuroprotective and lifespan-enhancing effects may be daf-16 dependent, suggesting that the protective effects of linagliptin may involve different molecular pathways. Our studies reveal a positive role of linagliptin in a neuronal system, which may concomitantly with its protective effect in a vasculature system of the diabetic retina, as a result of a combined effect on neurovascular unit.