Effects of Liraglutide on glucose-induced neuronal damage in Ceanorhabditis elegans

Aims/hypothesis: Ceanorhabditis elegans (C. elegans) was used as a model organism to study effects of the glucagon-like peptide-1 (GLP-1) analogue liraglutide, which is known to have neuroprotective effects. Experimental hyperglycemia caused neuronal dysfunction in C. elegans and reduced lifespan by increased reactive oxygen species (ROS) formation. Liraglutide enhanced the reduced lifespan and showed neuroprotective effects under high glucose conditions. These effects correlated with a reduction of ROS formation. In C. elegans, a key regulator for development, longevity and stress response is DAF-16/FOXO regulated, which is involved in stress resistance via up-regulation of catalase and MnSOD, two antioxidant enzymes involved in the detoxification of ROS. The purpose of this study is to evaluate potential molecular mechanisms underlying the effects of liraglutide.

Results: Under high glucose conditions, liraglutide increased mean lifespan from 23.2 ± 0.57 to 27.2 ± 1.43 days (P< 0.01) in wild-type C. elegans. In contrast, in knockout FOXO transcription factors (daf-16) nematodes, liraglutide did not significantly increase mean lifespan from 21.8 ± 2.18 to 23.9 ± 1.53 days (P= 0.09). An increase of relative head motility was also observed in wild-type C. elegans treated with liraglutide from 0.05 ± 0.00 to 0.08 ± 0.01 mm/s (P< 0.05) whereas in knockout FOXO transcription factors (daf-16) worms liraglutide did not significantly change this parameter from 0.05 ± 0.01 to 0.06 ± 0.01 mm/s (P= 0.26). A similar protective result was observed with body angular velocity and body bending frequency in wild-type C. elegans, which increased from 4.66 ± 0.19 to 6.67 ± 0.45 ^°Deg/s (P< 0.05) and from 0.13 ± 0.00 to 0.14 ± 0.01 Hz (P< 0.05), respectively. In knockout FOXO transcription factors (daf-16) nematodes, these two parameters did not change from 6.70 ± 1.00 to 7.45 ± 0.43 ^°Deg/s (P= 0.27) and from 0.10 ± 0.02 to 0.10 ± 0.01 Hz (P= 0.27), respectively. Surprisingly, liraglutide decreased ROS formation in a FOXO transcription factors (daf-16) independent manner. In wild-type C. elegans, liraglutide decreased ROS formation from 192.51 ± 0.69 to 165.87 ± 0.36 mean AU/pixel (P< 0.05) and also in knockout FOXO transcription factors (daf-16), from 262.55 ± 14.54 to 201.14 ± 0.41 mean AU/pixel (P< 0.05).

Conclusions/interpretation: Liraglutide has antioxidative properties in a daf-16 independent manner. In contrast, its neuroprotective effect and lifespan enhancement at least acts through daf-16 suggesting different pathways being involved in the protective effects of Liraglutide.