Sun_2021_Comp.Biochem.Physiol.C.Toxicol.Pharmacol__109038

Harmine is a beta-carboline and harmala alkaloid with extensive bioactivities. However, its toxicity, especially in neural system, is not systematically assessed and the toxic mechanism is not yet clear. Using Caenorhabditis elegans (C. elegans) as a model system, we found that harmine exhibited dosage dependent (0, 5, 10, 20, 40, 80, 160, and 320 micromol/L) toxic effect, such as growth inhibition, egg laying defects, shortened life span and increased mortality. Although harmine did not result in obvious structural alterations in neurite or death of neurons, it did show direct acetylcholinesterase inhibition activity. Further, we found that harmine treatment decreased worm pharyngeal pump rate and lowered the content of nitric oxide (NO) in worm body, implying foraging disorders, which is an indicator of acetylcholinergic neuron activity inhibition. Besides, network pharmacology and molecular docking reveals that acetylcholinesterase is one of the major neural toxicity targets as well. Above all, harmine can directly inhibit the activity of acetylcholinesterase, leading to excessive accumulation of acetylcholine, which may be one of the harmine neurotoxicity mechanisms.