Artemisinins and their impact on inhibitory neurotransmission.

Artemisinin, a major extract of the annual mugwort Artemisia annua, and its semisynthetic derivatives represent state-of-the-art antimalarial drugs. These compounds also target, via poorly understood mechanisms, various mammalian pathways, thereby exhibiting anticancer and immunomodulatory properties. Recently, crystal structures of artemisinins with two mammalian targets were determined, namely, gephyrin, the prime scaffolding protein at inhibitory postsynapses, and pyridoxal kinase, a central metabolic enzyme synthesizing vitamin B6. These structures and corresponding functional studies demonstrate that artemisinins play a dual role in modulating inhibitory synapses, acting on postsynaptic sites by impeding inhibitory neurotransmitter receptor clustering and on presynaptic terminals by limiting the biosynthesis of the inhibitory neurotransmitter γ-aminobutyric acid. These studies pave the way for further investigations of artemisinins as inhibitory neurotransmission modulators in humans.