Discovery, structural characterization, chemical synthesis, anti-migraine effect, and pharmacological mechanism of ligualkaloid B: an alkaloid from Ligusticum chuanxiong.

Migraine is a common neurological disorder and imposes a heavy burden on individuals and society. The rhizomes of Ligusticum chuanxiong Hort. are known as an excellent medicine for headache. Our previous study demonstrated that its total alkaloids possess significant anti-migraine effects. However, the effective compounds and pharmacological mechanisms remain unclear. In this study, a previously undescribed alkaloid (named ligualkaloid B) with an unusual linkage of a phenylpropene unit and an amino acid unit was isolated from L.chuanxiong. Subsequently, it was total synthesized by a five-step process to obtain a sufficient amount for pharmacological studies. Functional characterization revealed that ligualkaloid B significantly suppressed the production of IL-6, TNF-α, NO, and ROS in BV-2 cells via modulation of the NF-κB pathway. In reserpine-induced migraine mouse model, ligualkaloid B significantly increased serotonin metabolism markers (5-HT and 5-HIAA) and upregulated 5-HT1B receptor expression, while effectively downregulating CGRP, c-Jun, and c-Fos protein levels, along with concomitant suppression of the NF-κB pathway. In addition, ligualkaloid B exhibited analgesic effects in this model. Collectively, these in vitro and in vivo findings demonstrate that ligualkaloid B exerts multifaceted therapeutic effects against migraine, including the attenuation of neurogenic inflammation, modulation of cerebrovascular tone, regulation of neuromediators, and analgesic action.