Activation of gαq pathway rescues mesaconitine-induced neurotoxicity in Caenorhabditis elegans.

Mesaconitine (MA), a major active component of Aconitum species, exhibits analgesic and anti-inflammatory properties, but its narrow therapeutic window poses a high risk of neurotoxicity, and the underlying molecular mechanisms, particularly the downstream signaling pathways, remain poorly understood. In this study, we used Caenorhabditis elegans as an in vivo model to comprehensively evaluate the neurotoxicity of MA and to characterize its potential mechanisms. We assessed the impacts of different concentrations of MA (0-1600 μM) on worm development, locomotor behavior, chemotaxis, and avoidance, and performed genetic intervention using neurotransmitter synthesis loss-of-function mutants (tbh-1, tph-1, eat-4, unc-25, cat-2) and a downstream signaling mutant (egl-30). The results showed that MA inhibited development, and locomotor behavior in a concentration- and time-dependent manner, with the most severe impairment observed at 1600 μM for 72 h. Genetic analysis revealed that disfunction of tbh-1 (octopamine/noradrenaline synthesis) partially rescued MA-induced chemotaxis impairment, whereas a gain-of-function mutation of its downstream target egl-30 (Gαq) completely rescued the chemotaxis and locomotor deficits. These findings indicate that the noradrenergic system underlies MA neurotoxicity, and that activation of Gαq signaling completely rescues MA-induced neurotoxicity in C. elegans, highlighting Gαq as a core downstream transduction node. This study provides important genetic evidence for the mechanisms of MA neurotoxicity and identifies potential targets for developing intervention strategies against MA toxicity.