Ellagic acid protects against deoxyaconitine-induced neurotoxicity by improving mitochondrial function.

Abstract

Ellagic acid (EA), a naturally occurring polyphenol abundant in fruits and nuts, is known for its diverse pharmacological properties, with recent investigations demonstrating its beneficial neuroprotective effects. The clinical application of Aconitum alkaloids, particularly the neurotoxic diester-type alkaloid deoxyaconitine (DA), remains challenging due to incomplete understanding of its toxicological mechanisms. In this study, we systematically investigated the neuroprotective efficacy of EA against DA-induced Caenorhabditis elegans (C. elegans) model. EA alleviated DA-induced neurodegeneration across dopaminergic, serotonergic, glutamatergic, and GABAergic circuits, coupled with reduced ROS levels, lipofuscin deposition, and apoptotic cell death. Mechanistically, EA exerted neuroprotection by attenuating oxidative stress, restoring energy metabolism homeostasis, modulating amino acid and neurotransmitter synthesis/metabolism, ameliorating mitochondrial dysfunction, and activating the insulin/insulin-like growth factor (IIS) signaling pathway and the p38 mitogen-activated protein kinase (MAPK) signaling cascade. Collectively, these findings position EA as a promising adjuvant agent to counteract DA-associated neurotoxicity, thereby expanding the therapeutic window for DA-based clinical applications and making traditional Aconitum-based medicines safer for clinical use.