The Olive Oil Lignan (+)-Acetoxypinoresinol Peripheral Motor and Neuronal Protection against the Tremorgenic Mycotoxin Penitrem A Toxicity via STAT1 Pathway

Penitrem A, PA, is an indole diterpene alkaloid produced by several fungal species. PA acts as a selective Ca2+-dependent K-channels (Maxi-K, BK) antagonist in brain, causing motor system dysfunctions including tremors and seizures. However, its molecular mechanism at the peripheral nervous system (PNS) is still ambiguous. The Mediterranean diet key ingredient extra-virgin olive oil (EVOO) provides a variety of minor bioactive phenolics. (+)-Pinoresinol (PN) and (+)-1-acetoxypinoresinol (AC) are naturally occurring lignans in EVOO with diverse biological activities. AC exclusively occurs in EVOO, unlike PN, which occurs in several plants. Results suggest that PA neurotoxicity molecular mechanism is mediated, in part, through distortion of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. PA selectively activated the STAT1 pathway, independently of the interferon-γ (IFN-γ) pathway, in vitro in Schwann cells and in vivo in Swiss albino mice sciatic nerves. Preliminary in vitro screening of an EVOO phenolic compounds library for the ability to reverse PA toxicity on Schwann cells revealed PN and AC as potential hits. In a Swiss albino mouse model, AC significantly minimized the fatality after intraperitoneal administration of PA fatal doses and normalized most biochemical factors by modulating the STAT1 expression. The olive lignan AC is a novel lead that can prevent the neurotoxicity of food-contaminating tremorgenic indole alkaloid mycotoxins.