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 Ca++-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 occur in several plants. Results suggest that PA neurotoxicity molecular mechanism is mediated, in part, through distortion of JAK/STAT pathway. PA selectively activated STAT1 pathway, independently of IFN-γ pathway, in vitro in Schwann cells and in vivo in Swiss albino mice sciatic nerves. Preliminary in vitro screening of EVOO phenolic compounds library for 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 intra-peritoneal 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.