Simple Summary
T-2 toxin is widely found in agricultural products. Although the neurotoxicity of T-2 has been reported, the key molecules and underlying regulatory mechanisms remain unclear. Betulinic acid (BA), a natural triterpenoid from birch bark, possesses strong antioxidant and anti-inflammatory properties. The mechanisms of BA and T-2 toxin in neuroinflammation remain elusive. Therefore, we established a T-2 toxin-exposed mouse model to explore the protective role of BA against T-2 toxin-induced brain damage. We demonstrated that BA could alleviate T-2 toxin-induced hippocampal and cortical injury, oxidative stress, and an imbalance in inflammatory cytokines by restoring BBB integrity, reducing ROS, and regulating the Nrf2/Keap1 signaling pathway. Collectively, these findings confirmed that BA mitigated T-2 toxin-induced neurotoxicity through regulation of the Nrf2/NLRP3 axis, providing new insights into the mechanisms of T-2-induced central nervous system (CNS) injury and potential therapeutic ways.
Abstract
T-2 toxin is widely present in agricultural products and poses a significant neurotoxicity threat. Betulinic acid (BA), a natural triterpenoid, exhibits strong antioxidant and anti-inflammatory properties. However, its protective role against T-2 toxin-induced neuroinflammation remains poorly understood. This study aimed to elucidate the mechanisms underlying T-2 toxin-induced neurotoxicity and evaluate the therapeutic potential of BA. Our results demonstrated that T-2 toxin (1 mg/kg/bw) exposure caused significant pathological damage in the hippocampus and cerebral cortex. T-2 toxin also induced marked oxidative stress, reflected by elevated reactive oxygen species (ROS) accumulation. At the inflammatory level, T-2 toxin upregulated the mRNA expression of pro-inflammatory cytokines (Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)) and altered anti-inflammatory IL-10 expression. In addition, T-2 toxin exhibited strong binding affinity for the tight junction proteins Occludin and Claudin-1 (docking energies of −4.41 and −5.53 kcal/mol, respectively), and molecular dynamics simulations confirmed stable protein–ligand interactions. At the molecular level, T-2 toxin suppressed Nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression, increased Kelch-like ECH-associated protein 1 (Keap1) expression, and activated the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway. Furthermore, molecular docking analysis revealed that BA displayed strong binding affinity to proteins associated with the blood–brain barrier and the Nrf2/NLRP3 signaling pathway. Collectively, these findings indicate that BA mitigates T-2 toxin-induced neuroinflammation through regulating the Nrf2/NLRP3 signaling pathway in mice. Not only do these results clarify a key mechanism of T-2 toxin-induced central nervous system injury, but they also highlight BA as a promising candidate for developing interventions targeting mycotoxin-related neurological disorders.