Neuroprotection Against a Panel of Toxicants via a Novel Analog of the Natural Product Fraxinellone

Humans are exposed to a myriad of environmental pollutants, with recent evidence indicating several of these toxicants serve as risk factors for neurodevelopmental disorders and neurodegenerative diseases. Given this, there is a need for both interventional and protective strategies; however, of concern, the mechanistic targets of these environmental pollutants are variable or unknown in some cases. A prior report indicated that analogs of the natural product fraxinellone act as potent NRF2 activators, mitigating excessive reactive oxygen species (ROS) generation and Glu toxicity in vitro. Using one of the most effective fraxinellone analogs (i.e., analog 2) for NRF2 activation identified, we sought to determine the range of protection, in vitro, against a panel of neurotoxicants with varying mechanisms for adverse effects, including 6-hydroxydopamine (6-OHDA), organochlorine pollutants, and a fungicide. The data for analog 2 were compared to those for a structurally similar but inactive analog (i.e., analog 1). The dose-response for each toxicant with PC12 and SH-SY5Y cell lines was determined. Interestingly, the fraxinellone analog provided significant protection against all agents screened: 6-OHDA, dieldrin, benomyl, PCB52 hydroxy and sulfate metabolites, and rotenone. The extent to which the fraxinellone analog mitigated toxicity varied for each toxicant. In all cases, pretreatment with analog 2 significantly decreased total cellular ROS production, and in addition, generation of mitochondrial ROS via rotenone was mitigated. Furthermore, analog 2 provides some degree of restoration of cell viability following rotenone insult. In summary, our data indicate that an analog of the natural product fraxinellone potently inhibited ROS production and toxicity, thereby protecting cells against a panel of agents with varying mechanisms from adverse outcomes.