Piericidin A

Piericidin A (AR-054) is a natural mitochondrial NADH-ubiquinone oxidoreductase (complex I) inhibitor. Piericidin A is a potent neurotoxin and inhibits mitochondrial respiration by disrupting the electron transport system through its action on NADH-ubiquinone reductase. Piericidin A is also a potential quorum-sensing inhibitor that suppresses the expression of the virulence genes of Erwinia carotovora subsp. atroseptica (Eca). Piericidin A is an ADC cytotoxin and has anti-bacterial, anticancer, insecticidal activity^[1][2][2]. In Vitro: In a cell free assay, the potency of Piericidin A to inhibit mitochondrial complex I is ∼2 fold smaller than the one of annonacin. In cultured neurons, Piericidin A potently induces the redistribution of phosphorylated tau from the dendrites into the cell soma and induces cell death^[1].
The viability of Tn5B1-4 cells is inhibited by Piericidin A in a time- and concentration-dependent manner with IC₅₀ value of 0.061 μM, whilst Piericidin A shows slight inhibitory effect on the viability of HepG2 and Hek293 cells with IC₅₀ value of 233.97 μM and 228.96 μM, respectively. Piericidin A induces apoptosis of Tn5B1-4 cells coincides with a decrease in the mitochondrial membrane potential^[3]. In Vivo: Piericidin A (0.5 mg/kg/d; for 28 days via osmotic minipumps) significantly increases the number of phospho-tau immunoreactive cells in the cerebral cortex in P301S^+/+ mice. Piericidin A leads to increased levels of pathologically phosphorylated tau only in P301S^+/+ mice. The synaptic density is reduced by Piericidin A treatment in P301S^+/+ mice. Exposure to Piericidin A aggravates the course of genetically determined tau pathology^[1].