Exposure to Phosphodiesterase Inhibitors Impairs Physiological Processes in Juvenile Nematodes

Abstract

Meloidogyne spp. (root‐knot nematodes) are the most damaging plant‐parasitic nematodes to commercial agriculture. Currently used nematicides are of limited effectiveness as well as toxic to other organisms. The present study examines whether disruption of cyclic nucleotide signaling pathways using phosphodiesterase (PDE) inhibitors could serve as the basis for novel nematicides with greater efficacy and reduced environmental impact. To explore this, we carried out an evolutionary analysis of nematode phosphodiesterases (PDEs) and found that nematodes contain only 6 of the 11 members of the vertebrate PDE superfamily. Evolutionary trace analysis reveals nematode‐specific amino acid residues in the drug binding pocket of several nematode PDEs, suggesting the feasibility of developing compounds that selectively inhibit individual nematode PDEs. We also examined the physiological effects of PDE inhibitors on both C. elegans and M. hapla. We found that IBMX (non‐selective), cilostazol and milrinone (PDE3‐selective), rolipram (PDE4‐selective), and papaverine (PDE10 inhibitor) can reduce C. elegans dauer locomotion velocity by 30‐50%. IBMX, cilostazol, and rolipram also reduce by 50‐70% the chemotactic response of C. elegans to salt. Treatment of juvenile M. hapla with cilostazol or rolipram reduced by 蠅50% their ability to invade plant roots. We conclude that inhibitors that target individual PDE families present in nematodes can disrupt locomotion, chemosensation, and/or processes required to invade plant roots, and thus may have nematicidal applications.This work was supported by the New Hampshire Agricultural Experiment Station (USDA).