Modulation of serotonergic, dopaminergic and tubulin-associated pathways by tannin-free natural products in Caenorhabditis elegans reveals effective anthelmintic drug targets

Abstract

Despite of the Southeast Asias rich medicinal flora, Bangladesh behinds in utilizing the Caenorhabditis elegans model for lead anthelmintic compound discovery. Moreover, target-specific resistance (TSR) and non-target-specific resistance (NTSR) surge have influenced the lead compounds bio-discovery over the past decades. To date, prior researches are limited to basic efficacy tests and conventional extraction protocol. Therefore, the study was designed to assess the anthelmintic potency of 19 tannin-free natural products (NPs) induced alterations of neurotransmission in C. elegans. The anthelmintic activity was assessed by examining the motility (head thrashes and body bends), mortality, egg hatch inhibition (EHI) and expression of cat-1, ser-1, dat-1, and tba-1 genes. Eleven (11) plant extracts, Azadirachta indica A. Juss., Cassia alata L., Portulaca oleracea L., Saraca asoca (Roxb.) W.J.de Wilde, Eleusine indica L. Gaertn., Persicaria hydropiper L. Delarbre, Foeniculum vulgare Mill., Clerodendrum infortunatum L., Linum usitatissimum L., Hibiscus rosa-sinensis L., and Vitex negundo L. revealed a significant neurobehavioral and developmental impairments in C. elegans. Persicaria hydropiper L. Delarbre @ 1{square}mg/mL, caused the lowest body bending (31{square}{+/-}{square}1.7, p{square}<{square}0.01), while Eleusine indica L. Gaertn. reduced head thrashing (66.3{square}{+/-}{square}3.0, p{square}<{square}0.01). L. usitatissimum L. exhibited the highest lethality (87.3{square}{+/-}{square}1.8%, p{square}<{square}0.01) and the LD{square}{square} values of Eleusine indica L. Gaertn. (0.40{square}mg/mL) and Linum usitatissimum L. (0.411{square}mg/mL) were the lowest. Interestingly, C. infortunatum L. exhibited the strongest EHI (97.5{square}{+/-}{square}3.0%, p{square}<{square}0.01). Gene expression analysis revealed a significant down-regulation of the dopaminergic and serotonergic pathway indicating the metabolic and reproductive disruptions. This pioneering study underscores the anthelmintic potency of native plant extracts, highlighting their neuromodulatory and developmental impact on C. elegans. Altogether, these findings suggest that the selected genes may serve as potential drug targets, paving the way for lead compounds identification and development to the advance anthelmintic drug discovery from the NPs.