Mahato_2026_Toxicon__109038

Agriculture workers are especially at risk from insecticide (INSECT) exposure, which is associated with neurological disorders, such as Parkinson's disease (PD). The present study evaluated the mechanism of neurotoxicity induction in a commercial insect containing chlorpyrifos (50%) and cypermethrin (5%) in Caenorhabditis elegans models, as well as the neuroprotective efficacy of two custom peptides (CPs), HNP (heptadeca-neuropeptide) and TNP (trideca-neuropeptide), derived from snake venom nerve growth factor. CPs significantly mitigated INSECT-induced neurotoxicity by preventing chemosensory alterations, reducing oxidative stress (reactive oxygen species generation), restoring mitochondrial membrane potential, lowering nitrite and lipid peroxidation levels, and inhibiting acetylcholinesterase disruption in the N2 (wild-type) strain of C. elegans. CPs pretreatment significantly reduced dopaminergic neuron damage from INSECT exposure in C. elegans (BZ555 strain) and reduced accumulation of alpha-synuclein, a hallmark of PD, by a marked elevation in the expression of key autophagy genes (lgg-1, atg-7, lgg-2, atg-18, epg-5, vps-34) and proteasomal degradation components (rpn-2, rpt-4, ubc-12) in the transgenic (NL5901) strain of C. elegans. Quantitative reverse transcription polymerase chain reaction revealed that CPs pretreatment modulates the INSECT-induced upregulation of p38 mitogen-activated protein kinase (MAPK)/antioxidant/heat shock response/ genes and delays apoptosis in C. elegans. However, TNP conferred slightly greater neuroprotective effects than HNP. Proteomic analysis demonstrated that TNP downregulated genes in the skn-1 oxidative stress pathway, thereby suppressing pro-apoptotic signalling and neuronal injury. CPs at a 10 mg/kg dose (i.v. route) did not demonstrate acute, subacute, and sub-chronic toxic effects in Swiss albino mice, and they significantly reduced (p >= 0.05) the levels of proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha, as compared to controls. The pharmacokinetic profiling demonstrated that TNP effectively penetrates the blood-brain barrier (8.95%) in Wistar rats, indicating its potential central nervous system bioavailability.