Neuroprotective effects of chemical constituents from Nicotiana tabacum L. in Parkinson’s disease

Abstract

Parkinson’s disease (PD), the second most common neurodegenerative disorder globally, arises from selective dopaminergic neuron degeneration. While current therapies address symptoms, disease-modifying agents remain an unmet need. Herein, we investigated Nicotiana tabacum L. (Solanaceae), a plant linked epidemiologically to reduced PD risk, as a source of multi-target neuroprotective compounds. From ultra-low nicotine (< 0.04%) tobacco leaves, we isolated 22 molecules, including a novel 21-norsesterterpenoid (Nicotiazanorpenoid A) and eight previously unreported compounds. Systematic evaluation revealed three synergistic neuroprotective mechanisms: (1) Antioxidant activity: Scopoletin (3) and isoferulic acid (6) showed significant radical scavenging capacity (ABTS assay; IC50 = 27.74, and 18.13 μM, respectively); (2) Neuronal protection: cis-11,14,17-Eicosatrienoic acid methyl ester (14) enhanced survival (93.94% vs. control) in 6-OHDA-induced PC12 cells, surpassing rasagiline (88.36% at equivalent concentrations); (3) MAO-B inhibition: five compounds displayed selective inhibition, with scopoletin (3) exhibiting highest potency (Ki = 20.7 μM). Notably, plant prostaglandins (10/11) were identified as competitive MAO-B inhibitors first time through molecular docking and 100-ns MD simulations, revealing stable binding at the FAD site (ΔG = − 10.42, and − 9.75 kcal/mol, respectively).