Imidacloprid unique and repeated treatment produces cholinergic transmission disruption and apoptotic cell death in SN56 cells

• Published in: Food and chemical toxicology 2024-11, Vol.193, p.114988, Article 114988
• Main Authors: Moyano, Paula, Flores, Andrea, San Juan, Javier, García, Jimena, Anadón, María José, Plaza, Jose Carlos, Naval, Maria Victoria, Fernández, María de la Cabeza, Guerra-Menéndez, Lucía, del Pino, Javier
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; AChE; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Apoptosis - drug effects; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Cell Line; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; HSP70; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Imidacloprid; Insecticides - toxicity; Mice; Neonicotinoids - toxicity; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nitro Compounds; Oxidative Stress - drug effects; Proteasome 20S; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Reactive Oxygen Species - metabolism; SN56 basal forebrain cholinergic neurons; Synaptic Transmission - drug effects; Tau; tau Proteins - genetics; tau Proteins - metabolism
• ISSN: 0278-6915; 1873-6351; 1873-6351
• DOI: 10.1016/j.fct.2024.114988

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), β-amyloid-precursor-protein (βAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3β), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 μM–800 μM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aβ and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools. [Display omitted] •IMI induces cell death on basal forebrain cholinergic neurons.•IMI induces cell death through AChE-S, HSP70, and P20S disruption and Aβ/Tau accumulation.•IMI decreases ACh levels through AChE activity inhibition.•IMI induces oxidative stress through ROS production and NRF2 pathway downregulation.•IMI induces Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S disruption.