Lactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway. (October 2016)

• Record Type: Journal Article
• Authors: Venkatesan, Ramu; Subedi, Lalita; Yeo, Eui-Ju; Kim, Sun Yeou
• Is Part Of: Neurochemistry international. Volume 99(2016)
• Page Start: 133
• Page End: 146
• Publication Date: 2016-10
• Subjects: Lactucopicrin -- Scopolamine -- ROS -- NRF2 -- Antioxidant -- AChE inhibitors; ROS reactive oxygen species -- AD Alzheimer's disease -- AChE acetylcholine esterase -- CNS central nervous system -- NGF neurotrophic nerve growth factor -- Δψm mitochondrial membrane potential -- SOD superoxide dismutase -- GPx glutathione peroxidase -- NRF2 nuclear factor (erythroid-derived 2)-like 2 -- DCFH-DA 2′, 7′-dichlorofluorescin diacetate -- FBS fetal bovine serum -- mAChR muscarinic acetylcholine receptor -- FITC fluorescein isothiocyanate -- PI propidium iodide -- ANOVA analysis of variance -- P probability -- F degree of freedom -- BcL-2 B-cell CLL/lymphoma 2 -- Bax BcL-2-associated X Protein -- N2a cell mouse neuroblastoma cell -- C6 cell rat glioma cell -- ERK extracellular signal-regulated kinase -- GSK-3β glycogen synthase kinase-3β -- BcL-xl B-cell lymphoma extra-large -- Bad Bcl-2-associated death promoter -- Cyto C cytochrome C; Lactucopicrin (PubChem CID: 174880) -- Galantamine hydrobromide (PubChem CID: 121587) -- (-)-Scopolamine hydrobromide trihydrate (PubChem CID: 20055509) -- Retinoic acid (PubChem CID: 444795) -- 2′, 7′-Dichlorofluorescein diacetate (PubChem CID: 104913) -- Rhodamine 123 (PubChem CID: 65217) -- Thiazolyl blue tetrazolium bromide (PubChem CID: 64965); Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2016.06.010
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Cholinergic activity plays a vital role in cognitive function, and is reduced in individuals with neurodegenerative diseases. Scopolamine, a muscarinic cholinergic antagonist, has been employed in many studies to understand, identify, and characterize therapeutic targets for Alzheimer's disease (AD). Scopolamine-induced dementia is associated with impairments in memory and cognitive function, as seen in patients with AD. The current study aimed to investigate the molecular mechanisms underlying scopolamine-induced cholinergic neuronal dysfunction and the neuroprotective effect of lactucopicrin, an inhibitor of acetylcholine esterase (AChE). We investigated apoptotic cell death, caspase activation, generation of reactive oxygen species (ROS), mitochondrial dysfunction, and the expression levels of anti- and pro-apoptotic proteins in scopolamine-treated C6 cells. We also analyzed the expression levels of antioxidant enzymes and nuclear factor (erythroid-derived 2)-like 2 (NRF2) in C6 cells and neurite outgrowth in N2a neuroblastoma cells. Our results revealed that 1 h scopolamine pre-treatment induced cytotoxicity by increasing apoptotic cell death via oxidative stress-mediated caspase 3 activation and mitochondrial dysfunction. Scopolamine also downregulated the expression the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase, and the transcription factor NRF2. Lactucopicrin treatment protected C6 cells from scopolamine-induced toxicity by reversing the effects of scopolamine on those markers of toxicity. In addition, scopolamine attenuated the secretion of neurotrophic nerve growth factor (NGF) in C6 cells and neurite outgrowth in N2a cells. As expected, lactucopicrin treatment enhanced NGF secretion and neurite outgrowth. Our study is the first to show that lactucopicrin, a potential neuroprotective agent, ameliorates scopolamine-induced cholinergic dysfunction via NRF2 activation and subsequent expression of antioxidant enzymes. Graphical abstract: Highlights: Lactucopicrin prevents scopolamine-induced apoptosis by blocking caspase 3 cleavage. Scopolamine-induced C6 cell toxicity by ROS generation, considered as valid neurodegeneration model. Lactucopicrin recovers mAChR and antiapoptotic proteins expression. Lactucopicrin enhance Δψm, NRF2- mediated antioxidative enzyme and inhibits cyto C release in scopolamine model. Induces NGF secretion and neurite outgrowth by lactucopicrin treatment in Scopolamine model.