2 reference(s) found. Listing paper details in reverse chronological order. We are grateful to Keith Bradnam for improvment of this script
Title: Selenepezil, a Selenium-Containing Compound, Exerts Neuroprotective Effect via Modulation of the Keap1-Nrf2-ARE Pathway and Attenuates Abeta-Induced Cognitive Impairment in Vivo Yan J, Pang Y, Zhuang J, Lin H, Zhang Q, Han L, Ke P, Huang X Ref: ACS Chem Neurosci, 10:2903, 2019 : PubMed
Oxidative stress is a major risk factor for neurodegenerative disease. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is one of the most potent defensive systems against oxidative stress. Selenepezil, a selenium-based compound, was previously found to exhibit excellent acetylcholinesterase (AChE) inhibition, to mimic endogenous glutathione peroxidase (GPx) activity, and to exhibit scavenging activity for hydrogen peroxide in vitro. However, none of these activities have been evaluated in a cellular model, and detailed molecular mechanisms are not elucidated. Moreover, whether selenepezil ameliorates memory deficits in vivo remains unknown. This study validated the cytoprotective effect of selenepezil against 6-hydroxydopamine (6-OHDA)- or H2O2-induced SH-SY5Y cell damage via alleviation or neutralization of intracellular microtubule disorder, reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and cell apoptosis. Our study clearly demonstrated that selenepezil pretreatment exhibited remarkable cytoprotective effect in a Nrf2-dependent manner via activating the Keap1-Nrf2-ARE pathway and stimulating the transcription of Nrf2-ARE-regulated cytoprotective genes. Moreover, selenepezil.HCl exerts neuroprotective effect via attenuating Abeta-induced cognitive impairment in Alzheimer's disease (AD) rat and was more active than the reference drug donepezil. In summary, selenepezil deserves further consideration for AD therapy.
        
Title: Synthesis and Evaluation of Multi-Target-Directed Ligands against Alzheimer's Disease Based on the Fusion of Donepezil and Ebselen Luo Z, Sheng J, Sun Y, Lu C, Yan J, Liu A, Luo HB, Huang L, Li X Ref: Journal of Medicinal Chemistry, 56:9089, 2013 : PubMed
A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 muM for Electrophorus electricus acetylcholinesterase and 0.097 muM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 muM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (nu0 = 123.5 muM min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.