title: ATP-γ-S-(α,β-CH2) protects against oxidative stress and amyloid beta toxicity in neuronal culture.
abstract: Amyloid beta (Aβ) oligomers and oxidative stress, typical of Alzheimer's disease, are highly neurotoxic. Previously we identified ATP-γ-S as a most promising antioxidant and neuroprotectant. To further improve both potency and metabolic stability of ATP-γ-S, we designed a related analogue, ATP-γ-S-(α,β-CH2). We found that ATP-γ-S-(α,β-CH2) effectively inhibited ROS formation in PC12 cells subjected to Fe(II)-oxidation, slightly better than ATP-γ-S (IC50 0.18 and 0.20 μM, respectively). Moreover, ATP-γ-S-(α,β-CH2) rescued primary neurons from Aβ42 toxicity, 4-fold more potently than ATP-γ-S, (IC50 0.2 and 0.8 μM, respectively). In addition, the metabolic stability of ATP-γ-S-(α,β-CH2) in PC12 cells during 4 h of incubation, was up to 20% greater than that of ATP-γ-S and ATP. Previously, we found that ATP-γ-S-(α,β-CH2) resisted hydrolysis by ecto-nucleotidases such as, NPPs and TNAP, and was found to be ∼7-fold more potent agonist than ATP at P2Y11 receptor. Therefore, we propose ATP-γ-S-(α,β-CH2) as a promising agent for rescue of neurons from insults typical of Alzheimer's disease.
authors: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel. Electronic address: ortal5000@gmail.com.
authors: Ortal
authors: O
authors: Danino
authors: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel. Electronic address: shlomo.grossman@biu.ac.il.
authors: Shlomo
authors: S
authors: Grossman
authors: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel. Electronic address: bilha.fischer@biu.ac.il.
authors: Bilha
authors: B
authors: Fischer
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate
keywords: Amyloid beta; Antioxidant; Neuroprotectant; Nucleotide