ATP-γ-S-(α,β-CH2) protects against oxidative stress and amyloid beta toxicity in neuronal culture.

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.