Nucleoside 5′-phosphorothioate derivatives are highly effective neuroprotectants

Abstract

The brain is especially sensitive to oxidative stress due to its high rate of oxidative metabolism, relatively low levels of antioxidant enzymes, and high concentrations of Fe/Cu ions. During the neurodegeneration process, the aggregation of proteins Aβ, accompanies oxidative stress. We explored the potential of thiophosphate derivatives to rescue neurons from oxidative stress and Aβ toxicity. We evaluated the neuroprotective effect of ATP-γ-S, ADP-β-S, and GDP-β-S on primary cortical neuronal cells exposed to several insults, including treatment with FeSO4, co-application of H2O2 and FeSO4, and addition of Aβ42. Upon treatment with FeSO4, phosphorothioate analogues exhibited up to 3000-fold better neuroprotectant activity than the corresponding parent nucleotides. Likewise, phosphorothioate analogues proved to be up to 30-fold better neuroprotectants than the corresponding parent nucleotides upon treatment with both H2O2 and FeSO4. When we exposed primary neuron and astrocyte cultures to 50μM Aβ42-induced cell death, we found that ATP-γ-S significantly improved cell morphology and maintained culture viability with an IC50 value of 0.8μM. Finally, we evaluated the viability of neuroblastoma cells under hypoxic conditions in the presence of ATP-γ-S and found that the latter was involved in the regulation of HIF-1a and stabilized mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), which promote cell survival and proliferation. Based on its high potency as a neuroprotectant, we propose ATP-γ-S as a highly promising, biocompatible, and water-soluble drug candidate for the treatment of neurodegenerative disorders.