Entwicklung von biocompatiblen und Blut-Gehirn-Schranke gängigen, neuroprotektiven Substanzen mit einer Doppelaktivität als Antioxydantien und P2Y-Receptor Liganden

Currently, there is an urgent need for neuroprotective drugs, especially for treating damage after ischemic brain insults. This need and our previous promising results in the field motivated us to develop neuroprotective agents based on a novel concept. We showed that certain nucleotides play a dual role, both as potent antioxidants, which reduce the oxidative stress damage, and as activators of neuronal P2Y-receptors (P2Y-Rs), which protect nerves after injury. We propose to utilize these beneficial properties of certain nucleotides to develop biocompatible, metabolically stable and blood-brain-barrier-(BBB)-permeable neuroprotective agents. Our project includes: a. Synthesis of novel nucleotide/dinucleotide candidates of improved potency at specific P2Y-Rs; b. Evaluation of the antioxidant properties of the analogues both in cell-free oxidative systems and in neuronal cells; c. Evaluation of the activity of the analogues at P2Y-R subtypes; d. Synthesis of 3H/32P-labelled nucleotide candidates; e. Development of BBB-permeable nucleotide pro-drugs; f. Evaluation of the membrane and BBB-permeability of labelled nucleotide-pro-drugs; g. Evaluation of the neuroprotective potential of the analogues in brain cells and slices. The proposed nucleotide candidates may bring about amplified neuroprotection, due to their two independent and possibly synergistic mechanisms of  action. This research is expected to contribute to the fundamental knowledge on neuroprotection mechanisms. This project funded German-Israeli-Foundation (GIF) .