The susceptibility of neurons to free radical toxicity partially underlies the pathomechanism of neurodegenerative diseases. On the other hand, excitotoxicity also contributes to neurodegeneration. Our previous studies demonstrated the unique properties of D2AAK1 as a potent multi-target ligand of aminergic G protein-coupled receptors (GPCRs) which dose-dependently stimulates growth, survival of neurons, and promotes their integrity. The aim of our study was to investigate the potential neuroprotective and antioxidant properties of D2AAK1. Here we show that D2AAK1 activates cellular and molecular neuroprotective mechanisms, prevents cells from excitotoxicity and free radicals. Furthermore, D2AAK1 induced no genotoxic events in neuronal cells in vitro. Most importantly, D2AAK1 protects neurons from the effects of high temperatures by molecular chaperones activation. The D2AAK1 effects on selected organs was further evaluated in mice and no pathological changes were observed after chronic administration. In the light of our experiments, D2AAK1 can be further developed into a potential treatment for neurodegenerative diseases, in particular related to memory impairment. In summary, D2AAK1 has promising properties for potential treatments of neurodegenerative diseases.
Keywords: Chaperones; Excitotoxicity; Hyperthermia; Neurons; Neuroprotection; Redox balance.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.