Novel Neuroprotective Neurotrophic NAP Analogs Targeting Iron Toxicity and Oxidative Stress in Neurodegenerative Diseases

摘要

Several factors, among them metal ion (Fe~(3+/2+), Cu~(2+), Zn~(2+)) dyshomeostasis, inflammatory processes, reduced expression of neurotrophic factors, and oxidative stress, have all been implicated in the neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD). Iron and iron-related oxidative stress are thought to play a pivotal role in the pathogenesis of these disorders. Accordingly, multifunctional compounds combining metal chelating and antioxidative activity hold a great promise as potential drugs for treating AD and PD. The 8-amino acid peptide NAP (NAPVSIPQ), derived from Activity-Dependent Neuroprotective Protein (ADNP), has been shown to possess potent neuroprotective action. However, NAP has no significant iron chelating capabilities in vitro or in vivo. In this study, two novel NAP analogs, one with a hydroxamate moiety (M98) and the other with an 8-hydroxyquinoline moiety (M99), were designed and investigated in the aim to improve the poor metal chelating and antioxidative activity of their parent peptide NAP.