Novel neuroprotective neurotrophic NAP analogs targeting metal toxicity and oxidative stress: potential candidates for the control of neurodegenerative diseases.

A large body of data indicates that a cascade of events contributes to the neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD). Metal (Fe, Cu, Zn) dyshomeostasis and oxidative stress are believed to play a pivotal role in the pathogenesis of these diseases. Accordingly, multifunctional compounds combining metal chelating and antioxidative activity hold a great promise as potential drugs for treating AD and PD. In this study, two novel NAPVSIPQ (NAP) analogs (M98 and M99) with potential antioxidant-metal chelating ability were designed and investigated, aiming to improve the poor metal chelating and antioxidative activity of NAP. Our studies showed that both M98 and M99 formed stable metal (Fe, Cu, Zn) complexes in water and demonstrated good metal (Fe, Cu, Zn) chelating properties as opposed to the poor metal (Fe, Cu, Zn) chelating properties of their parent peptide NAP. M98 and M99 exhibited significant inhibition of iron-induced lipid peroxidation in rat brain homogenates at concentrations of > or = 30 microM, while NAP failed to show any inhibition even at 100 microM. In human neuroblastoma cell (SH-SY5Y) culture, M98 and M99 at 1 microM completely protected against 6-hydroxydopamine (6OHDA) toxicity with potency similar to NAP and desferal (DFO), a strong iron chelator and a highly potent radical scavenger. In PC12 cell culture, M98 at the range of 0.001-1 microM displayed potent protection against 6-OHDA toxicity, comparable to NAP and DFO. These results suggest that M98 and M99 deserve further investigation as potential drug candidates for neuroprotection.