Therapeutic targets and potential of the novel brain‐ permeable multifunctional iron chelator–monoamine oxidase inhibitor drug, M‐30, for the treatment of Alzheimer's disease1

Abstract

Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple CNS targets. We have synthesized a multifunctional non‐toxic, brain permeable iron chelator drug, M‐30, possessing propargyl monoamine oxidase (MAO) inhibitory neuroprotective and iron‐chelating moieties, from our prototype iron chelator VK‐28. In the present study M‐30 was shown to possess a wide range of pharmacological activities, including pro‐survival neurorescue effects, induction of neuronal differentiation and regulation of amyloid precursor protein (APP) and β‐amyloid (Aβ) levels. M‐30 was found to decrease apoptosis of SH‐SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via reduction of the pro‐apoptotic proteins Bad and Bax, and inhibition of the apoptosis‐associated phosphorylated H2A.X protein (Ser 139) and caspase 3 activation. In addition, M‐30 induced the outgrowth of neurites, triggered cell cycle arrest in G₀/G₁ phase and enhanced the expression of growth associated protein‐43. Furthermore, M‐30 markedly reduced the levels of cellular APP and β‐C‐terminal fragment (β‐CTF) and the levels of the amyloidogenic Aβ peptide in the medium of SH‐SY5Y cells and Chinese hamster ovary cells stably transfected with the APP ‘Swedish’ mutation. Levels of the non‐amyloidogenic soluble APPα and α‐CTF in the medium and cell lysate respectively were coordinately increased. These properties, together with its brain selective MAO inhibitory and propargylamine‐ dependent neuroprotective effects, suggest that M‐30 might serve as an ideal drug for neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, in which oxidative stress and iron dysregulation have been implicated.