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 b-amyloid (Ab) 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 G 0 /G 1 phase and enhanced the expression of growth associated protein-43. Furthermore, M-30 markedly reduced the levels of cellular APP and b-C-terminal fragment (b-CTF) and the levels of the amyloidogenic Ab 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 APPa and a-CTF in the medium and cell lysate respectively were coordinately increased. These properties, together with its brain selective MAO inhibitory and propargylaminedependent 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.

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

“…Levels of the nonamyloidogenic soluble APP␣ and ␣-C-terminal fragment in the medium and cell lysate, respectively, were coordinately increased. 125 These results support the implication that M-30 was involved in the regulation of iron-homeostasis-associated protein, such as APP (FIG. 3).…”

“…125 In this model system, the SH-SY5Y neuroblastoma cells exposed to long-term serum deprivation exhibited a significant increase in apoptotic cells compared with cells grown in full serum. M-30 caused a marked decrease in the level of apoptotic cells and significantly reduced phosphorylated histone H2A.X, a marker of apoptosis and cleaved caspase-3 appearance.…”

“…32,124 A recent study 125 has demonstrated that M-30 has a wide range of pharmacological activities, including a significant downregulation of membrane-associated holo-APP levels in the mouse hippocampus and in SH-SY5Y neuroblastoma cells, presumably by chelating intracellular iron pools. Indeed, M-30 was found to suppress translation of a luciferase reporter mRNA via the APP 5'UTR sequence that includes the APP IRE.…”

“…Indeed, M-30 was found to suppress translation of a luciferase reporter mRNA via the APP 5'UTR sequence that includes the APP IRE. 125,126 Furthermore, M-30 markedly reduced the levels of cellular APP and ␤-C-terminal fragment, and the levels of the amyloidogenic A␤ peptide in the medium of SH-SY5Y cells and Chinese hamster ovary cells stably transfected with the APP "Swedish" mutation (CHO/⌬NL). Levels of the nonamyloidogenic soluble APP␣ and ␣-C-terminal fragment in the medium and cell lysate, respectively, were coordinately increased.…”

Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity

“…This, in turn, is transported from the cytosol into intracellular vesicles by a second transporter (vesicular monoamine transporter 2) where the dopamine is stored for future use. There are three enzymes that metabolize dopamine to less toxic products (10). Two of these enzymes, monoamine oxidase and catechol O-methyltransferase, are found both inside and outside of the cell.…”