Novel multifunctional neuroprotective iron chelator‐monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition

Abstract

Iron-dependent oxidative stress, elevated levels of iron and of monoamine oxidase (MAO)-B activity, and depletion of antioxidants in the brain may be major pathogenic factors in Parkinson's disease, Alzheimer's disease and related neurodegenerative diseases. Accordingly, iron chelators, antioxidants and MAO-B inhibitors have shown efficacy in a variety of cellular and animal models of CNS injury. In searching for novel antioxidant iron chelators with potential MAO-B inhibitory activity, a series of new iron chelators has been designed, synthesized and investigated. In this study, the novel chelators were further examined for their activity as antioxidants, MAO-B inhibitors and neuroprotective agents in vitro. Three of the selected chelators (M30, HLA20 and M32) were the most effective in inhibiting iron-dependent lipid peroxidation in rat brain homogenates with IC 50 values (12-16 lM), which is comparable with that of desferal, a prototype iron chelator that is not has orally active. Their antioxidant activities were further confirmed using electron paramagnetic resonance spectroscopy. In PC12 cell culture, the three novel chelators at 0.1 lM were able to attenuate cell death induced by serum deprivation and by 6-hydroxydopamine. M30 possessing propargyl, the MAO inhibitory moiety of the anti-Parkinson drug rasagiline, displayed greater neuroprotective potency than that of rasagiline. In addition, in vitro, M30 was a highly potent nonselective MAO-A and MAO-B inhibitor (IC 50 < 0.1 lM). However, HLA20 was more selective for MAO-B but had poor MAO inhibition, with an IC 50 value of 64.2 lM. The data suggest that M30 and HLA20 might serve as leads in developing drugs with multifunctional activities for the treatment of various neurodegenerative disorders.

Metal ions, Alzheimer's disease and chelation therapy

“…A series of 8-hydroxyquinoline analogues (VK-28, HLA-20 and MA-30) (Fig. 4) have shown the greatest potential for the treatment of several neurodegenerative diseases (61) and one of these compounds, clioquinol (PBT1, Fig. 5), reached the pilot phase II clinical trial (62)(63)(64)(65)(66), which suggests that clioquinol improves cognition and lowers plasma levels of Ab42 in some patients.…”

Selective Acetylcholinesterase Inhibitor Activated by Acetylcholinesterase Releases an Active Chelator with Neurorescuing and Anti-Amyloid Activities

“…Neurosci. (2010), 1, 737-746 pubs.acs.org/acschemicalneuroscience Article production of ROS, as well as a potent scavenger to scavenge radicals (33,34). It have been shown that the combination treatment of a metal chelator and a radical scavenger protect brain tissue from OS to a greater degree than is achievable with either of them.…”

“…Irreversible nonselective MAO-A and -B in liver and intestine is associated with "cheese effect", a sharp elevation in blood pressure that may be life-threatening (48,49). HLA20, possessing a neuroprotective moiety (a propargylamine) from anti-Parkinson's drug rasagiline, is a weak MAO-A/B inhibitor in vitro with a 66.21% and 33.21% inhibition for MAO-B and MAO-A, respectively, at a concentration of 100 μM (34). Attachment of a dimethyl carbamyl moiety at the 8-hydroxyl oxygen in HLA20 slightly increases the inhibitory activity as seen with HLA20A (about 9% and 5% inhibition of MAO-B and MAO-A, respectively, at a concentration of 10 μM in vitro).…”

“…HLA20 has relatively poor selectivity for MAO-B, with an IC 50 value of 110 μM versus >200 μM for MAO-A. It acts as a neuroprotective chelator with a wide range of pharmacological activities, including pro-survival neurorescue effects, induction of neuronal differentiation and regulation of APP and Aβ levels, and inhibition of oxidative stress and Aβ aggregation induced by metal ions (Cu and Zn) (34)(35)(36). Like other nonspecific chelators, HLA20 has the potential to chelate metal ions both in…”

“…Recently, we have developed a number of new chelators, including 5-(4-propargyl-piperazin-1-ylmethyl)-8-hydroxyquinoline (HLA20, Chart 1) (33,34). HLA20 was rationally designed by incorporating the neuroprotective and neurorestorative propargyl-amine moiety from the anti-Parkinson drug rasageline (Azilect, Teva, Kansas City, MO, USA) into our prototype chelator (5-[4-(2-hydroxyethyl) piperazine-1-ylmethyl]-8-hydroxyquinoline (VK28, Chart 1).…”