Abstract
Based on a multimodal drug design strategy for age-related neurodegenerative diseases, we have synthesized a multifunctional nontoxic, brain-permeable iron-chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase-B inhibitor, rasagiline and the antioxidant–iron chelator moiety of the 8-hydroxyquinoline derivative of the iron chelator, VK28. In the present short overview, we describe the neuroprotective and the neurorestorative activity of M30, acting against multiple brain targets, including regulation on amyloid β, neurogenesis, and activation of hypoxia inducible factor signaling pathways. The diverse pharmacological properties and several pathological targets of M30 make this drug potential valuable for therapeutic strategy of Alzheimer's-like neuropathology and aging.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Weinreb O, Amit T, Mandel S, Kupershmidt L, Youdim MB (2010) Neuroprotective multifunctional iron chelators: from redox-sensitive process to novel therapeutic opportunities. Antioxid Redox Signal 13(6):919–949
Bandyopadhyay S, Huang X, Lahiri DK, Rogers JT (2010) Novel drug targets based on metallobiology of Alzheimer's disease. Expert Opin Ther Targets 14(11):1177–1197
Olivares D, Huang X, Branden L, Greig NH, Rogers JT (2009) Physiological and pathological role of alpha-synuclein in Parkinson's disease through iron mediated oxidative stress: the role of a putative iron-responsive element. Int J Mol Sci 10(3):1226–1260
Roberts BR, Ryan TM, Bush AI, Masters CL, Duce JA (2012) The role of metallobiology and amyloid-β peptides in Alzheimer's disease. J Neurochem 120(Suppl 1):149–166
Smith MA, Zhu X, Tabaton M, Liu G, McKeel DW Jr, Cohen ML, Wang X, Siedlak SL, Dwyer BE, Hayashi T, Nakamura M, Nunomura A, Perry G (2010) Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 19(1):363–372
Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik ZI, Warshawsky A, Youdim MB, Fridkin M (2005) Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorg Med Chem 13(3):773–783
Zheng H, Fridkin M, Youdim MB (2012) From antioxidant chelators to site-activated multi-target chelators targeting hypoxia inducing factor, beta-amyloid, acetylcholinesterase and monoamine oxidase A/B. Mini Rev Med Chem 12(5):364–370
Shachar DB, Kahana N, Kampel V, Warshawsky A, Youdim MB (2004) Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lesion in rats. Neuropharmacology 46(2):254–263
Gal S, Zheng H, Fridkin M, Youdim MBH (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem 95(1):79–88
Gal S, Abassi ZA, Youdim MB (2010) Limited potentiation of blood pressure in response to oral tyramine by the anti-Parkinson brain selective multifunctional monoamine oxidase-AB inhibitor, M30. Neurotox Res 18(2):143–150
Gal S, Zheng H, Fridkin M, Youdim MB (2010) Restoration of nigrostriatal dopamine neurons in post-MPTP treatment by the novel multifunctional brain-permeable iron chelator-monoamine oxidase inhibitor drug, M30. Neurotox Res 17(1):15–27
Zhu W, Xie W, Pan T, Xu P, Fridkin M, Zheng H, Jankovic J, Youdim MB, Le W (2007) Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. FASEBJ 21(14):3835–3844
Kupershmidt L, Weinreb O, Amit T, Mandel S, Carri MT, Youdim MB (2009) Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. FASEB J 23(11):3766–3779
Smith TG, Talbot NP (2010) Prolyl hydroxylases and therapeutics. Antioxid Redox Signal 12(4):431–439
Gorres KL, Raines RT (2010) Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol 45(2):106–124
Harten SK, Ashcroft M, Maxwell PH (2010) Prolyl hydroxylase domain inhibitors: a route to HIF activation and neuroprotection. Antioxid Redox Signal 12(4):459–480
Chavez A, Miranda LF, Pichiule P, Chavez JC (2008) Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors. Ann N Y Acad Sci 1147:312–320
Avramovich-Tirosh Y, Bar-Am O, Amit T, Youdim MBH Weinreb O (2010). Up-regulation of hypoxia-inducible factor (HIF) -1a and HIF-target genes in cortical neurons by the novel multifunctional iron chelator anti-Alzheimer drug, M30. Curr Alzheimer Res 7(4): 300–306
Kupershmidt L, Weinreb O, Amit T, Mandel S, Bar-Am O, Youdim MB (2011) Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain. Neuroscience 189:345–358
Kupershmidt L, Amit T, Bar-Am O, Youdim MB, Weinreb O (2012) Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice. Mech Ageing Dev 133(5):267–274
Kupershmidt L, Amit T, Bar Am O, Youdim MB, Weinreb O (2012) The novel multi-target iron chelating-radical scavenging compound M30 possesses beneficial effects on major hallmarks of Alzheimer's disease. Antioxid Redox Signal 17(6):860–877
Commercial interest
MBH Youdim is the scientific founder of Varinel Inc and has commercial interest in M30 drug.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kupershmidt, L., Amit, T., Bar-Am, O. et al. Multi-target, Neuroprotective and Neurorestorative M30 Improves Cognitive Impairment and Reduces Alzheimer's-Like Neuropathology and Age-Related Alterations in Mice. Mol Neurobiol 46, 217–220 (2012). https://doi.org/10.1007/s12035-012-8304-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-012-8304-7