title: M30, a brain permeable multitarget neurorestorative drug in post nigrostriatal dopamine neuron lesion of parkinsonism animal models.
abstract: The anti-Parkinson iron chelator brain selective monoamine oxidase (MAO) AB inhibitor M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease (PD) and ALS. We examined the effect of M30 on a pre-existing lesion induced by the parkinsonism-inducing toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this neurorescue/neurorestorative paradigm, M30 was orally administered to mice for 14 days (2.5-5 mg/kg/day) following post MPTP or lactacystin lesion and was shown to significantly elevate striatal dopamine, serotonin and noradrenaline levels, reduce their metabolism, and elevate tyrosine-hydroxylase protein levels. Importantly, M30 elevated MPTP-reduced dopaminergic and transferrin receptor cell count in the substantia nigra pars compacta (SNpc). Finally, M30 was shown to decrease mitosis and elevate HIF (hypoxia induced factor) which regulates the neurotrophins BDNF, GDNF, VEGF and erythropoietin by elevating their brain levels, thus providing additional protection. These findings indicates that brain-permeable M30 has neurorestorative activity, which may clearly be of clinical importance for the treatment of PD.
authors.affiliation: Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Technion-Rappaport Family Faculty of Medicine, Haifa, Israel. youdim@tx.technion.ac.il
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D006912:Hydroxyquinolines / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D006912:Hydroxyquinolines