title: Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice.
abstract: Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral β-amyloid plaques. In addition, our results demonstrate that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of aged mice, compared with vehicle-treated aged control mice. In summary, the present study indicates that the novel MAO inhibitor/iron chelating drug, M30, acting against multiple brain targets could reverse age-associated memory impairment and provide a potential treatment against the progression of neurodegeneration in ageing.
authors.affiliation: Eve Topf Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute Technion-Faculty of Medicine, Haifa 31096, Israel.
authors.forename: Lana
authors.initials: L
authors.lastname: Kupershmidt
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
authors.forename: Orit
authors.initials: O
authors.lastname: Bar-Am
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
mesh_terms: D000375:Aging / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000032:analysis; D000818:Animals; D054022:Cerebrum / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003072:Cognition Disorders / Q000188:drug therapy; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D007501:Iron / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D009483:Neuropsychological Tests
chemical_list: C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D006912:Hydroxyquinolines; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D007501:Iron