Restoration of nigrostriatal dopamine neurons in post-MPTP treatment by the novel multifunctional brain-permeable iron chelator-monoamine oxidase inhibitor drug, M30.
The anti-Parkinson iron chelator-monoamine oxidase inhibitor M30 [5-(N-methyl-N-propargyaminomethyl)-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, and ALS. In the present study we sought to examine 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 paradigm, M30 orally administered to mice for 14 days (2.5 mg/kg/day) following MPTP was shown to significantly elevate striatal dopamine levels, reduce its metabolism, and elevate tyrosine-hydroxylase protein levels (from 25.86 +/- 5.10 to 68.35 +/- 10.67% of control) and activity (from 7.52 +/- 0.98 to 16.33 +/- 2.92 pmol/mg protein/min). Importantly, M30 elevated MPTP-reduced dopaminergic (from 62.8 +/- 4.1 to 84.2 +/- 5.9% of control) and transferrin receptor (from 31.3 +/- 2.6 to 80.4 +/- 7.6% of control) cell count in the SNpc. Finally, M30 was shown to decrease mitosis, thus providing additional protection. These findings suggest that brain-permeable M30 may clearly be of clinical importance for the treatment of PD.
Gal
Shunit
S
Department of Pharmacology, Technion-Rappaport Family Faculty of Medicine, Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Efron St, P.O. Box 9697, Haifa, 31096, Israel.
Zheng
Hailin
H
Fridkin
Mati
M
Youdim
Moussa B H
MB
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D006719:Homovanillic Acid / Q000378:metabolism; D006912:Hydroxyquinolines / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D011990:Receptors, Transferrin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D006912:Hydroxyquinolines; D011990:Receptors, Transferrin; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid