The pivotal role of iron in NF-kappa B activation and nigrostriatal dopaminergic neurodegeneration. Prospects for neuroprotection in Parkinson's disease with iron chelators.
R-Apomorphine (APO) the catechol-derived dopamine D1-D2 receptor agonist has been shown to be highly potent iron chelator and radical scavenger and inhibitor of membrane lipid peroxidation in vitro, in vivo and in cell culture employing PC12 cells. Its potency has been compared to the prototype iron chelator desferrioxamine (desferal), dopamine, nifedipine and dopamine D2 receptor agonists, bromocriptine, lisuride, pergolide and pramipexole. APO also inhibits brain and mitochondrial protein oxidation. In vivo APO protects against MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)- induced striatal dopaminergic neurodegeneration in C57 black mice with as low as 5 mg/kg. APO is a reversible competitive inhibitor of monoamine oxidase (MAO) A and B with IC50 values of 93 and 214 uM, respectively. The iron chelating and radical scavenging actions of desferal and APO explains their ability to inhibit iron and 6-hydroxydopamine (6-OHDA)-induced neurodegeneration and activation of redox-sensitive transcription factor NF-kappa B and the subsequent transactivation of promoters of genes involved in inflammatory cytokines. Iron is thought to play a pivotal role in neurodegeneration, and APO may be an ideal drug to investigate neuroprotection in Parkinson's disease where iron and oxidative stress have been implicated in the pathogenesis of nigrostriatal dopamine neuron degeneration.
Youdim
M B
MB
Technion, Faculty of Medicine, Eve Topf, Haifa, Israel. youdim@tx.technion.ac.il
Grünblatt
E
E
Mandel
S
S
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018663:Adrenergic Agents; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001058:Apomorphine / Q000494:pharmacology / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000293:injuries; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents; D005293:Ferritins / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000037:antagonists & inhibitors / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000517:prevention & control; D016627:Oxidopamine / Q000037:antagonists & inhibitors; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D015259:Dopamine Agents; D016328:NF-kappa B; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D005293:Ferritins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine