Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist; apomorphine
There have been many attempts to discover neuroprotective drugs for the treatment of Parkinson’s disease (PD). Many ofthese compounds either do not cross the blood brain barrier or are not very effective in the 6-hydroxydopamine or MPTP (N-methyl-4-phenyl-1,2,3,6-terahydropyridine) models of PD. We have examined several compounds including dopamine receptor agonist bromocritine, lisuride, pergolide and R-apomorphine for their neuroprotective action against the above neurotoxins in PC12 and dopamine neuroblastoma cell lines in culture and in vivo. R-apomorphine exhibited relatively potent neuroprotective action in vitro, cell culture and in vivo as a radical scavenger and iron chelator, because of its catechol structure. The recent clinical trials with apomorphine, where parkinsonian subjects can be weaned off L-dopa would suggest that this drug either exerts a neuroprotective action or that continuous sustained stimulation of dopamine receptor may be responsible for its unusual pharmacological activity. Apomorphine has a far more broad neuroprotective activity in the various models as compared with 1-selegiline and may therefore be an ideal drug to study neuroprotection in parkinsonian subjects with the use of PET or SPECT.
KeywordsPC12 Cell Iron Chelator Dopamine Neuron Dopamine Receptor Agonist Cytoprotective Property
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- Dexter D.T., Jenner P, Schapira A.H., Marsden C.D. (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson’s Disease Research Group. Ann Neurol 32 [Suppl]: S94-100Google Scholar
- Esterbauer H (1980) Aldehydes of lipid peroxidation. In: McBrien DCH, Slater TF (eds) Free radicals, peroxidation, and cancer. Academic Press, London, pp 101–122Google Scholar
- Jellinger K, Linert L, Kienzl E, Herlinger E, Youdim M.B., Ben Shachar D, Riederer P (1991) Chemical evidence for 6-hydroxydopamine to be an endogenous toxic factor in the pathogenesis of Parkinson’s disease Iron-melanin interaction and lipid peroxidation: implications for Parkinson’s disease. J Neural Transm 57 [Suppl]: 1609–1614Google Scholar
- Monteiro H.P., Winterbourn C.C., Mytilineou C, Danias P (1989) 6-Hydroxydopamine releases iron from ferritin and promotes ferritin-dependent lipid peroxidation 6-Hydroxydopamine toxicity to dopamine neurons in culture: potentiation by the addition of superoxide dismutase and N-acetylcysteine. Biochem Pharmacol 38: 1872–1875CrossRefGoogle Scholar
- Shoham S, Glinka Y, Tenne Z, Youdim M.B.H. (1996) Brain iron: function and dysfunction in relation to cognitive processes. In: Hallberg L, Asp NG (eds) Iron nutrition in health and disease. John Libbey, London, pp 205–218Google Scholar
- Youdim M.B.H. (1990) Neuropharmacological and neurochemical aspects of iron deficiency. In: Dobbing J (ed) Brain, behaviour and iron in the infant brain. Springer, Berlin Heidelberg New York Tekyo, pp 83–132Google Scholar
- Youdim M.B.H., Ben-Shachar D, Riederer P (1993a) Iron-melanin interaction and Parkinson’s disease. NIPS 8: 45–49Google Scholar