Mechanisms of MPTP toxicity and their implications for therapy of Parkinson's disease.
Parkinson's disease is one of the major neurodegenerative disorders. This disease is mainly characterized by tremor, bradykinesia, rigidity and postural instability that results primarily from a loss of dopaminergic neurons of nigrostriatal pathway. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is well known to damage the nigrostriatal dopaminergic pathway as seen in Parkinson's disease. Recent evidence shows that glial-related response plays a key role in the MPTP neurotoxic process and the blockade of glial activation may be a new therapeutic approach, which has applicability for Parkinson's disease. On the other hand, dopamine transporters (DAT) are important to the appearance of MPTP neurotoxicity because to be neurotoxin, an MPTP metabolite must first gain access to the dopaminergic neurons via DAT. Several studies suggest that DAT is a mandatory factor for expression of MPTP neurotoxicity and may explain the selective neuronal damage in the substantia nigra in MPTP toxicity. Therefore, DAT is thought to play an important role in the MPTP neurotoxic process and specific blockade of DAT with high-affinity inhibitors in neurodegenerative diseases such as Parkinson's disease, where the effective levels of dopamine are markedly reduced, may have beneficial consequences. In view of these new insights, this article suggests that the overexpression of S100beta protein secreted by glial cells may be an exacerbating factor in the neurodegeneration of dopaminergic cells. In this review, we also demonstrate the possible role of DAT in the brain cells in MPTP neurotoxicity. Thus this review provides valuable information for progressive neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.
Watanabe
Yu
Y
Department of Drug Metabolism and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, Japan.
Himeda
Toshiki
T
Araki
Tsutomu
T
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C493214:SLC6A3 protein, human; C493215:Slc6a3 protein, mouse; D004298:Dopamine