MPTP: a review of its mechanisms of neurotoxicity |
| |
| Affiliation: | 1. Neuroscience Research, Movement Disorders Division, Department of Neurology, Columbia University, New York, NY 10032, USA;2. Department of Pathology, Columbia University, New York, NY 10032, USA;1. Department of Neurology, Linzi Maternal & Child Health Hospital of Zibo, Zibo, Shandong, China;2. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China;3. Shenzhen Research Institute of the Hong Kong Polytechnic University, State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen, Guangdong, China;4. Department of Pathophysiology, Medical College, Qingdao University, Qingdao, Shandong, China;5. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China;1. The Central Laboratory, Changchun Normal University, Changchun, Jilin, PR China;2. College of Life Science, Changchun Normal University, Changchun, Jilin, PR China;3. Higher Education Research Institute, Changchun Normal University, Changchun, Jilin, PR China;1. Institute of Analytical and Bioanalytical Chemistry, Ulm University, Ulm, Germany;2. Institute of General Physiology, Ulm University, Ulm, Germany;1. Brain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3US, UK;2. Royal Hallamshire Hospital, Department of Neurosurgery, Sheffield S10 2JF, UK;1. Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden;2. Department of Neurology, Scania University Hospital, Lund, Sweden |
| |
| Abstract: | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinson's disease (PD). After systemic administration of MPTP, its active metabolite, MPP+, accumulates within SNpc DA neurons, where it inhibits ATP production and stimulates superoxide radical formation. The produced superoxide radicals react with nitric oxide (NO) to produce peroxynitrite, a highly reactive tissue-damaging species that damages proteins by oxidation and nitration. Only selected proteins appear nitrated, and among these is found tyrosine hydroxylase (TH), the rate limiting enzyme in DA synthesis, and the pre-synaptic protein α-synuclein. Peroxynitrite also nicks DNA, which, in turn, activates poly(ADP-ribose) polymerase (PARP). PARP activation consumes ATP, and thus acutely depletes the cell energy stores. This latter event aggravates the preexisting energy failure due to MPP+-induced mitochondrial respiration blockade and precipitates cell death. On the other hand, MPP+ also activates highly regulated cell death-associated molecular pathways that participate in the relentless demise of neurons in PD. Altogether, these findings support the view that MPTP's deleterious cascade of events include mitochondrial respiration deficit, oxidative stress, energy failure and activation of apoptotic genetic programs. Because of the similarity between the MPTP mouse model and PD, it is tempting to propose that a similar scenario applies to the pathogenesis of PD. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
