MPTP-induced parkinsonism

Nitric oxide has also been implicated in PD. Thus animals with MPTP-induced Parkinsonism not only show extensive gliosis in the substantia nigra (like humans) in which the glial cells produce NO, but Liberatore and colleagues have found that in iNOS (inducible nitric oxide synthase) knock-out mice the toxicity of MPTP is halved. Since NO releases iron from ferritin and produces toxic peroxinitrate in the presence of superoxide radicals it could accelerate, even if it does not initiate, dopaminergic cell death (see Hirsch and Hunot 2000 for further details). 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

Fujikawa T, Miguchi S, Kanada N, et al. Acanthopanax senticosus Harms as a prophylactic for MPTP-induced Parkinson s disease in rats. J Ethnopharmacol 2005 97 375-381. 

Chiueh, C.C., Miyake, J., Peng, M.T. Role of dopamine autoxidation, hydroxyl radical generation, and calcium overload in underlying mechanisms involved in MPTP-induced parkinsonism. Adv. Neurol. 60 251, 1993. 

Schneider J. S. (1992). MPTP-induced Parkinsonism Acceleration of biochemical and behavioral recovery by GM ganglioside treatment. J. Neurosci. Res. 31 112-119. 

SALICYLATE PROTECTS AGAINST MPTP-INDUCED PARKINSONISM... 

Langston JW, Langston EB, Irwin I. MPTP-induced parkinsonism in human and non-human primates—clinical and experimental aspects. Acta Neurol Scandi 1984 suppl 100 49-54. 

Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing MPTP-induced parkinsonism and is currently under study as a neuroprotective agent. 

Stern Y, Langston JW. 1985. Intellectual changes in patients with MPTP-induced parkinsonism. Neurology 35 1506-1509. 

Benazzouz A, Boraud T, Dubedat P, Boireau A, Stutzmann JM, Gross C (1995) Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey a pilot study. Eur J Pharmacol 284 299-307. 

Emborg ME, Tetrud JW, Moirano J, McLaughlin WW, Bankiewicz KS (2003) Rest tremor in rhesus monkeys with MPTP-induced parkinsonism. Front Biosci 3 48-54. 

Imbert C, Bezard E, Guitraud S, Boraud T, Gross CE (2000) Comparison of eight clinical rating scales used for the assessment of MPTP-induced parkinsonism in the Macaque monkey. J Neurosci Meth 96 71-76. 

This patient had taken ecstasy 10 times during the year before, the last time about 3 months before the onset of symptoms. Apart from marijuana, he denied using other substances. He was treated with maximal tolerable doses of levodopa and pramipexole, without improvement. The authors reported that they had no explanation for this patient s symptoms, other than the use of ecstasy. They felt that the parkinsonian symptoms most closely resembled MPTP-induced parkinsonism. They further postulated that this could be a delayed neurotoxic effect of ecstasy in the substantia nigra and striatum and could have occurred as a result of neuronal damage by free radicals. 

Jenner P, Marsden CD. MPTP induced parkinsonism A model of Parkinson s disease and its relevance to the disease process. In Jankovic J, Tolosa E (eds), Parkinson s disease and movement disorders, Williams and Wilkins, Baltimore, MD, 1993, pp. 69 75. 

The potential benefits of alleviating dopamine deficiency in the brains of Parkinson s patients by tissue implantation have been widely discussed from both clinical and ethical perspectives. Conventional dopamine replacement therapy suffers from well known and serious limitations. The most recent data indicate that fetal-tissue transplants into patients with idiopathic or MPTP-induced Parkinson s disease are clinically encouraging and may be highly beneficial for at least some patients (6,7). 

Mandir, A. S., Przedborski, S., Jackson-Lewis, V., Wang, A., Simbulan-Rosenthal, C. M., Smulson, M. E., et al. (1999) Poly(ADP-ribose) polymerase activation mediates l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc. Natl. Acad. Sci. USA 96, 5774-5779. 

Filion M, Tremblay L (1991) Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res., 547, 142-151. 

Bodis-Wollner, I., Chung, E., Ghilardi, M.F., Glover, A., Onofrj, M., Pasik, P. and Samson, Y. (1991) Acetyl-levo-carnitine protects against MPTP-induced parkinsonism in primates. J. Neural Transm. (P-D Sect.) 3 63-72. 

Langston, J.W., Irwin, I., Langston, E.B. and Fomo, L.S. (1984b) Pargyline prevents MPTP-induced parkinsonism in primates. Science 225 1480-1482. 

Importantly, the neuropathological and clinical characteristic features of MPTP-induced parkinsonism invariably resemble idiopathic Parkinson s disease rather more intimately than anyother previous human or experimented animal disorder exhibited by toxins, viruses, metals, or other modes. In short, the molecular pathophysiology of the ensuring MPTP neurotoxicity has virtually decephered the mystery surrounding the neurodegenerative mechanisms particularly associated with the idiopathic parkinsonism. 

Mandir AS, Simbirlan Rosenthal CM, Poitras MF et al. A novel in vivo post-translational modification of p53 by PARP-1 in MPTP-induced parkinsonism. J Neutochem 2002 83(1) 186-192. 

Brownell A-L, Elmaleh DR, Meltzer P, et al.(1996) Cocaine congeners as PET imaging probes for dopamine terminals in normal and MPTP induced parkinsonism in nonhuman primate brain. J Nucl Med 37 1186-92... 

---