Toxins as PD cause/MPTP
An American student named Barry Kidston was unwittingly responsible for a major advance in PD research when he accidentally manufactured MPTP and gave himself PD. This paved the way for the reproduction of PD in laboratory animals.
In 1947 a North American pharmaceutical company named Hoffmann La Roche set about finding painkiller compounds that were less addictive than heroin. One of these was a derivative of a synthetic opiate called Demerol. A researcher named Albert Ziering developed a new compound called 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP), which proved to be no better than Demerol, and it was never marketed. In 1977 a 23 year old Maryland chemistry graduate named Barry Kidston read a paper by Ziering on this research and decide to explore MPPP’s potential as a recreational drug. He manufactured a quantity of it in his parent’s garage. However an error in the processing meant that he actually produced a subtly different compound called 1-methyl-4-phenylpyridinium or MPTP
Kidston experimentally injected the drug into himself and within three days had developed chronic and irreversible Parkinson’s Disease. Once MPTP was in his brain it was metabolized by the enzyme MAO-B of glial cells, and went on to interfere with Complex_1 of the electron transport chain, a component of mitochondrial metabolism leading to dopaminergic cell death and the buildup of free radicals, toxic molecules that contributed further to cell destruction.
The National Institute of Mental Health became involved and reproduced Kidston’s experiment. They tested the substance on rats, but due to the rodents' tolerance for this type of neurotoxin nothing was observed. Subsequently MPTP was successfully used to engender PD in squirrel monkeys and later on in laboratory mice.
Kidston's parkinsonism was successfully treated with levodopa but he died 18 months later from a (possibly deliberate) cocaine overdose. A post mortem was carried out and the havoc which MPTP had wrought to the dopaminergic neurons in his substantia nigra was revealed.
History repeated itself in 1982 when seven people in Santa Clara County, California were diagnosed with Parkinsonism after having used MPPP contaminated with MPTP. The neurologist J. William Langston in collaboration with NIH tracked down MPTP as the cause. Eventually the motor symptoms of two of the seven patients were successfully treated at Lund University Hospital in Sweden with neural grafts of foetal tissue.
Kidston unwittingly advanced the course of medical science by providing researchers with a drug which could induce PD in laboratory animals, thus opening a path for the closer study of the pathogenesis of the disease and the development of new therapies. There is speculation that MPTP might occur as a trace compound naturally and be the prime causative agent of P.D., but this hypothesis awaits proof.
"VPA was able to partially prevent striatal dopamine depletion and almost completely protect against substantia nigra DAergic cell loss. These results suggest that VPA may be a potential disease-modifying therapy for PD."
“The results suggest that the kynurenines here reported represent a family of synthetic compounds with neuroprotective properties against PD, and that they can serve as templates for the design of new drugs able to target the mitochondria."
Archer and Fredriksson  have shown that excercise reduces the effects of MPTP. Their conclusions state:-
"Physical exercise markedly attenuated the hypokinesic effect of MPTP in the exercise condition, MPTP-exercise, but not in the non-exercise conditions, MPTP-Cage and MPTP-Wheel, for both spontaneous motor activity and L: -dopa-induced activity. MPTP-induced loss of DA was also attenuated by exercise."
" Collectively, our results highlight a novel sterol-based neuroprotective mechanism with direct relevance to PD.Cell Death and Differentiation."
" Immunohistochemical studies using anti-tyrosine hydroxylase (TH) antibody showed that medication of kaempferol could prevent the loss of TH-positive neurons induced by MPTP. Taken together, we propose that kaempferol has shown anti-parkinsonian properties in our studies. More work is needed to explore detailed mechanisms of action."
“The data suggest that the S,S-enantiomer of hydroxybupropion may possess potential antiparkinsonian activity.”
Patel et al  have treated MPTP-induced mice with an angiogenic inhibitor, cyclic RGDfV, and reversed the Parkinsonin symptoms. Their conclusions include the statement:-
“These data suggest that cyRGDfV, and perhaps other anti-angiogenic drugs, are neuroprotective following acute MPTP treatment and may suggest that compensatory angiogenesis and BBB dysfunction may contribute to inflammation and DA neuron loss.”
Masilamoni et al  have carried out experiments with MPTP-induced Parkinsonian monkeys and concluded that:-
“Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease.”
“ These results demonstrate that treatment with rapamycin is able to rescue dopaminergic neurons and ameliorate the loss of DOPAC following MPTP treatment, likely via activation of autophagy/lysosome pathways. The use of rapamycin may therefore be a promising therapeutic agent for the treatment of PD.”
Duty, S and Jenner, P Br J Pharmacol. 2011 Apr 12. doi: 10.1111/j.1476-5381.2011.01426.x
Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease.
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- Kidd, S.K. and Schneider, J.S.Neuroscience.Aug. (2011) Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/21846494
- Brain Res Bull. 2011 May 30;85(3-4):133-40. Acuña-Castroviejo, D.; Tapias, V.; López, L.C.; Doerrier, C.; Camacho, E.; Carrión; M.D.; Mora, F.; Espinosa, A. and Escames, G. Protective effects of synthetic kynurenines on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. http://www.ncbi.nlm.nih.gov/pubmed/21419832
- Archer and Ferguson, A. (2011 Aug) Neurotox Res..Delayed Exercise-Induced Functional and Neurochemical Partial Restoration Following MPTP.http://www.ncbi.nlm.nih.gov/pubmed/21830164
- Lim, L.; Jackson-Lewis, V.; Wong; L.C.; Shui; G.H.; Goh, A,X.; Kesavapany, S.; Jenner, A.M.; Fivaz, M.; Przedborsk, i S. and Wenk, M.R. (2011 Aug.) Cell Death Differ. 2011 Aug 5. Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/21818119
- Li, S. and Pu, X.P. (2011) Biol Pharm Bull. 2011;34(8):1291-6. Neuroprotective effect of kaempferol against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/21804220
- Hansard, M.J.; Jackson, M.J.; Smith, L.A.; Rose, S. and Jenner, P. (2011) Behav. Pharmacol. 22 (3) 269-274 A major metabolite of bupropion reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. http://www.ncbi.nlm.nih.gov/pubmed/21522056
- Patel. A.; Toia, G.V.; Colletta, K.; Bradaric, B.D.; Carvey, P.M. and Hendey,B. (2011) Exp. Neurol. 231(1):160-70. An angiogenic inhibitor, cyclic RGDfV, attenuates MPTP-induced dopamine neuron toxicity. http://www.ncbi.nlm.nih.gov/pubmed/21703263
- Masilamoni, G.J; Bogenpohl, J.W.; Alagille, D.; Delevich, K.; Tamagnan, G.; Votaw; J.R.; Wichmann, T. and Smith, Y. (2011) Brain 134 (pt.7) 2057 – 2073 Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. http://www.ncbi.nlm.nih.gov/pubmed/21705423
- liu, K.; Lu, C.; Shen, L.; Shi,J.; Zhang, T.; Zhou,Y.; Zhou, L. And Sun, X. (2011 Jun.) Neurochem. Int. Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. http://www.ncbi.nlm.nih.gov/pubmed/21672587 </big