Editing MPTP (section)

==Toxicity==
{{More citations needed|section|date=December 2022}}
Injection of MPTP causes rapid onset of [[Parkinsonism]], hence users of MPPP contaminated with MPTP will develop these symptoms.

MPTP itself is not toxic, but it is a [[lipophilicity|lipophilic]] compound and can therefore cross the [[blood–brain barrier]]. Once inside the brain, MPTP is metabolized into the toxic [[cation]] [[1-methyl-4-phenylpyridinium]] (MPP<sup>+</sup>)<ref>{{cite journal|title=Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat|year=1994|doi=10.1073/pnas.91.11.5104|doi-access=free|last1=Frim|first1=D. M.|last2=Uhler|first2=T. A.|last3=Galpern|first3=W. R.|last4=Beal|first4=M. F.|last5=Breakefield|first5=X. O.|last6=Isacson|first6=O.|journal=Proceedings of the National Academy of Sciences|volume=91|issue=11|pages=5104–5108|pmid=8197193|pmc=43940|bibcode=1994PNAS...91.5104F}}</ref> by the enzyme [[monoamine oxidase B]] (MAO-B) of [[glial cell]]s, specifically astrocytes. MPP<sup>+</sup> kills primarily [[dopaminergic|dopamine-producing]] [[neurons]] in a part of the brain called the [[pars compacta]] of the [[substantia nigra]] (SNc). MPP<sup>+</sup> interferes with [[complex I]] of the [[electron transport chain]], a component of [[mitochondria]]l metabolism, which leads to cell death and causes the buildup of [[free radical]]s, toxic molecules that contribute further to cell destruction.

Because MPTP itself is not directly harmful, toxic effects of acute MPTP poisoning can be mitigated by the administration of [[monoamine oxidase inhibitor]]s (MAOIs) such as [[selegiline]]. MAOIs prevent the metabolism of MPTP to MPP<sup>+</sup> by inhibiting the action of MAO-B, minimizing toxicity, and preventing neural death.

Dopaminergic neurons are selectively vulnerable to MPP<sup>+</sup> because DA neurons exhibit dopamine [[reuptake]] which is mediated by [[dopamine transporter]] (DAT), which also has high-affinity for MPP<sup>+</sup>.<ref>{{cite journal | last1=Richardson | first1=Jason | title=Richardson, Jason R., et al. "Paraquat neurotoxicity is distinct from that of MPTP and rotenone. | url=https://academic.oup.com/toxsci/article-abstract/88/1/193/1662975 | journal=Toxicological Sciences  | year=2005 | volume=88 | issue=1 | pages=193–201 | doi=10.1093/toxsci/kfi304 | pmid=16141438 | doi-access=free}}</ref> The dopamine transporter scavenges for excessive dopamine at the synaptic spaces and transports them back into the cell. Even though this property is exhibited by both VTA and SNc neurons, VTA neurons are protective against MPP<sup>+</sup> insult due to the expression of [[calbindin]]. Calbindin regulates the availability of Ca<sup>2+</sup> within the cell, which is not the case in SNc neurons due to their high-calcium-dependent autonomous pacemaker activity.

The gross depletion of dopaminergic neurons severely affects [[cerebral cortex|cortical]] control of complex movements. The direction of complex movement is based from the substantia nigra to the [[putamen]] and [[caudate nucleus]], which then relay signals to the rest of the brain. This pathway is controlled via dopamine-using neurons, which MPTP selectively destroys, resulting, over time, in parkinsonism.

MPTP causes Parkinsonism in [[primate]]s, including humans. [[Rodent]]s are much less susceptible. Rats are almost immune to the adverse effects of MPTP. Mice were thought to only suffer from cell death in the substantia nigra (to a differing degree according to the strain of mice used) but do not show Parkinsonian symptoms;<ref name="william">{{cite book | author = Langston, J. W. | chapter = Chapter 30 The Impact of MPTP on Parkinson's Disease Research: Past, Present, and Future | title = Parkinson's Disease. Diagnosis and Clinical Management | editor = Factor, S. A. | editor2 = Weiner, W. J. | publisher = Demos Medical Publishing | year = 2002 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK10185/}}</ref> however, most of the recent studies indicate that MPTP can result in Parkinsonism-like syndromes in mice (especially chronic syndromes).<ref>{{cite web | url = http://www.ndineuroscience.com/userfiles/Parkinson's%20info.pdf | title = Parkinson's Disease Models | publisher = Neuro Detective International | access-date = 2012-03-06 }}</ref><ref>{{ cite journal |author1=Luo Qin |author2=Peng Guoguang |author3=Wang Jiacai |author4=Wang Shaojun | year = 2010 | title = The Establishment of Chronic Parkinson's Disease in Mouse Model Induced by MPTP | journal = Journal of Chongqing Medical University | volume = 2010 | issue = 8 | pages = 1149–1151 | url = http://caod.oriprobe.com/articles/24182813/The_establishment_of_chronic_parkinson__s_desease_in_mouse_model_indud.htm | access-date = 2012-03-06}}</ref> It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this.<ref name="william"/>