MPTP
Encyclopedia
MPTP is a neurotoxin
precursor to MPP+
, which causes permanent symptoms of Parkinson's disease
by destroying dopaminergic neuron
s in the substantia nigra
of the brain
. It has been used in study disease models in various animal studies.
While MPTP itself does not have opioid
effects, it is related to MPPP
, a synthetic opioid drug
with effects similar to those of morphine
and meperidine (Demerol). MPTP can be accidentally produced during the illicit manufacture of MPPP, which is how its Parkinson-inducing effects were first discovered.
, hence users of MPPP contaminated with MPTP will develop these symptoms.
MPTP itself is not toxic, and as a lipophilic compound can cross the blood-brain barrier
. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+
) by the enzyme MAO-B of glial cell
s. MPP+ kills primarily dopamine-producing
neurons in a part of the brain called the pars compacta of the substantia nigra
. MPP+ interferes with complex I of the electron transport chain
, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, 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 inhibitors (MAOIs) such as selegiline
. MAOIs prevent the metabolism of MPTP to MPP+ by inhibiting the action of MAO-B, minimizing toxicity and preventing neural death.
MPP+ has quite selective abilities to cause neuronal death in dopaminergic cells, it is presumed through a high-affinity uptake process in nerve terminals normally used to reuptake
dopamine after it has been released into the synaptic cleft
. The dopamine transporter
moves MPP+ inside the cell.
The resulting gross depletion of dopaminergic neurons has severe implications on 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 differing degree according to the strain of mice used) but do not show parkinsonian symptoms, however most of the recent studies indicates that MPTP can result in pakinsonism-like syndromes in mice (especially chronic syndromes). It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this.
, synthesized MPPP with MPTP as a major impurity, and self-injected the result. Within three days he began exhibiting symptoms of Parkinson's disease. The National Institute of Mental Health
found traces of MPTP and other pethidine
analogues in his lab. They tested the substances on rats, but due to rodents' tolerance for this type of neurotoxin nothing was observed. Kidston's parkinsonism was successfully treated with levodopa
but he died 18 months later from a cocaine
overdose. Upon autopsy, destruction of dopaminergic neurons in the substantia nigra was discovered.
In 1982, 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, and its effects on primates were researched. The motor symptoms of two of the seven patients were eventually successfully treated at Lund University Hospital
in Sweden
with neural grafts of fetal tissue.
Langston documented the case in his 1995 book The Case of the Frozen Addicts, which was later featured in two NOVA
productions by PBS
.
s resulted in parkinsonism, symptoms of which were subsequently reduced by levodopa
, a precursor for the neurotransmitter dopamine, currently the drug-of-choice in treatment of Parkinson's. The symptoms and brain structures of MPTP-induced Parkinson's are fairly indistinguishable to the point that MPTP may be used to simulate the disease in order to study Parkinson's physiology and possible treatments within the laboratory. Mouse studies have shown that susceptibility to MPTP increases with age.
Knowledge of MPTP and its use in reliably recreating Parkinson's disease in experimental models has inspired scientists to investigate the possibilities of surgically replacing neuron loss through fetal tissue implants, subthalamic
electrical stimulation
and stem cell
research, all of which have demonstrated initial, provisional successes.
It has been postulated that Parkinson's disease may be caused by minute amounts of MPP+-like compounds from ingestion or exogenously through repeated exposure and that these substances are too minute to be detected significantly by epidemiological studies.
In 2000, another animal model for Parkinson's Disease was found. It was shown that the pesticide
and insecticide
rotenone
causes parkinsonism in rats by killing dopaminergic neurons in the substantia nigra. Like MPP+, rotenone also interferes with complex I of the electron transport chain
.
in 1947 by Ziering et al. by reaction of phenylmagnesium bromide
with 1-methyl-4-piperidinone
.It was tested as a treatment for various conditions, but the tests were halted when Parkinson-like symptoms were noticed in monkeys. In one test of the substance, two of six human subjects died.
MPTP is used in industry as a chemical intermediate; the chloride
of the toxic metabolite MPP+ was turned into the herbicide
cyperquat.
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...
precursor to MPP+
MPP+
MPP+ is a positively charged molecule with chemical formula C12H12N+. It is toxic and acts by interfering with oxidative phosphorylation in mitochondria, causing depletion of ATP and cell death...
, which causes permanent symptoms of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
by destroying dopaminergic neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. It has been used in study disease models in various animal studies.
While MPTP itself does not have opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
effects, it is related to MPPP
MPPP
1-Methyl-4-phenyl-4-propionoxypiperidine or Desmethylprodine is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. It is not used in clinical practice, but has been illegally manufactured for recreational drug use...
, a synthetic opioid drug
Recreational drug use
Recreational drug use is the use of a drug, usually psychoactive, with the intention of creating or enhancing recreational experience. Such use is controversial, however, often being considered to be also drug abuse, and it is often illegal...
with effects similar to those of morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
and meperidine (Demerol). MPTP can be accidentally produced during the illicit manufacture of MPPP, which is how its Parkinson-inducing effects were first discovered.
Toxicity
Injection of MPTP causes rapid onset of ParkinsonismParkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
, hence users of MPPP contaminated with MPTP will develop these symptoms.
MPTP itself is not toxic, and as a lipophilic compound can cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+
MPP+
MPP+ is a positively charged molecule with chemical formula C12H12N+. It is toxic and acts by interfering with oxidative phosphorylation in mitochondria, causing depletion of ATP and cell death...
) by the enzyme MAO-B of glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s. MPP+ kills primarily dopamine-producing
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
neurons in a part of the brain called the pars compacta of the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
. MPP+ interferes with complex I of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, 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 inhibitors (MAOIs) such as selegiline
Selegiline
Selegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
. MAOIs prevent the metabolism of MPTP to MPP+ by inhibiting the action of MAO-B, minimizing toxicity and preventing neural death.
MPP+ has quite selective abilities to cause neuronal death in dopaminergic cells, it is presumed through a high-affinity uptake process in nerve terminals normally used to reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
dopamine after it has been released into the synaptic cleft
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
. The dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
moves MPP+ inside the cell.
The resulting gross depletion of dopaminergic neurons has severe implications on cortical
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
control of complex movements. The direction of complex movement is based from the substantia nigra to the putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
and caudate nucleus
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
, 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
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s including humans. Rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
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 differing degree according to the strain of mice used) but do not show parkinsonian symptoms, however most of the recent studies indicates that MPTP can result in pakinsonism-like syndromes in mice (especially chronic syndromes). It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this.
Discovery in users of illicit drugs
The neurotoxicity of MPTP was hinted at in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in MarylandMaryland
Maryland is a U.S. state located in the Mid Atlantic region of the United States, bordering Virginia, West Virginia, and the District of Columbia to its south and west; Pennsylvania to its north; and Delaware to its east...
, synthesized MPPP with MPTP as a major impurity, and self-injected the result. Within three days he began exhibiting symptoms of Parkinson's disease. The National Institute of Mental Health
National Institute of Mental Health
The National Institute of Mental Health is one of 27 institutes and centers that make up the National Institutes of Health...
found traces of MPTP and other pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
analogues in his lab. They tested the substances on rats, but due to rodents' tolerance for this type of neurotoxin nothing was observed. Kidston's parkinsonism was successfully treated with levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
but he died 18 months later from a cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
overdose. Upon autopsy, destruction of dopaminergic neurons in the substantia nigra was discovered.
In 1982, seven people in Santa Clara County, California
Santa Clara County, California
Santa Clara County is a county located at the southern end of the San Francisco Bay Area in the U.S. state of California. As of 2010 it had a population of 1,781,642. The county seat is San Jose. The highly urbanized Santa Clara Valley within Santa Clara County is also known as Silicon Valley...
were diagnosed with Parkinsonism after having used MPPP contaminated with MPTP. The neurologist J. William Langston
William Langston
Dr. J. William Langston is the founder, CEO, and Scientific Director of the Parkinson's Institute. He is a graduate of the University of Missouri School of Medicine and was formerly a faculty member at Stanford University and chairman of neurology at Santa Clara Valley Medical Center in San Jose,...
in collaboration with NIH tracked down MPTP as the cause, and its effects on primates were researched. The motor symptoms of two of the seven patients were eventually successfully treated at Lund University Hospital
Lund University
Lund University , located in the city of Lund in the province of Scania, Sweden, is one of northern Europe's most prestigious universities and one of Scandinavia's largest institutions for education and research, frequently ranked among the world's top 100 universities...
in Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
with neural grafts of fetal tissue.
Langston documented the case in his 1995 book The Case of the Frozen Addicts, which was later featured in two NOVA
NOVA (TV series)
Nova is a popular science television series from the U.S. produced by WGBH Boston. It can be seen on the Public Broadcasting Service in the United States, and in more than 100 other countries...
productions by PBS
Public Broadcasting Service
The Public Broadcasting Service is an American non-profit public broadcasting television network with 354 member TV stations in the United States which hold collective ownership. Its headquarters is in Arlington, Virginia....
.
Contribution of MPTP to research into Parkinson's disease
Langston et al.(1984) found that injections of MPTP in squirrel monkeySquirrel monkey
The squirrel monkeys are the New World monkeys of the genus Saimiri. They are the only genus in the subfamily Saimirinae.Squirrel monkeys live in the tropical forests of Central and South America in the canopy layer. Most species have parapatric or allopatric ranges in the Amazon, while S...
s resulted in parkinsonism, symptoms of which were subsequently reduced by levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
, a precursor for the neurotransmitter dopamine, currently the drug-of-choice in treatment of Parkinson's. The symptoms and brain structures of MPTP-induced Parkinson's are fairly indistinguishable to the point that MPTP may be used to simulate the disease in order to study Parkinson's physiology and possible treatments within the laboratory. Mouse studies have shown that susceptibility to MPTP increases with age.
Knowledge of MPTP and its use in reliably recreating Parkinson's disease in experimental models has inspired scientists to investigate the possibilities of surgically replacing neuron loss through fetal tissue implants, subthalamic
Subthalamus
The subthalamus is a part of the diencephalon. Its major part is the subthalamic nucleus. Functionally, it also encompasses the globus pallidus, which is topographically part of the telencephalon.-Anatomy:...
electrical stimulation
Deep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...
and stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
research, all of which have demonstrated initial, provisional successes.
It has been postulated that Parkinson's disease may be caused by minute amounts of MPP+-like compounds from ingestion or exogenously through repeated exposure and that these substances are too minute to be detected significantly by epidemiological studies.
In 2000, another animal model for Parkinson's Disease was found. It was shown that the pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
and insecticide
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...
rotenone
Rotenone
Rotenone is an odorless chemical that is used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the roots and stems of several plants such as the jicama vine plant...
causes parkinsonism in rats by killing dopaminergic neurons in the substantia nigra. Like MPP+, rotenone also interferes with complex I of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
.
Synthesis and uses
MPTP was first synthesized as an analgesicAnalgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
in 1947 by Ziering et al. by reaction of phenylmagnesium bromide
Phenylmagnesium bromide
Phenylmagnesium bromide, with the simplified formula , is a magnesium-containing organometallic compound. It is so commonly used that it is commercially available as a solution in diethyl ether or tetrahydrofuran . Phenylmagnesium bromide is a Grignard reagent...
with 1-methyl-4-piperidinone
4-Piperidinone
4-Piperidinone is a derivative of piperidine with the molecular formula C5H9NO. 4-Piperidone is used as an intermediate in the manufacture of chemicals and pharmaceutical drugs .-Piperidones:...
.It was tested as a treatment for various conditions, but the tests were halted when Parkinson-like symptoms were noticed in monkeys. In one test of the substance, two of six human subjects died.
MPTP is used in industry as a chemical intermediate; the chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
of the toxic metabolite MPP+ was turned into the herbicide
Herbicide
Herbicides, also commonly known as weedkillers, are pesticides used to kill unwanted plants. Selective herbicides kill specific targets while leaving the desired crop relatively unharmed. Some of these act by interfering with the growth of the weed and are often synthetic "imitations" of plant...
cyperquat.
External links
- Surprising Clue to Parkinson's, Time Magazine, 24 June 2001
- History of The Parkinson's Institute dates back to 1982
- How a Junkie's Brain Helps Parkinson's Patients, Wired, 21 September 2007