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MPP+
Skeletal formula of MPP+
Ball-and-stick model of the MPP+ cation
Names
Preferred IUPAC name
1-Methyl-4-phenylpyridin-1-ium
Other names
  • Cyperquat
  • 1-Methyl-4-phenylpyridinium; N-Methyl-4-phenylpyridine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
EC Number
  • 248-939-7
MeSH 1-Methyl-4-phenylpyridinium
UNII
  • InChI=1S/C12H12N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-10H,1H3/q+1 checkY
    Key: FMGYKKMPNATWHP-UHFFFAOYSA-N checkY
  • C[n+]1ccc(cc1)c2ccccc2
Properties
C12H12N+
Molar mass 170.25 g/mol
Appearance White to beige powder
10 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

MPP+ (1-methyl-4-phenylpyridinium) or cyperquat is a positively charged organic molecule with the chemical formula C12H12N+. It is a monoaminergic neurotoxin that acts by interfering with oxidative phosphorylation in mitochondria by inhibiting complex I, leading to the depletion of ATP and eventual cell death.[1]

MPP+ arises in the body as the toxic metabolite of the closely related compound MPTP. MPTP is converted in the brain into MPP+ by the enzyme MAO-B, ultimately causing parkinsonism in primates by killing certain dopamine-producing neurons in the substantia nigra. The ability for MPP+ to induce Parkinson's disease has made it an important compound in Parkinson's research since this property was discovered in 1983.[2][3]

The chloride salt of MPP+ found use in the 1970s as an herbicide under the common name cyperquat.[4][3] Though no longer in use as an herbicide, cyperquat's closely related structural analog paraquat still finds widespread usage, raising some safety concerns.

History

[edit]

MPP+ has been known since at least the 1920s, with a synthesis of the compound being published in a German chemistry journal in 1923.[5] Its neurotoxic effects, however, were not known until much later, with the first paper definitively identifying MPP+ as a Parkinson's-inducing poison being published in 1983.[6] This paper followed a string of poisonings that took place in San Jose, California in 1982 in which users of an illicitly synthesized analog of meperidine were presenting to hospital emergency rooms with symptoms of Parkinson's.[2] Since most of the patients were young and otherwise healthy and Parkinson's disease tends to afflict people at a much older age, researchers at the hospital began to scrutinize the illicitly synthesized opiates that the patients had ingested.[2] The researchers discovered that the opiates were tainted with MPTP, which is the biological precursor to the neurotoxic MPP+.[2] The MPTP was present in the illicitly synthesized meperidine analog as an impurity, which had a precedent in a 1976 case involving a chemistry graduate student synthesizing meperidine and injecting the resulting product into himself.[7] The student came down with symptoms of Parkinson's disease, and his synthesized product was found to be heavily contaminated with MPTP.[7]

The discovery that MPP+ could reliably and irreversibly induce Parkinson's disease in mammals reignited interest in Parkinson's research, which had previously been dormant for decades.[8] Following the revelation, MPP+ and MPTP sold out in virtually all chemical catalogs, reappearing months later with a 100-fold price increase.[8]

Synthesis

[edit]

Laboratory

[edit]
Reaction scheme for the laboratory synthesis of MPP+.

MPP+ can be readily synthesized in the laboratory, with Zhang and colleagues publishing a representative synthesis in 2017.[9] The synthesis involves reacting 4-phenylpyridine with methyl iodide in hot acetonitrile for 24 hours.[9] An inert atmosphere is used to ensure a quantitative yield.[9] The product is formed as the iodide salt, and the reaction proceeds via an SN2 pathway.[9] The herbicide cyperquat (MPP chloride) can be made in the same manner by using methyl chloride instead of methyl iodide.

Biological

[edit]

MPP+ is produced in vivo from the precursor MPTP. The process involves two successive oxidations of the molecule by monoamine oxidase B to form the final MPP+ product.[10] This metabolic process occurs predominantly in astrocytes in the brain.[10]

Metabolism of MPTP to MPP+ in cerebral astrocytes.

Mechanism of toxicity

[edit]

MPP+ exhibits its toxicity mainly by promoting the formation of reactive free radicals in the mitochondria of dopaminergic neurons in the substantia nigra.[10][11] MPP+ can siphon electrons from the mitochondrial electron transport chain at complex I and be reduced, in the process forming radical reactive oxygen species which go on to cause further, generalized cellular damage.[10][11] In addition, the overall inhibition of the electron transport chain eventually leads to stunted ATP production and eventual death of the dopaminergic neurons, which ultimately displays itself clinically as symptoms of Parkinson's disease.[1][10][11]

MPP+ also displays toxicity by inhibiting the synthesis of catecholamines, reducing levels of dopamine and cardiac norepinephrine, and inactivating tyrosine hydroxylase.[1]

The mechanism of uptake of MPP+ is important to its toxicity. MPP+ injected as an aqueous solution into the bloodstream causes no symptoms of Parkinsonism in test subjects, since the highly charged molecule is unable to diffuse through the blood-brain barrier.[10] Furthermore, MPP+ shows little toxicity to cells other than dopaminergic neurons, suggesting that these neurons have a unique process by which they can uptake the molecule, since, being charged, MPP+ cannot readily diffuse across the lipid bilayer that composes cellular membranes.[10]

Unlike MPP+, its common biological precursor MPTP is a lipid-soluble molecule that diffuses readily across the blood-brain barrier.[10] MPTP itself is not cytotoxic, however, and must be metabolized to MPP+ by MAO-B to show any signs of toxicity.[10] The oxidation of MPTP to MPP+ is a process that can be catalyzed only by MAO-B, and cells that express other forms of MAO do not show any MPP+ production.[10] Studies in which MAO-B was selectively inhibited showed that MPTP had no toxic effect, further cementing the crucial role of MAO-B in MPTP and MPP+ toxicity.[12]

Studies in rats and mice show that various compounds, including nobiletin, a flavonoid found in citrus, can rescue dopaminergic neurons from degeneration caused by treatment with MPP+.[11] The specific mechanism of protection, however, remains unknown.[11]

Uses

[edit]

In scientific research

[edit]

MPP+ and its precursor MPTP are widely used in animal models of Parkinson's disease to irreversibly induce the disease.[2] Excellent selectivity and dose control can be achieved by injecting the compound directly into cell types of interest.[10][11] Most modern studies use rats as a model system, and much research is directed at identifying compounds that can attenuate or reverse the effects of MPP+.[8][11] Commonly studied compounds include various MAO inhibitors and general antioxidants.[8][11] While some of these compounds are quite effective at stopping the neurotoxic effects of MPP+, further research is needed to establish their potential efficacy in treating clinical Parkinson's.[11]

The revelation that MPP+ causes the death of dopaminergic neurons and ultimately induces symptoms of Parkinson's disease was crucial in establishing the lack of dopamine as central to Parkinson's disease.[2] Levodopa or L-DOPA came into common use as an anti-Parkinson's medication thanks to the results brought about by research using MPP+.[2] Further medications are in trial to treat the progression of the disease itself as well as the motor and non-motor symptoms associated with Parkinson's, with MPP+ still being widely used in early trials to test efficacy.[13]

As a pesticide

[edit]
Paraquat, an herbicide structurally similar to cyperquat, is still widely used in agriculture.[3] The molecule is depicted here as the chloride salt.

MPP+, sold as the chloride salt under the common name cyperquat, was used briefly in the 1970s as an herbicide to protect crops against nutsedge, a member of the cyperus genus of plants.[3] MPP+ as a salt has much lower acute toxicity than its precursor MPTP due to the inability of the former to pass through the blood-brain barrier and ultimately access the only cells that will permit its uptake, the dopaminergic neurons.[10] While cyperquat is no longer used as an herbicide, a closely related compound named paraquat is.[3] Given the structural similarities, some[3] have raised concerns about paraquat's active use as an herbicide for those handling it. However, studies have shown paraquat to be far less neurotoxic than MPP+, since paraquat does not bind to complex I in the mitochondrial electron transport chain, and thus its toxic effects cannot be realized.[12]

The HRAC resistance classification puts cyperquat in Group L (Aus), Group D (global), Group 22 (numeric).[14]

Safety

[edit]

MPP+ is commonly sold as the water-soluble iodide salt and is a white-to-beige powder.[15] Specific toxicological data on the compound is somewhat lacking, but one MSDS quotes an LD50 of 29 mg/kg via an intraperitoneal route and 22.3 mg/kg via a subcutaneous route of exposure.[16] Both values come from a mouse model system.[16]

MPP+ encountered in the salt form is far less toxic by ingestion, inhalation, and skin exposure than its biological precursor MPTP, due to the inability of MPP+ to cross the blood-brain barrier and freely diffuse across cellular membranes.[12]

There is no specific antidote to MPP+ poisoning. Clinicians are advised to treat exposure symptomatically.[16]

References

[edit]
[edit]
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MPP+

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from Grokipedia
MPP⁺, or 1-methyl-4-phenylpyridinium, is a positively charged heterocyclic cation with the molecular formula C₁₂H₁₂N⁺, known primarily as a potent and selective that targets neurons. It serves as the of the protoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which is converted to MPP⁺ by in glial cells, enabling its uptake into neurons via the . This compound gained prominence in the early following accidental human exposures that induced irreversible Parkinsonian symptoms, highlighting its role in mimicking the neurodegeneration characteristic of . The neurotoxicity of MPP⁺ stems from its ability to inhibit complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial , disrupting ATP production and generating that lead to and , particularly in dopamine-producing neurons of the . This selective vulnerability arises because MPP⁺ is actively transported into dopaminergic terminals by the (DAT), accumulating to toxic levels and depleting stores while sparing other neuronal types. Studies have shown that MPP⁺ reduces levels and inhibits activity, the rate-limiting enzyme in biosynthesis, further exacerbating the Parkinsonian phenotype. In research, MPP⁺ is extensively employed to create animal models of Parkinson's disease, allowing investigators to study disease mechanisms, test neuroprotective agents, and evaluate potential therapies for mitigating dopaminergic loss. For instance, intracerebral or systemic administration of MPP⁺ in rodents and primates reliably produces motor deficits, bradykinesia, and nigrostriatal degeneration akin to idiopathic Parkinson's, making it a cornerstone tool in neuropharmacology. Ongoing studies also explore MPP⁺'s interactions with cellular pathways, such as autophagy and alpha-synuclein aggregation, to deepen understanding of neurodegenerative processes. Despite its utility, handling MPP⁺ requires stringent safety protocols due to its high toxicity and potential for accidental exposure.

Chemical properties

Molecular structure

MPP+ is the organic cation known as 1-methyl-4-phenylpyridinium, with the molecular formula C12H12N+. It commonly occurs as a salt, such as the iodide (C12H12IN), where the iodide serves as the . This quaternary ammonium compound features a positively charged atom in the ring, rendering it highly polar and water-soluble compared to its precursors. The core structure of MPP+ consists of a six-membered aromatic ring, with a attached to the at position 1 and a phenyl at the para position (4). The quaternization at the —resulting from the addition of the —creates a permanent positive charge, delocalized across the ring, which is characteristic of ions. This charged aromatic system is planar and rigid, contributing to its stability and reactivity profile. MPP+ derives from the metabolic oxidation of its precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (), a neutral, non-aromatic compound with a partially saturated piperidine-like ring featuring double bonds between carbons 5-6 and an at 1-2. The conversion proceeds via a radical cation intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), involving dehydrogenation that aromatizes the ring and fully quaternizes the nitrogen. This transformation eliminates the saturated bonds in , replacing them with the conjugated π-system of the ring and introducing the positive charge absent in the neutral . The structure of MPP+ is confirmed through mass spectrometry, which displays a prominent molecular ion peak at m/z 184 corresponding to the [C12H12N]+ cation. Nuclear magnetic resonance (NMR) spectroscopy further verifies the aromatic nature, with 1H NMR signals for the N-methyl group around 4.3 ppm (singlet, 3H) and distinct aromatic proton resonances for the pyridine (8.0-9.0 ppm) and phenyl (7.2-7.5 ppm) rings. Infrared (IR) spectroscopy highlights the C=N+ stretch of the pyridinium ring near 1640 cm-1, indicative of the charged iminium functionality.

Physical and chemical characteristics

MPP+ is most commonly encountered as its iodide salt, which exists as a crystalline solid appearing as a to powder. The compound exhibits high in , reaching up to 100 mM, and is also moderately soluble in polar solvents such as (72 mg/mL) and 0.1 M HCl, owing to its ionic character as a quaternary cation; it is insoluble in non-polar solvents. The salt melts at 166–168 °C. MPP+ demonstrates good stability in aqueous solutions at neutral , with no significant observed in 4.2 mM solutions stored in the dark at 37 °C for 28 days; it remains thermally stable under desiccated conditions but decomposes under strong reducing environments. As a lipophilic cation, MPP+ is susceptible to reduction, undergoing one-electron electrochemical reduction at a standard potential of −1.120 V vs. SCE to form a neutral radical that equilibrates with its dimer, or two-electron reduction to yield MPDP+;

History

Discovery via MPTP

In 1982, a cluster of young drug users in developed acute and irreversible after injecting a synthetic analog known as MPPP, which was contaminated with the byproduct 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (). J. William Langston and his team at identified these cases, noting symptoms including severe bradykinesia, rigidity, and tremor that closely mimicked idiopathic but appeared suddenly in otherwise healthy individuals aged 23 to 42. Analysis of the injected substance revealed MPTP as the contaminant, produced during the clandestine synthesis of MPPP by an underground chemist attempting to replicate the effects of meperidine. The connection between and was publicly reported in 1983, alerting health authorities to the risks of designer drugs and prompting warnings from the (NIDA) and other agencies to monitor for similar cases among intravenous drug users. Langston's team confirmed MPTP's through postmortem examination of affected individuals, revealing selective destruction of neurons in the , a hallmark of . This discovery highlighted the dangers of unregulated synthetic narcotics and led to immediate regulatory actions, including restrictions on MPTP's commercial availability. Subsequent investigations identified MPP+ (1-methyl-4-phenylpyridinium) as the ultimate toxic of , formed via metabolism primarily by in glial cells. Animal studies, including primate models, demonstrated that systemically administered rapidly converts to MPP+, which accumulates preferentially in the brain and , reproducing the parkinsonian syndrome observed in humans. MPP+ was isolated from the tissues of affected individuals and experimental animals, confirming its role as the active agent. Early research noted structural similarities between MPP+ and , leading to hypotheses that this resemblance enables selective uptake and targeting of neurons via the .

Key research milestones

In the 1980s, MPP+ was identified as the primary toxic metabolite of responsible for selective neuron destruction in models of (PD). A seminal study in demonstrated that MPTP administration in squirrel monkeys led to profound nigrostriatal degeneration mimicking PD pathology, with subsequent work confirming MPP+ accumulation in the as the key mechanism. By 1984, researchers isolated MPP+ from brain tissue of MPTP-treated primates, establishing its role in inhibiting mitochondrial complex I and linking it directly to parkinsonian symptoms. These findings solidified MPP+ as a cornerstone for PD animal modeling, with studies showing irreversible loss persisting beyond MPTP clearance. During the 1990s, research expanded 's utility as a PD model, with genetic manipulations revealing the (DAT) as critical for MPP+ uptake and toxicity. Knockout studies in mice demonstrated that absence of DAT conferred resistance to MPP+-induced nigrostriatal damage, highlighting species-specific sensitivities and DAT's role in toxin selectivity. Epidemiological investigations in the late 1990s began drawing parallels between MPP+ toxicity and environmental exposures, though definitive links to —a structurally similar —emerged more prominently in the 2000s. In the 2000s, genetic association studies linked polymorphisms in the DAT gene () to heightened MPP+ sensitivity and PD risk, with variants altering transporter expression correlating to increased vulnerability in cellular and rodent models. Concurrently, epidemiological research strengthened connections between paraquat exposure and PD, noting its cycling properties akin to MPP+'s mitochondrial disruption, with cohort studies showing elevated PD incidence among agricultural workers exposed to . The 2010s brought advances in , including (PET) tracers like [¹⁸F]FE-PE2I for visualizing DAT-mediated MPP+ uptake in vivo, enabling precise mapping of dopaminergic loss in PD models. Research also elucidated MPP+'s role in promoting aggregation, with in vitro and studies showing MPP+ exposure accelerates fibril formation and Lewy body-like inclusions in neurons. In the 2020s, genomic analyses have revealed MPP+'s impact on mitochondrial , with transcriptomic profiling in MPP+-treated cells identifying downregulation of complex I subunits and upregulation of stress-response pathways, informing targeted therapies. Ongoing preclinical trials utilize MPP+ models for neuroprotective drug screening, such as evaluating mitochondria-targeted antioxidants that mitigate MPP+-induced ATP depletion and loss in iPSC-derived dopaminergic cultures. Seminal reviews, including those in high-impact journals like (1983) on MPTP's discovery, continue to frame these developments.

Synthesis

Laboratory methods

The primary laboratory method for producing MPP+ iodide involves the chemical oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (), which serves as a direct analog to the enzymatic process but employs synthetic oxidants for controlled conversion. For example, can be oxidized using in aqueous media to yield MPP+ via the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP⁺), with the reaction monitored and purified to isolate the salt. These approaches yield 70–90% MPP+ , depending on reaction scale and purity of starting , with common impurities (e.g., unreacted or MPDP⁺) minimized through filtration and extraction. Purification is achieved via recrystallization from ethanol-water mixtures or ion-exchange , ensuring high purity (>95%) suitable for biological assays; characterization relies on (HPLC) with UV detection at 295 nm or (TLC) on silica plates using methanol-ammonia eluents, confirming the product's identity by comparison to authentic standards. Yields are optimized for small-scale preparations (1–10 mg) in standard glassware under inert atmosphere to prevent side reactions, while gram-scale syntheses require larger volumes and careful temperature control to maintain efficiency. Handling strong oxidants necessitates strict safety protocols, including operation in a , use of gloves and , and immediate of spills with reducing agents to mitigate risks of explosion or skin irritation. An alternative synthetic route bypasses entirely through direct N-quaternization of 4-phenyl with excess methyl in hot or dry acetone, refluxed for 24–48 hours under to form the salt. The reaction proceeds via nucleophilic attack at the , yielding a precipitate that is collected by , washed with , and recrystallized from absolute ethanol to afford pure MPP+ in 70–90% yield. This method is favored for its simplicity and avoidance of hazardous tetrahydropyridine intermediates, with product purity verified by HPLC or TLC as above, and structural confirmation via ¹H NMR showing characteristic shifts for the methyl (δ ≈ 4.3 ppm) and aromatic protons. It supports both milligram-scale analytical preparations and gram-scale production for applications.

Biological production

MPP+ is endogenously produced in living organisms primarily through the bioactivation of its precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (), via a two-step oxidation process. The first step involves the catalytic oxidation of to the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) by (MAO-B), an enzyme predominantly expressed on the outer mitochondrial membrane. This reaction occurs in non-neuronal cells and generates as a byproduct. The subsequent step entails the auto-oxidation of MPDP+ to MPP+, which is a non-enzymatic process influenced by environmental factors and can occur spontaneously under physiological conditions. This production is tissue-specific, with primary sites including the liver, where MAO-B activity facilitates initial metabolism of systemically administered , and brain glial cells, particularly , which serve as the main locus for neurotoxic conversion within the . Once formed extracellularly, MPP+ accumulates selectively in dopaminergic neurons through uptake mediated by the (DAT), concentrating the toxin in vulnerable regions like the . This glial-neuronal interplay underscores the indirect mechanism by which exerts its effects. The kinetics of this pathway are governed by the stability and transformation rates of intermediates. MPDP+ is relatively unstable, with a ranging from approximately 90 minutes to 6 hours depending on cellular conditions such as the presence of pigments or environments. The auto-oxidation of MPDP+ to MPP+ is promoted by alkaline and higher oxygen levels, which accelerate the reaction, while acidic and lower oxygen tensions inhibit it, favoring extracellular conversion. MPP+ itself exhibits a longer persistence, with brain of about 3 hours in but up to 10 days in , contributing to prolonged toxicity. Species differences further modulate the process; for instance, like rats show faster peripheral oxidation of due to higher MAO activity at the blood- barrier, rendering them less susceptible compared to humans and non-human where brain-specific conversion predominates. Inhibition of biological MPP+ production targets the MAO-B step, with selective blockers like (deprenyl) effectively preventing the oxidation of to MPDP+ and thereby reducing downstream MPP+ formation. This blockade has been demonstrated to confer in -exposed models by halting the pathway at its initial enzymatic phase, highlighting MAO-B as a critical therapeutic target.

Mechanism of toxicity

Cellular uptake

MPP+ is primarily taken up into cells through high-affinity, transporter-mediated mechanisms, with the serving as the main entry point in nigrostriatal dopaminergic neurons. This uptake occurs via a sodium- and chloride-dependent process, exhibiting saturable kinetics with a Km of approximately 0.17 μM in striatal synaptosomes. The structural similarity of MPP+ to enables its recognition by DAT, facilitating selective entry into dopaminergic terminals. Uptake is energy-dependent and can be inhibited by DAT blockers such as nomifensine and , which compete with MPP+ for the transporter binding site. In addition to DAT, MPP+ is transported at lower affinities by the norepinephrine transporter (NET) and serotonin transporter (SERT), with Km values around 0.065 μM for NET in cortical synaptosomes and weaker binding to SERT in serotonergic regions. Despite the comparable or slightly higher affinity for NET, the lower expression and Vmax of NET compared to DAT result in minimal uptake in noradrenergic neurons, contributing to the relative sparing of these cell types. The process is temperature-sensitive, with negligible uptake at 4°C, underscoring its active nature. Once inside the neuron, MPP+ mimics in being sequestered into synaptic vesicles by the (VMAT2), driven by an ATP- and Mg²⁺-dependent proton antiport mechanism. This vesicular trapping leads to substantial intraneuronal accumulation, enhancing retention and selectivity for neurons. VMAT2-mediated uptake is sensitive to inhibitors like and . Due to the high density of DAT and VMAT2 in dopaminergic pathways, MPP+ exhibits preferential accumulation in the substantia nigra, where concentrations can increase over 72 hours following exposure, far exceeding levels in other brain regions such as the striatum or cortex. This regional selectivity underlies the specific vulnerability of nigrostriatal neurons.

Mitochondrial effects

MPP+ primarily targets mitochondrial complex I (NADH:ubiquinone oxidoreductase), inhibiting its function through competitive binding with respect to NADH, which disrupts the transfer of electrons from NADH to ubiquinone in the electron transport chain. This binding occurs at the rotenone-sensitive site, leading to a substantial reduction in electron transport chain activity, typically by 50–70% at physiologically relevant concentrations in experimental models. The inhibition is reversible, particularly at low doses, allowing potential recovery of complex I function upon removal of the toxin. The blockade of complex I impairs the proton gradient across the , resulting in increased production of (ROS), primarily anions from the site within the enzyme. This generation promotes , which can lead to the formation of through reaction with , further exacerbating mitochondrial damage via protein nitration and . Downstream consequences include severe energy failure, characterized by ATP depletion due to halted , alongside dysregulation of mitochondrial calcium that amplifies cellular stress. These disruptions activate intrinsic apoptosis pathways, notably through caspase-3 cleavage and executioner functions, culminating in . In isolated mitochondria, the dose-response for complex I inhibition shows an IC50 of approximately 10–50 μM, with effects becoming irreversible at higher exposures due to cumulative oxidative damage. Once accumulated within mitochondria via cellular uptake mechanisms, MPP+ achieves local concentrations sufficient to elicit these potent inhibitory effects.

Uses

In neuroscience research

MPP+ serves as a key tool in research for modeling (PD), particularly by inducing selective toxicity to neurons in the pars compacta (SNpc), thereby replicating core pathological features such as nigrostriatal degeneration and motor impairments. In animal models, MPP+ is administered either intracerebrally via stereotaxic injection into the SNpc or , or systemically in cases where its precursor is used to generate MPP+ , targeting and non-human to study neuron loss and associated behavioral deficits. This approach has facilitated investigations into PD mechanisms and therapeutic interventions, with rapid induction of lesions allowing for efficient preclinical testing. Standard protocols for administration in PD models typically involve unilateral or bilateral intracerebral injections, with doses ranging from 10–40 μg per site in rats to achieve dose-dependent degeneration of the . In mice, while direct systemic MPP+ is limited by poor blood-brain barrier penetration, equivalent effects are often elicited through intraperitoneal dosing at 20–30 mg/kg (leading to MPP+ formation), administered acutely (e.g., four injections at 2-hour intervals) or subchronically (e.g., daily for 5 days). Key endpoints include (TH) immunohistochemistry to assess SNpc loss, often revealing 50–90% reduction in cells, alongside striatal quantification and motor behavioral tests like the rotarod or open-field assays to evaluate akinesia and bradykinesia. In non-human primates, such as or rhesus monkeys, intracerebral MPP+ infusions at lower doses (e.g., 0.1–0.5 mg total) over days to weeks induce progressive , including tremors and rigidity, closely mimicking human symptoms. The advantages of MPP+-based models include their rapid onset of toxicity (within hours to days), high selectivity for neurons via the , and reproducibility, making them ideal for high-throughput drug screening and studies; for instance, glial cell-derived neurotrophic factor (GDNF) has demonstrated robust rescue of nigral neurons and functional recovery when administered in MPP+-lesioned . These models have been employed in thousands of preclinical investigations since the , contributing to advancements in understanding mitochondrial dysfunction in PD and evaluating therapies like GDNF . Despite their utility, MPP+ models have limitations, including the absence of formation or α-synuclein aggregates characteristic of idiopathic PD, incomplete replication of non-motor symptoms, and variable persistence of deficits in compared to the chronic progression in humans. Ethical concerns also arise with primate use due to the severity of induced and implications, prompting a shift toward refined protocols or alternative species.

In toxicology studies

MPP+ has been employed in assays to investigate defenses and cellular responses to mitochondrial toxins. In human cells, exposure to MPP+ depletes (GSH) levels and elevates markers of , such as , providing a model to evaluate protective agents like tectorigenin that restore , , and activities. These assays highlight MPP+'s role in inducing (ROS) accumulation, which exacerbates cellular damage beyond direct mitochondrial inhibition. In , MPP+ serves as an analog to herbicides like , both of which generate through redox cycling and DAT-mediated uptake, facilitating studies on pollutant-induced . Research using MPP+ has explored glial-neuronal interactions, where microglial activation amplifies MPP+-induced ROS production and promotes via release, mimicking environmental exposures that disrupt . Genotoxicity studies utilizing MPP+ demonstrate its capacity to induce DNA damage, as evidenced by comet assays in SH-SY5Y and PC12 cells, where MPP+ exposure results in increased tail moments indicative of strand breaks and apoptosis. Additionally, MPP+ triggers epigenetic alterations, including elevated histone acetyltransferase expression and hyperacetylation of H3K9 and H3K27 residues, which dysregulate gene expression linked to cellular stress responses. For of mitochondrial toxins, MPP+ models in larvae enable behavioral and proteomic phenotyping to identify neuroprotectants, revealing dose-dependent deficits suitable for library testing. Similarly, in , MPP+ intoxication provides a scalable platform for screening toxins, confirming its selectivity for neuronal degeneration in whole-organism assays.

Safety and regulation

Toxicity profile

MPP+ exhibits high in animal models, with an intraperitoneal LD50 of approximately 29 mg/kg in mice, indicating lethality at relatively low doses. Acute systemic exposure (e.g., intravenous or intraperitoneal) primarily causes peripheral , including irritation to , eyes, and , potentially leading to respiratory distress and death due to general mitochondrial inhibition in various cells. However, MPP+ does not readily cross the blood-brain barrier, so acute central neurological symptoms like muscle rigidity or bradykinesia are not typically observed with systemic administration; selective requires direct exposure or formation from precursor. Chronic exposure to MPP+ results in selective degeneration of neurons in the , closely mimicking the neuropathology of idiopathic (PD), with significant loss of tyrosine hydroxylase-positive cells and persistent depletion in the . In non-human , such damage is irreversible, showing no neuronal recovery even after extended periods, leading to stable parkinsonian motor deficits without spontaneous amelioration. This long-term selectivity underscores MPP+'s role as a model for PD, where low-dose regimens over weeks produce enduring nigrostriatal . Direct human exposure to MPP+ is unknown, as it forms from its precursor and is not encountered in environmental or occupational settings outside laboratories. Toxicity in humans is inferred from MPTP incidents, such as the 1982 California cluster where intravenous self-administration of contaminated synthetic (containing MPTP) led to permanent . In that outbreak, affected individuals developed irreversible loss and PD-like symptoms requiring lifelong treatment after estimated total MPTP exposures of several milligrams across multiple injections. At low doses, MPP+ demonstrates organ specificity in models, exerting primarily neurotoxic effects on the (via DAT uptake) with negligible hepatic, renal, or other systemic toxicity.

Handling and exposure risks

MPP+ (1-methyl-4-phenylpyridinium) requires stringent handling protocols to mitigate its risks. It should be manipulated exclusively in a well-ventilated or equivalent containment to prevent formation and exposure, with all operations conducted over disposable absorbent surfaces for easy . (PPE) is essential, including chemical-resistant gloves (e.g., ), coats, or face shields, and respiratory protection such as N95 masks or powered air-purifying respirators for tasks involving potential or high exposure volumes. To minimize generation, MPP+ is recommended for storage and use as aqueous solutions rather than dry powders, kept in tightly sealed, locked containers in a cool, well-ventilated area away from incompatible materials like strong oxidizers. Under U.S. regulatory frameworks, MPP+ is classified as a hazardous substance due to its , falling under OSHA's Communication Standard (29 CFR 1910.1200) as a toxic chemical requiring labeling, safety data sheets, and worker training. It is designated a UN2811 toxic substance (Class 6.1) for transport, but it is not specifically listed under major environmental statutes like SARA Title III or TSCA, reflecting its primary use in controlled settings rather than commercial production or environmental release. Oversight is thus focused on occupational safety in laboratories, with institutional committees often mandating risk assessments for its use. Direct environmental exposure is negligible, as MPP+ is lab-confined, and its charged structure limits ; improper disposal should be avoided to prevent localized aquatic contamination. Primary exposure routes for MPP+ include of dust or aerosols, dermal absorption through contact, and , with and direct injection posing the greatest risks in experimental contexts due to rapid systemic uptake. In case of exposure, immediate involves removing the individual from the source, providing fresh air for incidents, washing affected with and , rinsing eyes with copious for at least 15 minutes, and seeking medical attention without inducing for cases; there is no specific , so supportive care is emphasized.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/1-Methyl-4-phenylpyridinium
  2. https://www.sciencedirect.com/topics/neuroscience/mpp
  3. https://pubmed.ncbi.nlm.nih.gov/3496229/
  4. https://pubs.acs.org/doi/abs/10.1021/tx030015l
  5. https://academic.oup.com/toxsci/article/165/1/232/5042908
  6. https://www.medchemexpress.com/mpp-iodide.html
  7. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4496977.htm
  8. https://cdn.caymanchem.com/cdn/msds/16958m.pdf
  9. https://www.abcam.com/en-us/products/biochemicals/n-methyl-4-phenylpyridinium-iodide-mpp-dopaminergic-selective-neurotoxin-ab144783
  10. https://www.selleckchem.com/products/mpp-iodide.html
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