Neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is actively studied by researchers because the examination of this toxin allows for concluding about the causes of Parkinson’s disease (Daroff & Aminoff 2014). To understand how MPTP can cause damages in the basal ganglia of humans, it is necessary to focus on examining its neurotoxic effects. The purpose of this essay is to define MPTP and analyze how it produces neurotoxic effects while causing the development of parkinsonian symptoms.
Definition of MPTP
MPTP can be defined as a chemical compound that participates in producing 1-methyl-4-phenylpyridinium (MPP+), resulting in significant and irreversible pathological changes in the brain (Nestler, Hyman & Malenka 2015). MPTP has no critical effects on neurons in contrast to MPP+ which is known as the neurotoxin which provokes the symptoms associated with Parkinson’s disease (Curtis & Klaassen 2015). Therefore, researchers are inclined to speak about MPTP’s neurotoxicity because this compound is essential for producing MPP+ which affects dopaminergic neurons.
Discovery of MPTP’s Neurotoxicity
It is important to note that MPTP’s neurotoxicity associated with the symptoms similar to Parkinson’s disease was discovered in the 1980s (Daroff & Aminoff 2014). Clinicians and researchers focused on the group of drug addicts from California, the United States, who had specific symptoms typical of Parkinson’s disease which developed after the consumption of a synthetic drug. Thus, those persons had signs of hypokinesia, rigidity, and tremor (Daroff & Aminoff 2014; Nestler, Hyman & Malenka 2015). The problem was that the used meperidine analog included MPTP as the by-product which was assumed to produce certain neurotoxic effects on the studied persons (Daroff & Aminoff 2014; Nestler, Hyman & Malenka 2015).
MPTP’s Effects on Humans
Today, many researchers are focused on studying MPTP because of its specific effects on humans, as well as on non-human primates. The reason is that the effects of this toxin on people resemble the symptoms of such degenerative disorders as Parkinson’s disease (Nestler, Hyman & Malenka 2015). As a result, MPTP is used for developing models for studying MPTP’s neurotoxicity and the associated conditions. The most typical effects or symptoms of consuming MPTP include slowness of movements, rigidity, hypokinesia, tremor, and postural instability (Daroff & Aminoff 2014). After the consumption of MPTP, the death of cells and associated symptoms are observed during a short period of time in contrast to Parkinson’s disease which can develop during several years (Curtis & Klaassen 2015). Furthermore, when the acute stage of MPTP’s influence ends, it is still possible to observe irreversible changes in neurons.
Target Cells and Organs
Different toxins can have similar effects on the brain of humans, provoking neurological disorders, but only MPTP affects neurons that are responsible for the development of parkinsonism (Daroff & Aminoff 2014). While producing toxicological effects, MPTP targets the neuronal population in the brain which is known as nigral dopaminergic neurons. The loss of these specific pigmented dopaminergic neurons is associated with parkinsonism (Curtis & Klaassen 2015). Thus, MPTP can cause severe losses of selective neurons which are located in the substantia nigra, and these processes are related to the observed neurodegenerative effects. While speaking about the target cells and associated effects, researchers also identify cells and elements the presence and absence of which allow for concluding about the nature of parkinsonism (Daroff & Aminoff 2014; Maertens et al. 2015). Thus, the absence of specific Lewy inclusions, as well as the presence of melanin, indicates changes in cells caused by MPTP (Daroff & Aminoff 2014).
How MPTP Produces Neurotoxic Effects: Mechanisms of Neurotoxicity
The mechanisms of MPTP’s neurotoxicity should be discussed with reference to its metabolism. The systematic consumption of MPTP leads to increasing its capacity to cross the blood-brain barrier because of its lipophilic nature (Daroff & Aminoff 2014). In the brain, the metabolic processes continue, and MPTP affected by the enzyme monoamine oxidase B (MAO-B) becomes 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), and then, MPP+ (Daroff & Aminoff 2014; Li et al. 2017). Thus, MPP+ is a toxic element that can act in the extracellular space. As a result, MPP+ enters dopaminergic neurons with the help of plasma membrane transporters. In dopaminergic neurons, MPP+ can become bound to vesicular monoamine or dopamine transporters, concentrate in the mitochondria, or interact with specific cytosolic enzymes (Daroff & Aminoff 2014; Nestler, Hyman & Malenka 2015). These processes result in mitochondrial dysfunction, the oxidative stress damaging proteins, the activation of apoptotic factors, and finally, the adenosine triphosphate (ATP) depletion (Daroff & Aminoff 2014). Furthermore, neurotoxic effects of MPTP are also viewed as age-dependent because of the role of MAO-B in the process of MPTP’s metabolism.
MPTP is discussed by researchers and clinicians as a chemical compound that can provoke the production of MPP+, and this toxin leads to developing neurological effects associated with Parkinson’s disease. The cause of degenerative processes is the death of cells in the brain because of the ATP depletion and mitochondrial dysfunction. As a result, after consuming substances with MPTP, people develop such symptoms as hypokinesia, rigidity, and tremor.
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Daroff, R & Aminoff, M (eds.) 2014, Encyclopedia of the neurological sciences, 2nd edn, Academic Press, San Diego, CA.
Li, L, Shi, L, Liu, H, Luo, Q, Huang, C, Liu, W, Chen, X, Zeng, W & Chen, Z 2017, ‘Changes in blood anti-oxidation enzyme levels in MPTP-treated monkeys’, Neuroscience Letters, vol. 649, no. 1, pp. 93-99.
Maertens, A, Luechtefeld, T, Kleensang, A & Hartung, T 2015, ‘MPTP’s pathway of toxicity indicates central role of transcription factor SP1’, Archives of Toxicology, vol. 89, no. 5, pp. 743-755.
Nestler, E, Hyman, S & Malenka, R 2015, Molecular neuropharmacology: a foundation for clinical neuroscience, 3rd edn, McGraw-Hill Medical, New York, NY.