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MPTP-Induced Parkinsonism
Published in W. R. Wayne Martin, Functional Imaging in Movement Disorders, 2019
Parkinsonism is associated with cell loss and dopamine depletion in the nigrostriatal pathway.1 The biochemical pathology associated with Parkinson’s disease has provided evidence that neurological disorders may be caused by specific neurochemical alterations. The etiology of this neurochemical lesion is currently unknown. Viral, genetic, and environmental factors have been investigated. Patients with toxic exposure to manganese and carbon disulfide also have symptoms of parkinsonism, suggesting that a neurotoxin may be involved in the etiology of Parkinson’s disease.2 In support of this hypothesis, a major breakthrough occurred with the serendipitous finding of parkinsonism associated with the administration of an illicit narcotic in a group of drug addicts.3 The responsible compound, l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has since been shown in animal models to cause histological and biochemical lesions that are similar to Parkinson’s disease. This chapter will discuss the use of positron emission tomography (PET) for the in vivo evaluation of the dopamine system in MPTP-induced parkinsonism.
Sympathetic Neurotransmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The effectiveness of selegiline in the management of Parkinson’s disease and delaying the onset of disability has also recently been attributed to an elevation of superoxide dismutase (SOD) levels in the striatum (Clow et al. 1991). This enzyme protects against the neurotoxicity of reactive oxygen species such as hydroxyl radicals. The oxidation of amine substrates by MAO results in the production of H2O2, and in the absence of adequate levels of antioxidants (reduced glutathione and ascorbic acid) leads to the production of hydroxyl radical (OH). Further support for a neurotoxicity mechanism comes from the observation that the contaminant of designer heroin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), induced a Parkinson’s-like syndrome in addicts. MPTP is a substrate for MAO-B which converts it to MPDP plus H2O2 and thence to MPP+. This toxicity is prevented by selegiline (Youdim & Finberg 1991).
Effects of Drugs
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Di Paolo, Bedard, Daigle et al. (1986) studied the long-term effects of 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) on catecholamine concentrations in monkeys. They found that, at 5 months after the start of MPTP treatment, epinephrine and dopamine levels were decreased in the adrenal medulla but norepinephrine concentration remained unchanged.
Oleanolic acid and ursolic acid: therapeutic potential in neurodegenerative diseases, neuropsychiatric diseases and other brain disorders
Published in Nutritional Neuroscience, 2023
Chen Chen, Qidi Ai, Axi Shi, Nan Wang, Lina Wang, Yuhui Wei
Rai et al. found that UA (25 mg/kg) can improve the behavioral defects of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced PD mouse model, restore dopamine levels and protect dopaminergic neurons [37]. The research team subsequently discovered that MPTP causes increased expression of IBA1 and TNF-α, and activation of NF-κB, and these increased inflammatory response markers can also be reversed by UA (25 mg/kg), thereby acting as a neuroprotective agent [38]. In a rotenone-induced PD rat model, UA (5, 10 mg/kg) is found to improve motor function and cognitive dysfunction significantly, which may be attributed to the protection of TH (tyrosine hydroxylase)-positive neurons from degeneration. In addition, the oxidative stress and inflammation caused by rotenone are greatly reduced by UA. Mitochondrial dysfunction is also one of the pathogenic mechanism underlying PD, and UA can eliminate the inhibitory effect of rotenone on mitochondrial complex I and promote mitochondrial biogenesis [39]. α-synuclein (α-syn) plays a central role in the pathogenesis of PD, and UA (25 mg/kg) can reduce the overexpression of α-syn and regulate phosphorylation of signaling kinases related to cell survival including Akt and ERK in a rotenone-induced PD mouse model [40]. Excitotoxicity is the rapid neuronal death caused by glutamate receptor activation. When UA is at a low concentration (5-15 μM), it can resist the formation of free radicals and the decrease of mitochondrial membrane potential induced by kainic acid, a glutamate receptor agonist, and thus play a neuroprotective role [41].
Morphine reverses the effects of 1-methyl-4-phenylpyridinium in PC12 cells through activating PI3K/Akt
Published in International Journal of Neuroscience, 2019
Yuan Fan, Yan Chen, Se Zhang, Mengbing Huang, Shengdong Wang, Ye Li, Jie Bai
The Parkinson’s disease (PD) is a neurodegenerative disorder which is caused by the loss of dopaminergic neurons and decrease of dopamine level in the substantia nigra pars compacta (SNpc). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is metabolized into toxic 1-methyl-4-phenylpyridinium (MPP+) and transported into dopaminergic neurons and caused a severe parkinsonian syndrome [1]. MPTP/MPP+ induces oxidative stress and apoptosis in dopaminergic neurons. MPTP/MPP+ decreases the expression of thiordoxin-1 (Trx-1) [2]. MPP+ induces cell cycle arrest and Cyclin D1 degradation through inhibiting phosphatidylinositol-3-kinase (PI3K)/Akt pathway [3]. It has been reported that Cyclin-dependent kinase5 (Cdk5) plays a role in neuronal survival and is involved in dopaminergic neuron loss in PD [4,5].
SAR and molecular mechanism studies of monoamine oxidase inhibition by selected chalcone analogs
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Raed Shalaby, Jacobus P. Petzer, Anél Petzer, Usman M. Ashraf, Ealla Atari, Fawaz Alasmari, Sivarajan Kumarasamy, Youssef Sari, Ashraf Khalil
The synthesized compounds were initially screened at 10 μM final concentration against recombinant human MAO-A and MAO-B by using 1-methyl-4–(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP) as a nonselective substrate for both MAO-A and B. It is important to note that the Km values for human MAO-A and MAO-B were found to be 88 μM and 101 μM, respectively, and this is in accordance with previously reported values26,27. The formation of the dihydropyridinium species (MMDP+) as a MAO-catalyzed oxidation product of MMTP was monitored at 420 nm. The results showed that most of the chalcones, indeed, have a marked inhibitory effect on the MAO enzymes at this concentration. Based on this, the IC50 values were determined using kynuramine as a nonselective substrate. The rate of oxidation of kynuramine by MAO was monitored by measuring the fluorescence of the oxidation product, 4-hydroxyquinoline (λex= 310 nm; λem= 400 nm). Kynuramine and the chalcone analogs did not interfere with the measurement, as these drugs did not show any fluorescence.