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Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors

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Abstract

Monoamine oxidase (MAO) enzymes located in human mitochondria oxidize neurotransmitters and bioactivate the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by oxidation to directly-acting neurotoxic pyridinium cations (MPDP⁺/MPP⁺) that produce Parkinsonism. Antioxidants and MAO inhibitors are useful as neuroprotectants. Naturally-occurring substances, antioxidants and redox agents were assessed as inhibitors of the oxidation (bioactivation) of MPTP by human mitochondria and MAO enzymes. Methylene blue, 5-nitroindazole, norharman (β-carboline), 9-methylnorharman (9-methyl-β-carboline) and menadione (vitamin-K analogue) highly inhibited the oxidation of MPTP to the neurotoxic species, MPDP⁺/MPP⁺, in human mitochondria (IC₅₀ of 0.18, 3.1, 9.9, 7.3, and 12.6 μM, respectively). Inhibition by methylene blue was similar to R-deprenyl (IC₅₀ of 0.15 μM), a known neuroprotectant. The naturally-occurring β-carbolines, harmine, harmaline and tetrahydro-β-carboline, and the antioxidants, melatonin, resveratrol, quercetin and catechin showed little or no inhibition. Oxidation of MPTP in mitochondria was performed by human MAO-B and the above active compounds were also inhibitors of this isozyme. Norharman and 5-nitroindazole were competitive inhibitors of MAO-B whereas methylene blue inhibited MPTP oxidation (IC₅₀ of 50 nM) under a mixed type and predominantly uncompetitive mechanism. Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species.

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... These phenomena increase the risk of cell oxidative injury. Therefore, inhibition of MAO may protect against oxidative stress and neurotoxins [33,34]. The inhibition of metabolizing enzymes may increase brain concentrations of their substrates, and thus, reduce disease symptoms of psychiatric disorders. ...
... Inhibitors of MAOs are considered to be an effective therapeutic intervention with neuroprotective and antidepressant effects. The expected therapeutic strategy in the treatment of depression and mood disorders is primarily pharmacological modulation of the monoamine system [34]. Because neurotransmitters (dopamine, norepinephrine, and serotonin) are metabolized by monoamine oxidase (MAO), inhibition of the enzyme may attenuate disease symptoms by balancing the concentration of neurotransmitters in the brain. ...
... On postnatal day (PND) 21, VPA-induced male pups were separated and treated with B. monnieria (300 mg/kg/p.o.) from PND 21-35. Behavioral tests (nociception, locomotor activity, exploratory activity, anxiety, and social behavior) were performed during both adolescence (PND [30][31][32][33][34][35][36][37][38][39][40] and adulthood (PND . At the end of behavioral testing, animals were sacrificed for biochemical analysis (glutathione, serotonin, and nitric oxide) and histopathological examination. ...
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Terpenoids are widely distributed in nature, especially in the plant kingdom, and exhibit diverse pharmacological activities. In recent years, screening has revealed a wide variety of new terpenoids that are active against different psychiatric disorders. This review synthesized the current published preclinical studies of terpenoid use in psychiatric disorders. This review was extensively investigated to provide empirical evidence regarding the neuropharmacological effects of the vast group of terpenoids in translational models of psychiatric disorders, their relevant mechanisms of action, and treatment regimens with evidence of the safety and psychotropic efficacy. Therefore, we utilized nine (9) electronic databases and performed manual searches of each. The relevant data were retrieved from the articles published until present. We used the search terms “terpenoids” or “terpenes” and “psychiatric disorders” (“psychiatric disorders” OR “psychiatric diseases” OR “neuropsychiatric disorders” OR “psychosis” OR “psychiatric symptoms”). The efficacy of terpenoids or biosynthetic compounds in the terpenoid group was demonstrated in preclinical animal studies. Ginsenosides, bacosides, oleanolic acid, asiatic acid, boswellic acid, mono- and diterpenes, and different forms of saponins and triterpenoids were found to be important bioactive compounds in several preclinical studies of psychosis. Taken together, the findings of the present review indicate that natural terpenoids and their derivatives could achieve remarkable success as an alternative therapeutic option for alleviating the core or associated behavioral features of psychiatric disorders.
... Therefore, studying MAO enzymes and finding new MAO inhibitors as purported neuroprotectants is a subject of current interest in drug discovery 1,[18][19][20][21][22][23][24][25][26] . MAO enzymes are usually monitored by measuring the absorbance and/or fluorescence of the oxidation products generated from key amines (kynuramine, tryptamine, tyramine, etc) [27][28][29][30][31][32][33] . The purpose of this research was to evaluate the oxidation of the neurotoxin MPTP by human MAO isozymes (human MAO-A and B) through the chromatographic analysis of the toxic pyridinium species (MPDP + and MPP + ) generated, and subsequently use this approach as a new tool to search for new MAO inhibitors (MAO-A and B) and eventual protective agents. ...
... On the other hand, incubation experiments by using human liver mitochondria (HLM), which contain MAO-A and−B, instead of the recombinant enzymes, showed that in presence of R-deprenyl (1 μM) (a potent MAO-B inhibitor), the oxidation of MPTP is highly inhibited (>80%), whereas clorgyline (1 μM) (MAO-A inhibitor) produced little inhibition. These results clearly suggest that MAO-B is the key isozyme involved in the oxidation of MPTP in good agreement with previous results 19,33,36 . Nevertheless, results obtained here also suggest that MAO-A might somehow accomplish the oxidation of MPTP under certain circumstances, and particularly, at low concentration of the toxin. ...
... In the same assay, harman (1-methyl-β-carboline) did not show significant inhibition up to 20 μM, indicating that this β-carboline is a poor inhibitor of MAO-B. Inhibition of MAO-B and protection against MPTP oxidation was also observed for other agents such as 5-nitroindazole and the vitamin-K analogue menadione, suggesting possible actions of these compounds as protective agents (Figure 7) 19,33 . On the other hand, clorgyline that is an inhibitor of MAO-A, highly inhibited the oxidation of MPTP by MAO-A ( Figure 8) and this oxidation was also inhibited by the β-carboline harman with IC 50 of 2.8 ± 0.25 μM and an experimental K i of 0.19 μM as measured at different concentrations of MPTP. ...
Article
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Monoamine oxidase (MAO) enzymes catalyze the oxidative deamination of amines and neurotransmitters and inhibitors of MAO are useful as neuroprotectants. This work evaluates the human MAO-catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin, to the directly-acting neurotoxic metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) measured by High-Performance Liquid Chromatography (HPLC), and this approach is subsequently used as a new method for screening of MAO inhibitors and protective agents. Oxidation of MPTP by human MAO-B was more efficient than by MAO-A. R-Deprenyl, a known neuroprotectant, norharman (β-carboline), 5-nitroindazole and menadione (vitamin K3) inhibited MAO-B and reduced the formation of toxic pyridinium cations. Clorgyline and the β-carbolines, harman and norharman, inhibited the oxidation of MPTP by MAO-A. Cigarette smoke, as well as the naturally occurring β-carbolines (norharman and harman) isolated from smoke and coffee inhibited the oxidation of MPTP by MAO-B and/or MAO-A, suggesting protective effects against MPTP. The results show the suitability of the approach used to search for new MAO inhibitors with eventual neuroprotective activity.
... Powder of seeds and different extracts are used for making medicines against cestodes infections in animals as well as humans (Branch, 2012). Different effects of P. harmala against different forms of leishmaniasis are authentic in labs and on live animals (Herraiz and Guillén, 2011). Even if harmaline is used against this infection, it shows strong toxicity for the developing forms of this parasite that resides inside the blood cells. ...
... The effect of this plant against insects is also due to beta-carbolines (Fortunato et al., 2009). This plant causes prevention of the larvae of this pest that are present in the stored food, also inhibits its different developmental stages (Herraiz et al., 2011). One of the most important effects of harmaline are: inhibition of severe toxicity of the epithelial cells in the midgut (Jimenez et al., 2008). ...
Chapter
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Peganum harmala is known by different names such as Syrian rue. This plant has flowers and it is grown in many regions throughout the world. The seeds of this plant have essentially hallucinogenic and hypothermic properties. Functions of this plant's extract against the pain are very well understood. We can use the aqueous extract of P. harmala to increase the growth rate in rabbits. So, we isolate the E. coli bacteria from horses and use P. harmaline as an antibacterial drug. Different infectious diseases in wild-fish cause high number of deaths. P. harmala controls many bacterial diseases in aquaculture. It has been widely used against round worms of animals. This plant is used in almost all disorders of animals. P. harmala is a multipurpose, traditional medicinal plant that has very good impact on some viruses. The extract of this plant causes many reproductive changes such as: prolonged diestrus phase. The extract of this plant causes decrease in the number of litter size.
... The use of MAO inhibitors, particularly irreversibly inhibitors, may cause a hypertensive crisis when the patients consume tyramine-containing foods (the so-called "cheese effect") [1,18,69,70]. MAO also metabolizes toxic xenobiotic amines such as the neurotoxin MPTP and, in this regard, the inhibitors of MAO can be protective agents [13,14,71,72]. Moreover, the oxidation of amine substrates by MAO results in the production of hydrogen peroxide, ammonia, and aldehydes, which are risk factors for cell oxidative injury [12,17,73]. ...
... Moreover, the oxidation of amine substrates by MAO results in the production of hydrogen peroxide, ammonia, and aldehydes, which are risk factors for cell oxidative injury [12,17,73]. Therefore, the use of MAO-inhibiting substances can protect against toxicants and oxidative stress [11,17,71,74]. Currently, MAO inhibitors are being developed against Parkinsonism and neurodegeneration and as antidepressant drugs [1,[3][4][5][6][7][8][9]. ...
Article
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Monoamine oxidase (MAO) oxidizes neurotransmitters and xenobiotic amines, including vasopressor and neurotoxic amines such as the MPTP neurotoxin. Its inhibitors are useful as antidepressants and neuroprotectants. This work shows that diluted soy sauce (1/3) and soy sauce extracts inhibited human MAO-A and -B isozymes in vitro, which were measured with a chromatographic assay to avoid interferences, and it suggests the presence of MAO inhibitors. Chromatographic and spectrometric studies showed the occurrence of the β-carboline alkaloids harman and norharman in soy sauce extracts inhibiting MAO-A. Harman was isolated from soy sauce, and it was a potent and competitive inhibitor of MAO-A (0.4 µM, 44 % inhibition). The concentrations of harman and norharman were determined in commercial soy sauces, reaching 243 and 52 μg/L, respectively. Subsequently, the alkaloids 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (THCA) and 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) were identified and analyzed in soy sauces reaching concentrations of 69 and 448 mg/L, respectively. The results show that MTCA was a precursor of harman under oxidative and heating conditions, and soy sauces increased the amount of harman under those conditions. This work shows that soy sauce contains bioactive β-carbolines and constitutes a dietary source of MAO-A and -B inhibitors.
... Many compounds (drugs, natural products, as well as general chemicals) have been shown to inhibit MAO enzymes. In the clinic, drugs are used either as selective or nonselective MAO inhibitors in the therapy of several (Fritz et al. 1985;Glover et al. 1986;Herraiz 2012;Herraiz and Guillén 2011;Trevor et al. 1987aTrevor et al. , 1988 (Chaurasiya et al. 2014) Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
... Knowledge of the involvement of either MAO A, MAO B, or both enzymes in the metabolism of a drug allows for the prediction of drug-drug interactions with selective or non-selective MAO inhibitors. It should be emphasized that these are mitochondrial enzymes and that in vitro studies with microsomes will not include these enzymes or evaluate (Fritz et al. 1985;Glover et al. 1986;Herraiz 2012;Herraiz and Guillén 2011;Trevor et al. 1987aTrevor et al. , 1988 Nomifensine (Martini et al. 1981a(Martini et al. , 1981bNiwa et al. 2011;Oguchi et al. 1981;Shulman et al. 2013;Youdim and Weinstock 2004) Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
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This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, “general chemicals,” natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10–15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.
... 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), initially found to be present in the synthetic heroin, induces the selective degeneration of dopamine-synthesizing cells in the nigrostriatal area of the brain Dauer and Przedborski 2003;Srivastava et al. 2010;Gupta et al. 2014;Rasheed et al. 2017;Langston 2017). Although MPTP is not a very powerful neurodegenerative agent, it does cross the blood-brain barrier owing to its lipophilic nature and subsequently enters the astrocytes where it gets converted to 1-methyl-4-phenylpyridinium cation (MPP + ), a highly potent neurotoxicant, by an enzyme monoamine oxidase Gupta et al. 2014;Langston 2017;Herraiz and Guillén 2011). The adjoining dopaminergic neurons take up MPP + from the nigrostriatal astrocytes through monoamine transporters (Langston 2017;Cui et al. 2009). ...
... In MPTP-induced Parkinsonism, oxidative stress and mitochondrial dysfunction are found to be critical in addition to several other biological events (Ali et al. 1994). Acute MPTP mouse model is used in this study since it is widely employed to comprehend the molecular pathways involved in nigrostriatal dopaminergic neuronal loss and also to decipher the neuroprotective effectiveness of synthetic or natural antioxidants (Herraiz and Guillén 2011). MPTP was found to accelerate the depletion of striatal dopamine in the current experimental paradigm as observed in many previous investigations. ...
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exacerbates mitochondrial impairment and α-synuclein expression leading to Parkinsonism. Impaired mitochondria and over-expressed α-synuclein are degraded and eliminated via macroautophagy and chaperone-mediated autophagy. Owing to multiple properties, silymarin protects from oxidative stress–mediated cellular injury. However, its effect on MPTP-induced changes in autophagy is not yet known. The study aimed to decipher the effect of silymarin on MPTP-induced changes in autophagy. Male mice (20–25 g) were treated with silymarin (intraperitoneally, daily, 40 mg/kg) for 2 weeks. On day 7, a few animals were also administered with MPTP (intraperitoneally, 20 mg/kg, 4 injections at 2-h interval) along with vehicles. Striatal dopamine content was determined. Western blot analysis was done to assess α-synuclein, beclin-1, sequestosome, phosphorylated 5′ adenosine monophosphate–activated protein kinase (p-AMPK), lysosome-associated membrane protein-2 (LAMP-2), heat shock cognate-70 (Hsc-70), LAMP-2A, phosphorylated unc-51-like autophagy activating kinase (p-Ulk1), and phosphorylated mechanistic target of rapamycin (p-mTOR) levels in the nigrostriatal tissue. Silymarin rescued from MPTP-induced increase in beclin-1, sequestosome, p-AMPK, and p-Ulk1 and decrease in LAMP-2, p-mTOR, and LAMP-2A levels. Silymarin defended against MPTP-induced increase in α-synuclein and reduction in dopamine content. The results demonstrate that silymarin protects against MPTP-induced changes in autophagy leading to Parkinsonism.
... On the other hand, the oxidation of biogenic amines and neurotransmitters by MAO enzymes generates hydrogen peroxide (H 2 O 2 ), oxygen radicals, and aldehydes, which are risk factors for cell oxidative injury. Therefore, the inhibition of MAO may result in protection against oxidative stress and neurotoxins [1,3,4]. 2 BioMed Research International be involved [17]. Peganum harmala (family Zygophyllaceae) and Lepidium meyenii (family Brassicaceae) (maca) are plants with CNS effects and potential antidepressant actions [14,25,26]. ...
... MAO generates hydrogen peroxide (H 2 O 2 ) that is involved in oxidative cell damage and pathological conditions [1,3,4,[33][34][35][36]. Then, the inhibition of MAO may result in specific antioxidant actions [37]. ...
Article
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Monoamine oxidase (MAO) catalyzes the oxidative deamination of amines and neurotransmitters and is involved in mood disorders, depression, oxidative stress, and adverse pharmacological reactions. This work studies the inhibition of human MAO-A by Hypericum perforatum , Peganum harmala, and Lepidium meyenii, which are reported to improve and affect mood and mental conditions. Subsequently, the antioxidant activity associated with the inhibition of MAO is determined in plant extracts for the first time. H. perforatum inhibited human MAO-A, and extracts from flowers gave the highest inhibition (IC 50 of 63.6 μ g/mL). Plant extracts were analyzed by HPLC-DAD-MS and contained pseudohypericin, hypericin, hyperforin, adhyperforin, hyperfirin, and flavonoids. Hyperforin did not inhibit human MAO-A and hypericin was a poor inhibitor of this isoenzyme. Quercetin and flavonoids significantly contributed to MAO-A inhibition. P. harmala seed extracts highly inhibited MAO-A (IC 50 of 49.9 μ g/L), being a thousand times more potent than H. perforatum extracts owing to its content of β -carboline alkaloids (harmaline and harmine). L. meyenii root (maca) extracts did not inhibit MAO-A. These plants may exert protective actions related to antioxidant effects. Results in this work show that P. harmala and H. perforatum extracts exhibit antioxidant activity associated with the inhibition of MAO (i.e., lower production of H 2 O 2 ).
... myriad of activities demonstrated by resveratrol. [27] Although resveratrol itself has been shown to be largely devoid of MAO inhibitory activity, [28] we were able to establish MAO-B inhibition upon addition of a compound containing the dimethylamino group on the stilbene framework. MY containing a dimethylamino group was observed to be a more potent MAO-B inhibitor, showing an IC 50 value approximately 15 nm lower than that of azobenzene. ...
... [30] For instance, methylene blue has been shown to inhibit MAO-B and was shown to be neuroprotective in an MPTP toxin model. [28] Additionally, the metabolite of methylene blue, azure B, was shown to be a much more potent MAO-B inhibitor. [30,31] These dyes, therefore, might be a rich source of novel MAO-B inhibitors. ...
Article
Parkinson's disease (PD) is an age-related neurodegenerative disease affecting movement. To date, there are no currently available therapeutic agents which can prevent or slow disease progression. Here, we evaluated an azobenzene derivative, methyl yellow (MY), as a potential drug scaffold for PD; its inhibitory activity toward monoamine oxidase B (MAO-B) as well as drug-like properties were investigated. The inhibitory effect of MY on MAO activity was determined by a MAO enzyme inhibition assay. In addition, the in vitro properties of MY as a drug candidate (e.g., blood–brain barrier (BBB) permeability, serum albumin binding, drug efflux through P-glycoprotein (P-gp), drug metabolism by P450, and mitochondrial toxicity) were examined. In vivo effectiveness of MY was also evaluated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian mouse model. MY selectively inhibited MAO-B in a dose-dependent and reversible manner. MY was BBB-permeable, bound relatively weakly to serum albumin, was an unlikely substrate for both systems of P-gp and P450, and did not cause mitochondrial toxicity. Results from the MPTP Parkinsonian mouse model indicated that, upon treatment with MY, neurotoxicity induced by MPTP was mitigated. Investigations of MY demonstrate its inhibitory activity toward MAO-B, compliant properties for drug consideration, and its neuroprotective capability in the MPTP Parkinsonian mouse model. These data provide insights into potential use, optimization, and new design of azobenzene derivatives for PD treatment.
... It has been also proven that P. harmala-derived beta-carbolines interact with opioid, [21] dopamine, [24] GABA (Gamma-Aminobutyric acid), [31] 5-hydroxytryptamine, benzodiazepine, and imidazoline [32] receptors present in the nervous system and this way induce their many pharmacological effects. Moreover, these alkaloids are neuroprotective [31,33] and strong inhibitors of monoamine oxidase and this important feature makes them a preferable target in the treatment of some conditions like depression. [25] Mono amine oxidase inhibition and anti‑depressant effect Beta-carbolines present in P. harmala strongly inhibit monoamine oxidase enzyme that is the main factor in degradation and reuptake of monoamines like serotonin and norepinephrine. ...
... two of these endogenous compounds, norharman and 9-methylnorharman, have good anti-parkinsonism effects via inhibition of MAO-B, an enzyme involved in the production of parkinsonism-related substances from the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, naturally occurring beta-carbolines had almost no such inhibitory effect. [33] In contrast, several studies on the anti-parkinsonism effect of B. caapi revealed that its beta-carboline content (harmine and harmaline) has significant effect against this disease through the inhibition of MAO-B. [37,38] Although, these beta-carbolines with anti-parkinsonism effect are also present in P. harmala, there have been no st ...
Article
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Wild Syrian rue (Peganum harmala L. family Zygophyllaceae) is well-known in Iran and various parts of this plant including, its seeds, bark, and root have been used as folk medicine. Recent years of research has demonstrated different pharmacological and therapeutic effects of P. harmala and its active alkaloids, especially harmine and harmaline. Analytical studies on the chemical composition of the plant show that the most important constituents of this plant are beta-carboline alkaloids such as harmalol, harmaline, and harmine. Harmine is the most studied among these naturally occurring alkaloids. In addition to P. harmala (Syrian rue), these beta-carbolines are present in many other plants such as Banisteria caapi and are used for the treatment of different diseases. This article reviews the traditional uses and pharmacological effects of total extract and individual active alkaloids of P. harmala (Syrian rue).
... As the pyridinium species are the directly acting neurotoxins in vivo, the oxidation by MAO is considered a key route for the bioactivation of MPTP (Figure 2) [8]. Indeed, inhibitors of MAO-B usually protect against this neurotoxin and can be useful as neuroprotectants [37,40,41,54,55]. Although human MAO-A was also able to oxidize MPTP in vitro as well, a number of studies have shown that MAO-B is the main isoform involved in this oxidation [54][55][56][57]. ...
... Indeed, inhibitors of MAO-B usually protect against this neurotoxin and can be useful as neuroprotectants [37,40,41,54,55]. Although human MAO-A was also able to oxidize MPTP in vitro as well, a number of studies have shown that MAO-B is the main isoform involved in this oxidation [54][55][56][57]. ...
Article
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Metabolic enzymes are involved in the activation/deactivation of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyiridine (MPTP) neurotoxin and its naturally occurring analogs 2-methyltetrahydro-β-carbolines. The metabolic profile and biotransformation of these protoxins by three enzymes, monoamine oxidase (MAO), cytochrome P450, and heme peroxidases (myeloperoxidase and lactoperoxidase), were investigated and compared. The metabolite profile differed among the enzymes investigated. MAO and heme peroxidases activated these substances to toxic pyridinium and β-carbolinium species. MAO catalyzed the oxidation of MPTP to 1-methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP+), whereas heme peroxidases catalyzed the oxidation of MPDP+ to 1-methyl-4-phenylpyridinium (MPP+) and of 2-methyltetrahydro-β-carboline to 2-methyl-3,4-dihydro-β-carbolinium cation (2-Me-3,4-DHβC+). These substances were inactivated by cytochrome P450 2D6 through N-demethylation and aromatic hydroxylation (MPTP) and aromatic hydroxylation (2-methyltetrahydro-β-carboline). In conclusion, the toxicological effects of these protoxins might result from a balance between the rate of their activation to toxic products (i.e., N-methylpyridinium-MPP+ and MPDP+- and N-methyl-β-carbolinium—βC+—) by MAO and heme peroxidases and the rate of inactivation (i.e., N-demethylation, aromatic hydroxylation) by cytochrome P450 2D6.
... In the early 1980s, it was found that the dophaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrehydropiridine (MPTP), an analog of the narcotic meperidine, caused symptoms similar to those of PD [102]. Nowadays, MPTP is broadly used in toxic models of PD [54,[103][104][105][106]. Due to its lipophilicity, it easily crosses the blood-brain barrier. ...
Article
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Monoamine oxidase inhibitors are widely used for the symptomatic treatment of Parkinson’s disease (PD). They demonstrate antiparkinsonian activity in different toxin-based models induced by 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and pesticides (rotenone and paraquat). In some models, such as MPTP-induced PD, MAO inhibitors prevent the formation of the neurotoxin MPP⁺ from the protoxin MPTP. Regardless of the toxin’s nature, potent MAO inhibitors prevent dopamine loss reduction, the formation of hydrogen peroxide, hydrogen peroxide signaling, and the accumulation of hydrogen peroxide-derived reactive oxygen species responsible for the development of oxidative stress. It becomes increasingly clear that some metabolites of MAO inhibitors (e.g., the rasagiline metabolite 1-R-aminoindan) possess their own bio-pharmacological activities unrelated to the parent compound. In addition, various MAO inhibitors exhibit multitarget action, in which MAO-independent effects prevail. This opens new prospects in the development of novel therapeutics based on simultaneous actions on several prospective targets for the therapy of PD.
... Alkaloids such as β-carboline inhibit monoamine reuptake systems and inhibit monoamine oxidase (Cao et al., 2007;Fortunato et al., 2009;Splettstoesser et al., 2005;Herraiz and Guillén, 2011) leading to increase monoamines levels in the synapse, producing antidepressant-like activity. Alkaloids as barettin have structural similarities to serotonin, therefore may facilitate the function of 5HTR in case of 5-HTR disorders (Hedner, et al., 2006) and interact with 5HT. ...
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Abstract: Depression is a common mental disorder, causing disability worldwide and contributing to the overall global burden of disease. Antidepressant drug treatment takes several weeks to produce an effect; this effect is often accompanied by unwanted side effects. Therefore, the use of a crude form of herbal extracts could be an alternative therapy for depressive disorders. Aims of the Work: To investigate the phytochemical composition of aerial parts (flowers and leaves) Calicatome villosa extract; also to evaluate the neurobehavioral effect on the nervous system by applying the Irwin test, and to screen for the antianxiety and antidepressant-like activity using pulse maze and forced swimming maze. Material and Methods: The fresh aerial parts of calycatome villosa were collected in March 2018 from Alkums city -Libya. Preliminary Phytochemical analyses were carried out on the methanolic extract. Screening for the presence of various phytochemical compounds like; alkaloids, carbohydrates, tannins, phytosterols, saponins, flavonoids, and proteins were carried out. Conclusion: Preliminary phytochemical screening of Calycatome villosa methanolic extract revealed the presence of alkaloids, saponins, carbohydrates, phytosterols, phenols, and tannins. The pharmacological screening of the extract showed antidepressant, antipsychotic, CNS depression, and Muscle relaxant effects. The extract showed CNS depression using the Irwin test, while the spontaneous motor activity was not changed using EPM. Calycatome villosa methanolic extract with the dose used did not show an antianxiety-like effect using EPM. Keywords: Depression, Calycatome villosa, Antidepressant activity, Anxiolytic activity, preliminary phytochemical screening, Irwin blind test, Elevated plus-maze test, forced swimming maze test.
... The active neurotoxin MPP + is a by-product of MPTP via monoamine oxidase type B [75,76]. MPP + -dependent toxicity depends on the powerful inhibition of mitochondrial complex I activity [22,[25][26][27]51,52,[77][78][79]. ...
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The neurotoxins methamphetamine (METH) and 1-methyl-4-phenylpyridinium (MPP⁺) damage catecholamine neurons. Although sharing the same mechanism to enter within these neurons, METH neurotoxicity mostly depends on oxidative species, while MPP⁺ toxicity depends on the inhibition of mitochondrial activity. This explains why only a few compounds protect against both neurotoxins. Identifying a final common pathway that is shared by these neurotoxins is key to prompting novel remedies for spontaneous neurodegeneration. In the present study we assessed whether natural extracts from Bacopa monnieri (BM) may provide a dual protection against METH- and MPP⁺-induced cell damage as measured by light and electron microscopy. The protection induced by BM against catecholamine cell death and degeneration was dose-dependently related to the suppression of reactive oxygen species (ROS) formation and mitochondrial alterations. These were measured by light and electron microscopy with MitoTracker Red and Green as well as by the ultrastructural morphometry of specific mitochondrial structures. In fact, BM suppresses the damage of mitochondrial crests and matrix dilution and increases the amount of healthy and total mitochondria. The present data provide evidence for a natural compound, which protects catecholamine cells independently by the type of experimental toxicity. This may be useful to counteract spontaneous degenerations of catecholamine cells.
... Furthermore, these alkaloids were found to inhibit monoamine oxidase and have shown neuroprotective activity. is significant feature makes them a choice for the treatment of anxiety and depressive disorders [60,65,66]. ...
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Depression and anxiety are the most common disorders among all age groups. Several antidepressant drugs including benzodiazepine, antidepressant tricyclics, azapirone, noradrenaline reuptake inhibitors, serotonin selective reuptake inhibitors, serotonin, noradrenaline reuptake inhibitors, and monoamine oxidase inhibitors have been used to treat these psychiatric disorders. However, these antidepressants are generally synthetic agents and can cause a wide range of side effects. The potential efficacy of plant-derived alkaloids has been reviewed against various neurodegenerative diseases including Alzheimer's disease, Huntington disease, Parkinson's disease, schizophrenia, and epilepsy. However, data correlating the indole alkaloids and antidepressant activity are limited. Natural products, especially plants and the marine environment, are rich sources of potential new drugs. Plants possess a variety of indole alkaloids, and compounds that have an indole moiety are related to serotonin, which is a neurotransmitter that regulates brain function and cognition, which in turn alleviates anxiety, and ensures a good mood and happiness. The present review is a summary of the bioactive compounds from plants and marine sources that contain the indole moiety, which can serve as potent antidepressants. The prospects of naturally occurring as well as synthetic indole alkaloids for the amelioration of anxiety and depression-related disorders, structure-activity relationship, and their therapeutic prospects have been discussed.
... P. harmala and its active alkaloids possess a wide number of pharmacological activity on the nervous system involve psychoactive,analgesia, anti-depressant, Neuro protective, andstronginhibition of monoamine oxidase (MAO).Its analgesic effect acts both centrally and peripherally. Alkaloids also possess good anti-parkinsonism effects through inhibition of mono amin oxidase (MAO) (2,3,4).Various studies have revealed antiparasidal ...
Research
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A preliminary investigation on the effect of the aqueous extract of peganum harmala seeds on the blood picture of albina rats was studied, two oral dose levels of 38 and 98 mg/kg bodyweight were given for 49 weeks all blood investing actions comprising of haomoglobinplatiets, leucocytes and differential counts, packed cell volume and red blood cells morphology were within the normal range, no toxic side effects were observed throughout the course of the study. Introduction:
... MPTP is selectively taken up by astrocytes and is metabolized into methyl 1-4 phenyl pyridinium (MPP + ), this cation causing increased production of free radicals, depletion of ATP, and apoptosis. MPTP toxicity is selective to SNpc neurons and induced loss of striatal spines in non-human primates (150). Such striatal spine loss is a consistent neuropathologic finding in post-mortem PD human brains. ...
Article
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Prevention of neurodegenerative diseases is presently a major goal for our Society and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. Melatonin combines both chronobiotic and cytoprotective properties. As a chronobiotic, melatonin can modify phase and amplitude of biological rhythms. As a cytoprotective molecule, melatonin reverses the low degree inflammatory damage seen in neurodegenerative disorders and aging. Low levels of melatonin in blood characterizes advancing age. In experimental models of Alzheimer's disease (AD) and Parkinson's disease (PD) the neurodegeneration observed is prevented by melatonin. Melatonin also increased removal of toxic proteins by the brain glymphatic system. A limited number of clinical trials endorse melatonin's potentiality in AD and PD, particularly at an early stage of disease. Calculations derived from animal studies indicate cytoprotective melatonin doses in the 40–100 mg/day range. Hence, controlled studies employing melatonin doses in this range are urgently needed. The off-label use of melatonin is discussed.
... Complex interactions between these receptors are also possible, since I 2 can potentiate analgesic actions produced by opioid receptor ligands (Bektas et al., 2015). Furthermore, two studies demonstrated the neuroprotective effects of the alkaloids of P. harmala (Herraiz & Guillén, 2011;Splettstoesser, Bonnet, Wiemann, Bingmann, & Büsselberg, 2005), which could also be related to their analgesic effects (Mannelli et al., 2009). ...
Article
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Background and aims Pain is the most prevalent symptom of a health condition, and it is inappropriately treated in many cases. Here, we present a case report in which we observe a long-lasting analgesic effect produced by changa, a psychedelic drug that contains the psychoactive N,N-dimethyltryptamine and ground seeds of Peganum harmala, which are rich in β-carbolines. Methods We describe the case and offer a brief review of supportive findings. Results A long-lasting analgesic effect after the use of changa was reported. Possible analgesic mechanisms are discussed. We suggest that both pharmacological and non-pharmacological factors could be involved. Conclusion These findings offer preliminary evidence of the analgesic effect of changa, but due to its complex pharmacological actions, involving many neurotransmitter systems, further research is needed in order to establish the specific mechanisms at work.
... Nos analyses sur les tissus périphériques ont permis de mettre en évidence une cinq fois plus élevée que dans les autres tissus étudiés dans cette étude ,111 . De plus, l'affinité du MAO-B pour le MPTP est également plus élevée, jusqu'à être huit fois plus forte que dans les autres tissus112,113 . De ce fait, la conversion du MPTP vers sa forme active toxique, le MPP + , est plus rapide et sa concentration devient donc plus élevée. ...
Thesis
Un des rôles de la mitochondrie, qui possède son propre ADN (ADNmt), est la production de l'énergie nécessaire à la cellule, qu'elle synthétise sous forme d'ATP grâce aux oxydations phosphorylantes (OXPHOS). Ainsi, une altération du métabolisme énergétique mitochondrial peut provoquer l'apparition de pathologies mitochondriales dont, généralement, la sévérité est inversement proportionnelle à l'âge de début. De nombreuses études s'intéressent aux mécanismes d'apparition et de développement de ces maladies afin de mieux les comprendre et de pouvoir proposer des thérapies. Cependant, à ce jour, il est encore difficile de transformer l'ADNmt de façon ciblée (remaniement ou mutation). De plus, il existe encore peu de modèles animaux de pathologies mitochondriales qui permettraient de réaliser des études intégratives et d'essayer d'éventuelles molécules thérapeutiques. Dans le cadre de cette thèse, nous avons étudié deux types de modèles impliquant la modification du métabolisme mitochondrial. Dans un premier temps, nous nous sommes intéressés à la réalisation d'un modèle murin exprimant un grand nombre de caractéristiques du syndrome de Leigh, une maladie neurologique progressive. Pour cela nous avons utilisé une neurotoxine (MPTP) qui est connue pour sa toxicité envers les neurones dopaminergiques et aussi comme inhibiteur de la chaine respiratoire. Nous avons analysé l'activité de chaque complexe OXPHOS de différents tissus cérébraux et de tissus périphériques (cœur, foie, muscle et rein), prélevés sur des souris traitées et non-traitées. Nous avons retrouvé une inhibition des complexes III et/ou IV de la chaîne respiratoire dans le foie, le cortex, le striatum et le cervelet. Ces résultats, ajoutés à une neuro- dégénérescence accrue retrouvée dans une étude précédente, sont tous caractéristiques du syndrome de Leigh. Ces souris traitées par le MPTP semblent donc être un bon modèle pour l'étude de cette pathologie mitochondriale. Dans un second projet, nous nous sommes intéressés à l'effet des haplogroupes de l'ADNmt sur le métabolisme mitochondrial. En effet, bien qu'ils soient définis par des mutations neutres de l'ADNmt (polymorphismes), plusieurs études ont démontré des associations entre les haplogroupes et les pathologies, suggérant que les haplogroupes sont capables d'avoir un effet protecteur ou aggravant dans l'apparition d'une pathologie. Récemment, notre laboratoire a montré que certains haplogroupes avaient la capacité d'influencer le fonctionnement du métabolisme énergétique mitochondrial. Mon projet de recherche a donc consisté à mettre en place un modèle afin d'étudier les mécanismes cellulaires et moléculaires impliqués dans ce phénomène. Pour cela, nous avons recherché des haplogroupes d'intérêt dans la population française afin d'élaborer une collection de " cybrides " où chaque lignée de cellules possède un haplogroupe particulier mais un fonds génétique nucléaire commun à toutes les lignées. Nous avons caractérisé ces cybrides de manière biochimique (analyse de l'activité et des paramètres cinétiques de chaque complexe) et phénotypique (courbes de croissance). L'ensemble de ces résultats a été intégré dans un modèle informatique spécifiquement développé dans notre laboratoire pour modéliser la physiologie de la mitochondrie. Ce projet nous a permis de mettre en évidence l'influence des haplogroupes de l'ADNmt sur le métabolisme mitochondrial et de proposer une vision modulée des pathologies mitochondriales tant pour leur étude que pour leur diagnostic, en faisant ressortir la notion de médecine personnalisée. A l'avenir, il sera nécessaire de tenir compte du contexte génétique de l'ADNmt pour trouver de nouvelles stratégies ou de nouvelles cibles pour les thérapies des maladies mitochondriales.
... P. harmala and its active alkaloids possess a wide number of pharmacological activity on the nervous system involve psychoactive,analgesia, anti-depressant, Neuro protective, andstronginhibition of monoamine oxidase (MAO).Its analgesic effect acts both centrally and peripherally. Alkaloids also possess good anti-parkinsonism effects through inhibition of mono amin oxidase (MAO) (2,3,4).Various studies have revealed antiparasidal ...
Article
A preliminary investigation on the effect of the aqueous extract of peganum harmala seeds on the blood picture of albina rats was studied, two oral dose levels of 38 and 98 mg/kg bodyweight were given for 49 weeks all blood investing actions comprising of haomoglobinplatiets, leucocytes and differential counts, packed cell volume and red blood cells morphology were within the normal range, no toxic side effects were observed throughout the course of the study. Introduction:
... P. harmala and its active alkaloids possess a wide number of pharmacological activity on the nervous system involve psychoactive,analgesia, anti-depressant, Neuro protective, andstronginhibition of monoamine oxidase (MAO).Its analgesic effect acts both centrally and peripherally. Alkaloids also possess good anti-parkinsonism effects through inhibition of mono amin oxidase (MAO) (2,3,4).Various studies have revealed antiparasidal ...
Article
A preliminary investigation on the effect of the aqueous extract of peganum harmala seeds on the blood picture of albina rats was studied, two oral dose levels of 38 and 98 mg/kg bodyweight were given for 49 weeks all blood investing actions comprising of haomoglobinplatiets, leucocytes and differential counts, packed cell volume and red blood cells morphology were within the normal range, no toxic side effects were observed throughout the course of the study. Introduction:
... [ DOI: 10.29252/jnkums.6.4.697 ] [ Downloaded from journal.nkums.ac.ir on 2023-[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] ...
... TOXICITY[38,39]Plant parts of P. harmala are said to be toxic, but it is not in all the cases. Since the toxicity is dose dependent in animals. ...
Article
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ABSTRACT:P. harmalaLinn (P. harmala) is an indigenous plant of India .It is a highly branched and bushy perennialherb. Parts of the plant are known to possess therapeutic benefits. The plant is used locally in Indian medicine to cure various diseases. It is used in stomach complaints, urinary and sexual disorders, epilepsy, menstrual problems, mental and nervous illnesses etc. the chemical study of the plant reveals that the plant contains important alkaloids( harmine, harmaline, harmalol and peganine), steroid(lanosterol and kryptogenin)and Fatty acids/volatile acids/fixed oil(palmitic, stearic, arachidic, behenic, oleic, linoleic acids, β-sitosterol) etc. Based on the comprehensive literature survey phytochemistry, pharmacognosy, toxicity data and medicinal uses were discussed. Scientific information of the plant was collected from various sources like electronic (Google scholar, pub med) and some old classical text books of ayurveda and ethnopharmacology, In addition the paper covers the literature, primarily pharmacological, and importantfindings of the drug since last 25 years. This paper will be emerging tool for young researchers who want to start the meticulous research on P. harmalaKeywords:Peganamharmala,phytochemistry, pharmacognosy, ethnopharmacology, medicinal uses Peganam harmala Indian traditional plant: A Scientific Update.
... Peganum harmala contains b-carboline and quinazoline alkaloids which are responsible for the toxicological and pharmacological effects of the plant (Beyer et al., 2009;Herraiz et al., 2010;Pulpati et al., 2008). b-Carbolines are bioactive substances that exhibit activity on the central nervous system (CNS) through interaction with brain receptors and inhibition of MAO and kinases (El Gendy et al., 2012;Herraiz, 2016;Herraiz and Galisteo, 2015;Herraiz and Guillen, 2011;Rommelspacher and Wernicke, 2012;Ruben et al., 2015). Quinazoline alkaloids (i.e. ...
Article
Peganum harmala L. is a medicinal plant from the Mediterranean region and Asia currently used for recreative psychoactive purposes (Ayahuasca analogue), and increasingly involved in toxic cases. Its psychopharmacological and toxicological properties are attributed to quinazoline and β-carboline alkaloids. In this work three major quinazoline alkaloids were isolated from P. harmala extracts and characterized as peganine (vasicine), deoxypeganine (deoxyvasicine) and a novel compound identified by HPLC-DAD-MS and NMR as peganine β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (peganine glycoside). Peganine appeared in flowers and leaves in high levels; high amounts of deoxypeganine and peganine were found in immature and green fruits whereas peganine and peganine glycoside accumulated in high amount in dry seeds reaching up to 1 and 3.9% (w/w), respectively. Roots and stems contained low amount of quinazolines. Seeds extracts containing both quinazoline and β-carboline alkaloids potently inhibited human monoamine oxidase (MAO)-A. However, quinazoline alkaloids did not contribute to MAO inhibition that was due to β-carbolines, suggesting that MAO-related psychoactive or toxic actions do not arise from quinazolines. Quinazoline alkaloids were poor radical scavengers in the ABTS assay whereas seed extracts had good activity. Quinazoline alkaloids are known to exert bronchodilator and abortifacient actions, and could contribute to such effects reported in P. harmala.
... Consequently, BIO-A may safely reduce the aging brain oxidative stress by introducing a new mechanism for reversibly inhibiting both human MAOs with MAO-B inhibitory selectivity. There are other natural products with MAO-B inhibition proposed for neuroprotection [47][48][49], and there is a need to disclose their value in PD and AD patients. ...
Article
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Background Monoamine oxidase-B (MAO-B) inhibitors are widely used in the treatment of Parkinson’s disease. They increase vital monoamine neurotransmitters in the brain. However, there is a need for safer natural reversible MAO inhibitors with MAO-B selectivity. Our previous studies showed that Psoralea corylifolia seeds (PCS) extract contains compounds that inhibit monoamine oxidase-B. Methods In this study, six of PCS constituents sharing a benzopyrone structure were investigated. The compounds Biochanin-A (BIO-A), isopsoralen, 6-prenylnaringenin, neobavaisoflavone, psoralen, and psoralidin, were tested for their ability to inhibit recombinant human MAO-A and B (hMAO-A and hMAO-B) isozymes. The ability of these compounds to inhibit MAO-A and MAO-B were compared to that of PCS ethanolic extract (PCSEE) using spectrophotometric assays and confirmed by luminescence assays. The highly potent and selective MAO-B inhibitor, BIO-A, was further investigated for both isozymes reversibility and enzyme kinetics. Molecular docking studies were used to predict the bioactive conformation and molecular interactions of BIO-A with both isozymes. Results The data obtained indicate that benzopyrones inhibited hMAO-A and hMAO-B with different degrees as confirmed with the luminescence assay. BIO-A inhibited hMAO-B with high potency and selectivity in the present study (IC50 = 0.003 μg/mL) and showing 38-fold more selectivity than PCSEE (hMAO-B IC50 = 3.03 μg/mL, 17-fold selectivity) without affecting hydrogen peroxide. Furthermore, BIO-A reversibly and competitively inhibited both hMAOs with significantly lower inhibitory constant (Ki) in hMAO-B (3.8 nM) than hMAO-A (99.3 nM). Our docking studies indicated that the H-bonds and hydrophobic interactions at the human MAO-A and MAO-B active sites contributed to the reversibility and selectivity of BIO-A. Conclusions The data obtained indicate that BIO-A is a potent, reversible and selective MAO-B inhibitor and may be recommended for further investigation in its possible use in the therapeutic management of Parkinson’s and Alzheimer’s diseases.
... 20,24 It has been proven that the alkaloids possess good anti-parkinsonism effects via inhibition of MAO-B. 25,26 In an in vitro study desoxypeganine, one of the P. harmala alkaloids, lessened ethanol consumption in female Alko alcohol rats dose-dependently, with no effect on food and fluid consumption. 27 Various studies have revealed antiparasidal, 28 antifungal, antibacterial, 29 insecticidal 30-32 and antileishmanial 8,33 effects from P. harmala alkaloids. ...
Article
Full-text available
To review the pharmacological activities of Peganum harmala L. (P. harmala, Nitrariaceae) in traditional Iranian medicine (TIM) and modern phytotherapy. Opinions of TIM and modern phytotherapy about safety and acceptable dosage of this plant are discussed. Various medical properties of P. harmala were collected from important TIM references and added to scientific reports derived from modern medical databases like PubMed, Scirus, ScienceDirect and Scopus. The main medicinal part of the plant is the seed. In TIM resources, this plant possesses various Pharmacological activities such as carminative, galactagogue, diuretic, emmenagogue, antithrombotic and analgesic. In modern phytotherapy, P. harmala demonstrated numerous medicinal effects including cardiovascular, neurologic, antimicrobial, insecticidal, antineoplasmic, antiproliferative, gastrointestinal and antidiabetic effects. Adverse events such as neuro-sensorial symptoms, visual hallucination, bradycardia, hypotension, agitation, tremors, ataxia, abortion and vomiting cause people to use this plant cautiously. P. harmala is contraindicated during pregnancy, due to its abortive and mutagenic activities. Because of increasing the expression of CYP1A2, 2C19, and 3A4 and inhibition of monoamine oxidase, the pharmacokinetic parameters of drugs which are mainly metabolized by these enzymes may be affected by P. harmala. The medicinal properties declared for this plant in TIM are compared with those showed in modern phytotherapy. Some of the TIM properties were confirmed in modern phytotherapy like emetic and analgesic activities and some have not been evaluated in modern phytotherapy such as its therapeutic effects on paralysis, epilepsy and numbness. Finally, the current review provides the evidence for other researchers to use TIM properties of P. harmala as an efficacious natural drug. Further preclinical and clinical studies for adequate evaluating safety and therapeutic efficacy are recommended.
... MLT has been shown to have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson Disease [72]. Neurotoxin MPTP is bioactivated to its toxic metabolites preferentially by monoamine oxidase-B in the mitochondria. ...
Article
Full-text available
It is known that melatonin (MLT) and some of its metabolites act as antioxidants by scavenging free radicals as well as increasing the activity of antioxidant enzymes in the body.MLT is suggested to exert beneficial effects via various mechanisms in the treatment of many diseases, such as cancer, neurodegenerative diseases, epilepsy, diabetes mellitus and obesity. People working in nightshift exhibit decreased MLT levels that are suggested to be related with increased risk of hormone-related diseases. Similarly blind people were found to have increased MLT levels protecting against many diseases. This review briefly summarizes the published reports supporting these beneficial effects of MLT. Furthermore the present review involves recent developments related to the antioxidant effect of remarkable and multi-faceted molecule MLT as well as its metabolites and its synthesized analogues. The role of MLT as an inhibitor of bioactivation reactions is also discussed.
... MPP + inhibits mitochondrial respiration in the nigrostriatal neurons and leads to an energy-deficient condition and degeneration of the latter, resulting in Parkinson's disease [593]. In this type of toxicity, MAO inhibitors and antioxidants have the potential to prevent oxidation of MPTP + to MPDP + /MPP + in mitochondria and thus act as neuroprotective agents [604]. ...
Chapter
Drug-metabolizing enzymes (DMEs) are primarily expressed in the liver but their role in the extrahepatic tissues such as gastrointestinal tract (GIT), pulmonary, excretory, nervous, cardiovascular system, and skin cannot be neglected. Generally, the expression of DMEs in extrahepatic tissues is quantitatively lower than that in the liver, but there are a few enzymes such as CYP1A1, CYP1B1, CYP2F1, and CYP2U1 that are more abundant in extrahepatic organs. As many extrahepatic organs are portals for administered drugs, DMEs expressed in these organs can be responsible for significant metabolism, leading to first-pass effects and lower bioavailability. Extrahepatic DMEs are also involved in bioactivation of prodrugs and formation of reactive metabolites that may interact with cellular components, resulting in organ-specific toxicity. Activity and expression of extrahepatic DMEs is often altered by coadministered drugs, leading to drug–drug interactions. Expression of DMEs in living beings affected by a host of environmental and genetic factors such as genetic polymorphism, age, gender, pathophysiological conditions, inborn errors in metabolism, food habits, and environmental pollutants, contributing to varied drug effects and idiosyncratic toxicities.
... Inhibitors of MAO-A, an enzyme involved in monoamines deamination , are prescribed to relieve depression symptoms. Inhibition of MAO-A also prevents the production of H 2 O 2 that represents a risk factor for cell oxidative injury [27]. To our knowledge, this is the first report on the anti-MAO-A capacity of J. grandiflorum. ...
... Inhibitors of MAO-A, an enzyme involved in monoamines deamination , are prescribed to relieve depression symptoms. Inhibition of MAO-A also prevents the production of H 2 O 2 that represents a risk factor for cell oxidative injury [27]. To our knowledge, this is the first report on the anti-MAO-A capacity of J. grandiflorum. ...
Article
The dried flower buds of Jasminum grandiflorum L. are widely consumed as infusion and used in traditional medicine for psychiatric disorders. It is important to have a well-established method for the chemical characterization of J. grandiflorum since there are resemblances with a toxic species, Gelsemium sempervirens (L.) Jaume Saint-Hilaire. HPLC-DAD-ESI/MSn analysis allowed identifying six phenolic compounds for the first time. Moreover, the evaluation of in vitro activity against central nervous system (CNS) related enzymes was undertaken for the first time, as well as against reactive species in order to support the efficacy towards CNS disorders.
... In normal conditions, MPP + generates several ROS, including O 2 − , H 2 O 2 , and · OH [18], resulting in lipid peroxidation, DNA fragmentation, mitochondrial impairment, LDH leakage, GSH depletion [19], reduction of Na + K + -ATPase and catalase activities, increase of caspase-3 activity, and eventually cell death [20]. Thus, suppressants or inhibitors of MPP + -induced oxidative stress are considered to be potential agents for chemopreventive and chemotherapeutic strategies, though there are only a few studies regarding the protective effects of dietary factors on MPP + -induced apoptosis [21,22]. The present results showed that an abundantly available carotenoid, ATX, had protective effects on MPP + -induced apoptosis in PC12 cells and elucidated some of the underlying molecular mechanisms. ...
Article
Full-text available
Objective: To investigate astaxanthin (ATX) neuroprotection, and its mechanism, on a 1-methyl-4-phenyl-pyridine ion (MPP⁺)-induced cell model of Parkinson’s disease. Methods: Mature, differentiated PC12 cells treated with MPP⁺ were used as an in vitro cell model. The MTT assay was used to investigate cell viability after ATX treatment, and western blot analysis was used to observe Sp1 (activated transcription factor 1) and NR1 (NMDA receptor subunit 1) protein expression, real-time PCR was used to monitor Sp1 and NR1 mRNA, and cell immunofluorescence was used to determine the location of Sp1 and NR1 protein and the nuclear translocation of Sp1. Results: PC12 cell viability was significantly reduced by MPP⁺ treatment. The expression of Sp1 and NR1 mRNA and protein were increased compared with the control (p < 0.01). Following co-treatment with ATX and MPP⁺, cell viability was significantly increased, and Sp1 and NR1 mRNA and protein were decreased, compared with the MPP⁺ groups (p < 0.01). In addition, mithracycin A protected PC12 cells from oxidative stress caused by MPP⁺ by specifically inhibiting the expression of Sp1. Moreover, cell immunofluorescence revealed that ATX could suppress Sp1 nuclear transfer. Conclusion: ATX inhibited oxidative stress induced by MPP⁺ in PC12 cells, via the SP1/NR1 signaling pathway.
... More recent results show that quercetin (15d) is a potent and selective MAO-A inhibitor with an IC 50 = 0.010 μM [93]. In contrast with previous findings, it has been recently reported that 15d weakly inhibits MPTP bioactivation (33% at 10 μM concentration) and this suggests also a limited inhibition of the MAO-B activity [94]. Eugenol (4-allyl-2-methoxyphenol, 16) is the major component of clove, cinnamon, basil, and nutmeg oils and the major active principle of Rhizoma acori graminei (RAG), a botanical remedy described in Chinese pharmacopoeias and used as a palliative treatment of AD cognitive dysfunctions. ...
Article
Full-text available
The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.
Chapter
The environmental pollution may have an impact on the incidence of lung, skin, and eye diseases, as the corresponding organs are directly exposed to environmental stressors. Industrial, agricultural, pharmacological, and lifestyle applications have increased the types and amounts of xenobiotic agents to which humans are exposed. Unfortunately, the human body is also subject to injury from physical agents arising from occupational environments such as ionizing radiations and UV light, released by nuclear plants and therapeutic activities. Most of the chemical and physical agents mediate cellular injury by their ability to cause oxidative stress (OS) to cell components. They induce oxidative injury in susceptible biomolecules and/or modulate redox-sensitive elements including signal transduction pathways and gene expression. The interaction of these agents also leads to radical cascades and lipid peroxidation, thereby exacerbating the endogenous OS. This chapter is a very comprehensive review on the OS exerted by environmental contaminants including drugs, heavy metals, pesticides, aromatic hydrocarbons, and solvents. The authors emphasize that not all contaminants act as pro-oxidants in a similar fashion. Some of these agents are able to exert OS in a direct and major way such as therapeutic drugs, pesticides, and solvents. Others like heavy metals raise OS through a pleiotropic response that generates high levels of reactive species (RS). This chapter also covers the toxic effects of cigarette smoke and particles like asbestos, nanoparticles (NPs), and airborne particles on the lung. The various mechanisms by which toxins can induce oxidative damage to cells are also illustrated by consideration of aflatoxins and venom components.
Chapter
Monoamine oxidase (MAO) enzymes (MAO A and B) catalyze the oxidative deamination of biogenic amines, neurotransmitters, and xenobiotic amines and contribute to the regulation of the content of these active substances in mammalian organisms. The oxidation of biogenic amines by MAO produces hydrogen peroxide (H2O2) and aldehydes that represent risk factors for oxidative injury. The inhibitors of MAO are useful as antidepressants and neuroprotective agents. Usually, the assays of MAO determine amine deamination products or measure the H2O2 released by using direct spectrophotometric or fluorimetric methods. Direct methods are more prone to interferences and can afford inaccurate results. Those limitations can be avoided by using chromatographic techniques. This work describes a chromatographic method to assay MAO A and MAO B activity by using kynuramine as a nonselective substrate and the subsequent analysis of 4-hydroxyquinoline by RP-HPLC-DAD-fluorescence and mass spectrometry (MS). Alternatively, the assay uses the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin as a substrate of MAO that is oxidized (bioactivated) to neurotoxic pyridinium cations which are analyzed by HPLC. These methods are applied to assess the inhibition of MAO by bioactive β-carboline alkaloids occurring in foods, plants, and biological systems.
Article
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β-Carbolines (BC) are pyridoindoles, which can be found in various exogenous and endogenous sources. Recent studies revealed neurostimulative, neuroprotective, neuroregenerative and anti-inflammatory effects of 9-methyl-BC (9-Me-BC). Additionally, 9-me-BC increased neurite outgrowth of dopaminergic neurons independent of dopamine uptake into these neurons. In this study, the role of astrocytes in neurostimulative, neuroregenerative and neuroprotective properties of 9-me-BC was further explored. 9-Me-BC exerted anti-proliferative effects without toxic properties in dopaminergic midbrain and cortical astrocyte cultures. The organic cation transporter (OCT) but not the dopamine transporter seem to mediate at least part the effect of 9-me-BC on astrocytes. Remarkably, 9-me-BC stimulated the gene expression of several important neurotrophic factors for dopaminergic neurons like Artn, Bdnf, Egln1, Tgfb2 and Ncam1. These factors are well known to stimulate neurite outgrowth and to show neuroprotective and neuroregenerative properties to dopaminergic neurons against various toxins. Further, we show that effect of 9-me-BC is mediated through phosphatidylinositol 3-kinase (PI3K) pathway. Additionally, 9-me-BC showed inhibitory properties to monoamine oxidase (MAO) activity with an IC50 value of 1 µM for MAO-A and of 15.5 µM for MAO-B. The inhibition of MAO by 9-me-BC might contribute to the observed increased dopamine content and anti-apoptotic properties in cell culture after 9-me-BC treatment in recent studies. Thus, 9-me-BC have a plethora of beneficial effects on dopaminergic neurons warranting its exploration as a new multimodal anti-parkinsonian medication.
Article
Monoamine oxidase B (MAO B) inhibitors, which inhibit dopamine decomposition by antagonizing MAO B activity, are approved and widely used for clinical treatment of Parkinson's disease (PD). Nonetheless, the mechanism of the abnormally increased MAO B activity in PD is still unclear. Previous research showed transcription factor specificity protein 1 (SP1) directly regulates MAO B activity by binding the SP1 binding sequence in MAO B promoter. In our study, we first observed that the SP1 protein level and SP1 binding activity in the MAO B promoter were increased in 1‐methyl‐4‐phenylpyridinium (MPP⁺) neurotoxin‐induced SH‐SY5Y cells. Inhibition of SP1 by pretreatment with SP1 inhibitor mithramycin A (MMA) attenuated the abnormal increase in SP1 binding activity and the MAO B protein level to basal levels. Then, we investigated the neuroprotective effects of SP1 inhibition. In SH‐SY5Y cell models of PD, preincubation with MMA or knockdown by SP1‐specific small interfering RNA showed potent protection against MPP⁺‐induced apoptosis via SP1. In a male C57BL/6 mouse model of PD, MAO B activity and MPP⁺ concentrations in mouse brain following injection of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) were increased, whereas the elevated MAO B activity was decreased after pre‐injection of MMA. Moreover, MMA ameliorated MPTP‐induced loss of dopaminergic neurons in the substantia nigra pars compacta and mouse behavioral impairments. Altogether, our study suggests that SP1 is a principal factor regulating increases in MAO B activity, and SP1 inhibition produces neuroprotective effects in PD models through decreases in MAO B activity, which may be a new neuroprotective therapeutic strategy for PD treatment.
Article
Recently, we have described an HPLC-UV assay for the evaluation of inhibitors of plasma amine oxidase (PAO) using 6-(5-phenyl-2H-tetrazol-2-yl)hexan-1-amine (4) as a new type of substrate. Now we studied, whether this compound or homologues of it can also function as substrate for related amine oxidases, namely diamine oxidase (DAO), monoamine oxidase A (MAO A) and monoamine oxidase B (MAO B). Among these substances, 4 was converted by DAO with the highest rate. The best substrate for MAO A and B was 4-(5-phenyl-2H-tetrazol-2-yl)butan-1-amine (2). To validate the new assays, the inhibition values of known enzyme inhibitors were determined and the data were compared with those obtained with the substrate benzylamine, which is often used in amine oxidase assays. For the DAO inhibitor 2-(4-phenylphenyl)acetohydrazide an about 10fold lower IC50-value against DAO was obtained when benzylamine was applied instead of 4, indicating that 4 binds to the enzyme with higher affinity than benzylamine. The IC50-values of clorgiline and selegiline against MAO A and B, respectively, also decreased (two- and 30fold) replacing 2 by benzylamine. The discrepancies largely disappeared, when the enzymes were pre-incubated with the inhibitors for 15 min. This can be explained with the covalent inhibition mechanism of the inhibitors.
Article
Monoamine oxidase (MAO) enzymes catalyze the oxidative deamination of biogenic amines and neurotransmitters and produce ammonia, aldehydes, and hydrogen peroxide which is involved in oxidative processes. Inhibitors of MAO-A and -B isozymes are useful as antidepressants and neuroprotectants. The assays of MAO usually measure amine oxidation products or hydrogen peroxide by spectrophotometric techniques. Those assays are often compromised by interfering compounds resulting in poor results. This research describes a new method that combines in the same assay the oxidative deamination of kynuramine to 4-hydroxyquinoline analyzed by HPLC-DAD with the oxidation of tetramethylbenzidine (TMB) (or Amplex Rex) by horseradish peroxidase (HRP) in presence of hydrogen peroxide. The new method was applied to study the inhibition of human MAO-A and -B by bioactive compounds including β-carboline alkaloids and flavonoids occurring in foods and plants. As determined by HPLC-DAD, β-carbolines, methylene blue, kaempferol and clorgyline inhibited MAO-A and methylene blue, 5-nitroindazole, norharman and deprenyl inhibited MAO-B, and all of them inhibited the oxidation of TMB in the same extent. The flavonoids catechin and cyanidin were not inhibitors of MAO by HPLC-DAD but highly inhibited the oxidation of TMB (or Amplex Red) by peroxidase whereas quercetin and resveratrol were moderate inhibitors of MAO-A by HPLC-DAD, but inhibited the peroxidase assay in a higher level. For some phenolic compounds, using the peroxidase-coupled assay to measure MAO activity led to mistaken results. The new method permits to discern between true inhibitors of MAO from those that are antioxidants and which interfere with peroxidase assays but do not inhibit MAO. For true inhibitors of MAO, inhibition as determined by HPLC-DAD correlated well with inhibition of the oxidation of TMB and this approach can be used to assess the in vitro antioxidant activity (less hydrogen peroxide production) resulting from MAO inhibition.
Chapter
Neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD) are major health problems, and a growing recognition exists that efforts to prevent them must be undertaken by both governmental and nongovernmental organizations. In this context, the pineal product melatonin has a promising significance because of its chronobiotic/cytoprotective properties. One of the features of advancing age is the gradual decrease in endogenous melatonin synthesis. A limited number of therapeutic trials have indicated that melatonin has a potential therapeutic value as a neuroprotective drug in the treatment of AD, minimal cognitive impairment (which may evolve to AD), and PD. Both in vitro and in vivo, melatonin prevented the neurodegeneration seen in experimental models of AD and PD. For these effects to occur, doses of melatonin about two orders of magnitude higher than those required to affect sleep and circadian rhythmicity are needed. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50–100 mg/day are needed to assess its therapeutic validity in neurodegenerative disorders.
Article
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium cation (MPP+) are selective dopaminergic neurotoxins producing Parkinsonism. MPTP is activated by monoamine oxidase-B (MAO-B) to MPP+ that inhibits mitochondrial function. Molecules resembling MPTP which afford pyridinium cations are also neurotoxins. The herbicide paraquat (a bipyridinium dication) and the naturally-occurring β-carboline and isoquinoline alkaloids are structural analogues of MPTP/MPP+. Paraquat generates reactive oxygen species (ROS) producing neurotoxicity by a mechanism that differs from MPTP/MPP+. Human exposure to PQ is increasingly associated with neurodegeneration. Tetrahydro-β-carbolines (THβCs), β-carbolines (βCs) and tetrahydroisoquinolines (TIQs) are bioactive compounds occurring in foods and the human body. They are not MPTP-like toxins and do not appear to induce neurotoxicity at normal levels of exposure. Among TIQs, endogenous dopamine-derived TIQs (i.e. salsolinol) and 1-benzyl-TIQ are toxic through ROS generation. In contrast, β-carbolinium (βC+s) and isoquinolinium cations (IQ+s) are neurotoxicants resembling MPP+ although they are less potent and selective. βC+s and IQ+s have been detected in the human brain but their toxicological significance remains unknown. THβCs/βCs and TIQs are activated to toxic cations by N-methyltransferases (NMT) and/or heme peroxidases and are metabolized by cytochrome P450 enzymes. Remarkably, recent findings suggest, instead, that βCs and TIQs are neuroprotectants and neurorestorative, raising the interest of these molecules.
Chapter
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive molecules that are implicated in both normal and abnormal cellular processes. ROS and RNS are produced during normal cellular metabolism via diverse enzymatic pathways, but excessive production can occur in response to such stressors as toxicant exposure, radiation damage, and disease, resulting in local oxidative stress. These high levels of ROS/RNS induce a complex series of downstream adaptive and reparative events often associated with inflammation and fluid accumulation. Examples of ROS include peroxides and free oxygen ions generated during the normal metabolism of oxygen. Similarly, RNS such as nitric oxide (NO), peroxynitrite, and nitrogen dioxide are generated via the activity of enzymes such as inducible nitric oxide synthase 2 (NOS2) and NADPH oxidase (NOX). One of the main sources of ROS is the mitochondria where ROS superoxides are produced as a by-product of normal oxidative phophorylation; excess superoxide leaking into the cytoplasm can be converted into further ROS, whereas reactivity with NO generates peroxynitrite and further downstream nitrogen species. Here we review the main intracellular pathways and extracellular pathways involved in ROS and RNS signaling and the consequential damage to DNA, proteins, and lipids. Key mechanisms such as antioxidant defense and redox sensors are considered along with the key regulating kinases and transcription factors such as PI3K and NFkB. The roles of ROS and RNS in aging and associated diseases such as COPD, asthma, and neurodegeneration are discussed in detail along with an analysis of probable mechanisms. Finally, we consider future challenges such as how do ROS and RNS interact at multiple places within signaling networks and how do we understand and predict likely outcome? Also, how do ROS/RNS activate key molecules such as JNK and p38 MAPK and cell cycle genes? More detailed knowledge of these interactions may provide opportunities for future lifestyle advice and therapeutic intervention.
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β-Carbolines are bioactive pyridoindole alkaloids occurring in foods, plants and the human body. Their activity as hydroxyl radical (OH) scavengers is reported here by using three different methods: deoxyribose degradation, hydroxylation of benzoate and hydroxylation of 2'-deoxyguanosine to give 8-hydroxy-2'-deoxyguanosine (8-OHdG) as assessed by RP-HPLC (MS). Fenton reactions (Fe(2+)/Fe(3+) plus H2O2) were used for OH generation, and the radical increased in the presence of ascorbic acid or 6-hydroxydopamine as pro-oxidants. β-Carbolines were scavengers of OH in the three assays and in the presence of pro-oxidants. Tetrahydro-β-carboline-3-carboxylic acids were active against the hydroxylation of 2'-deoxyguanosine. β-Carbolines reacted with hydroxyl radicals (OH) affording hydroxy-β-carbolines, whereas tetrahydro-β-carbolines gave oxidative and degradation products. On the basis of IC50 and reaction rates (k), β-carbolines (norharman and harman), and tetrahydro-β-carbolines (tetrahydro-β-carboline, 1-methyltetrahydro-β-carboline and pinoline) were good OH radical scavengers and their activity was comparable to that of the indole, melatonin, which is an effective hydroxyl radical scavenger and antioxidant. Copyright © 2014 Elsevier Ltd. All rights reserved.
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This protocol describes our method of producing a reliable mouse model of Parkinson's disease (PD) using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We discuss the particulars of the model, provide key references and outline what investigators need to know to develop the MPTP mouse model of PD safely and successfully. Completion of this protocol depends on the regimen of MPTP used and on the actual planned studies, which often range from 7 to 30 d. This protocol calls for implementation of safety measures and for the acquisition of several pieces of equipment, which are a one-time investment worth making if one elects to use this model on a regular basis.
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In a previous study, a primary culture of midbrain cells was exposed to 9-methyl-beta-carboline for 48 h, which caused an increase in the number of tyrosine hydroxylase-positive cells. Quantitative RT-PCR revealed increased transcription of genes participating in the maturation of dopaminergic neurons. These in vitro findings prompted us to investigate the restorative actions of 9-methyl-beta-carboline in vivo. The compound was delivered for 14 days into the left cerebral ventricle of rats pretreated with the neurotoxin 1-methyl-4-phenyl-pyridinium ion (MPP+) for 28 days applying a dose which lowered dopamine by approximately 50%. Interestingly, 9-methyl-beta-carboline reversed the dopamine-lowering effect of the neurotoxin in the left striatum. Stereological counts of tyrosine hydroxylase-immunoreactive cells in the substantia nigra revealed that the neurotoxin caused a decrease in the number of those cells. However, when treated subsequently with 9-methyl-beta-carboline, the number reached normal values. In search of an explanation for the restorative activity, we analyzed the complexes that compose the respiratory chain in striatal mitochondria by 2-dimension gel electrophoresis followed by MALDI-TOF peptide mass fingerprinting.We found no changes in the overall composition of the complexes. However, the activity of complex I was increased by approximately 80% in mitochondria from rats treated with MPP+ and 9-methyl-beta-carboline compared to MPP+ and saline and to sham-operated rats, as determined by measurements of nicotinamide adenine dinucleotide dehydrogenase activity. Microarray technology and single RT-PCR revealed the induction of neurotrophins: brain-derived neurotrophic factor, conserved dopamine neurotrophic factor, cerebellin 1 precursor protein, and ciliary neurotrophic factor. Selected western blots yielded consistent results. The findings demonstrate restorative effects of 9-methyl-beta-carboline in an animal model of Parkinson's disease that improve the effectiveness of the respiratory chain and promote the transcription and expression of neurotrophin-related genes.
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Ringer's solution containing salicylic acid (5 nmol/microliters/min) was infused directly through an intracranial microdialysis probe to detect the generation of hydroxyl radicals (.OH) reflected by the formation of dihydroxybenzoic acids (DHBA) in the caudate nucleus of anesthetized rats. Brain dialysate was assayed for dopamine, 2,3-, and 2,5-DHBA by a high-pressure liquid chromatography-electrochemical (HPLC-EC) procedure. 1-Methyl-4-phenylpyridinium ions (MPP+, 0 to 150 nmol) increased dose-dependently the release of dopamine and the formation of DHBA. A positive linear correlation between the release of dopamine and the formation of 2,3- or 2,5-DHBA was observed (R2 = .98). The present results demonstrate the validity of the use of not only 2,3-DHBA but also 2,5-DHBA as an in vivo index of oxidative damage generated by reactive .OH radicals. In conclusion, the present study demonstrates a novel use of intracranial microdialysis of salicylic acid to assess the oxidative damage elicited by .OH in living brain.
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The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to generate reactive oxygen species during its interaction with monoamine oxidase type B (MAO-B). The kinetic parameters, Km and Vmax, for MAO-B-catalyzed oxidation of MPTP to the corresponding species MPDP+ were found to be 0.194 mM and 0.335 microM/min, respectively. The generation of superoxide (.O2-) and hydroxyl (.OH) radicals was detected as the 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) spin adduct by spin-trapping in combination with EPR techniques. Addition of Fe2+ (10 microM) to this system caused a 5-fold enhancement in EPR signal intensity of the DMPO-OH adduct. Catalase, a scavenger of hydrogen peroxide (H2O2), inhibited the DMPO-OH spin adduct formation in a dose-dependent manner, indicating that H2O2 is produced in the MAO-B catalyzed oxidation of MPTP. Ethanol, a well known scavenger of hydroxyl radical, rapidly produced an alpha-hydroxyethyl radical signal. Superoxide dismutase inhibited the formation of DMPO-O2- and DMPO-OH spin adducts in a dose-dependent fashion. These data suggest that superoxide radicals are produced during the oxidation of MPTP by MAO-B and that the generation of H2O2 and .OH was secondary to the production of .O2-. It appears likely that the nigrostriatal toxicity of MPTP leading to Parkinson's disease-like syndrome may in part be mediated via these reactive oxygen species.
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The concentration of an inhibitor that decreases the rate of an enzyme-catalysed reaction by 50%, symbolized i(0.5), is often used in pharmacological studies to characterize inhibitors. It can be estimated from the common inhibition plots used in biochemistry by means of the fact that the extrapolated inhibitor concentration at which the rate becomes infinite is equal to -i(0.5). This method is, in principle, more accurate than comparing the rates at various different inhibitor concentrations, and inferring the value of i(0.5) by interpolation. Its reciprocal, 1/i(0.5), is linearly dependent on v(0)/V, the uninhibited rate divided by the limiting rate, and the extrapolated value of v(0)/V at which 1/i(0.5) is zero allows the type of inhibition to be characterized: this value is 1 if the inhibition is strictly competitive; greater than 1 if the inhibition is mixed with a predominantly competitive component; infinite (i.e. 1/i(0.5) does not vary with v(0)/V) if the inhibition is pure non-competitive (i.e. mixed with competitive and uncompetitive components equal); negative if the inhibition is mixed with a predominantly uncompetitive component; and zero if it is strictly uncompetitive. The type of analysis proposed has been tested experimentally by examining inhibition of lactate dehydrogenase by oxalate (an uncompetitive inhibitor with respect to pyruvate) and oxamate (a competitive inhibitor with respect to pyruvate), and of cytosolic malate dehydrogenase by hydroxymalonate (a mixed inhibitor with respect to oxaloacetate). In all cases there is excellent agreement between theory and experiment.
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: To examine whether simple β-carbolines induce parkinsonian-like symptoms in vivo via N-methylation, the simple β-carbolines norharman (NH), 2-mono-N-methylated norharmanium cation (2-MeNH+), and 9-mono-N′-methylnorharman (9-MeNH) were systematically administered to C57BL/6 mice for 7 days. These substances induced bradykinesia with reduction of locomotion activity. NH or 2-MeNH+ decreased dopamine (DA) contents to 50–70% of values in controls in the striatum and midbrain. 9-MeNH potently decreased not only DA but also serotonin content in various regions. Immunohistochemical examination revealed that the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta of NH- and 9-MeNH-treated mice were diminished to 76 and 66% of values in control mice, respectively. The formation of a toxic metabolite, 2,9-di-N,N′-methylated norharmanium cation (2,9-Me2NH+), was 14 and eight times higher in the brain of mice receiving 9-MeNH than that in NH- and 2-MeNH+-treated mice, respectively. In cultured mesencephalic cells from rat embryo, 2,9-Me2NH+ selectively killed TH-positive neurons only at a lower dose but was toxic to all neurons at higher doses. Thus, the excess formation of 2,9-Me2NH+ would induce nonspecific neurotoxicity. These results indicated that 9-indole nitrogen methylation should be the limiting step in the development of the toxicity. NH, a selective dopaminergic toxin precursor, is sequentially methylated to form 2,9-Me2NH+, which could be an underlying factor in idiopathic Parkinson's disease.
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Monoamine oxidase type B (MAO-B) activity and free radicals are elevated in certain neurological diseases. Four natural flavonoids, quercitrin, isoquercitrin, rutin, and quercetin, were isolated for the first time from the leaves of Melastoma candidum D. Don. They exhibited an inhibitory effect on MAO-B. These potent flavonoids were purified using bioassay-guided fractionation and were separated by Diaion, Sephadex LH-20, and MCI CHP20P columns. The IC50 values of the four potent flavonoids, quercitrin, isoquercitrin, rutin, and quercetin on monoamine oxidase were 19.06, 11.64, 3.89, and 10.89 μM and enzyme kinetics analysis revealed apparent inhibition constants (Ki) of 21.01, 2.72, 1.83, and 7.95 μM, respectively, on the substrate, benzylamine. The four potent compounds also exhibited hydroxyl radical scavenging activity as determined using a spin trapping electron spin resonance method. This suggests that the four flavonoids from M. candidum possess both MAO-B inhibitory and free radical scavenging activities. These important properties may be used for preventing some neurodegenerative diseases in the future. Keywords: Melastoma candidum; monoamine oxidase B; quercitrin; isoquercitrin; quercetin; rutin; hydroxyl radical scavenging
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The present study elucidated the protective effect of β-carbolines (harmaline, harmalol, and harmine) on oxidative neuronal damage. MPTP treatment increased activities of total superoxide dismutase, catalase, and glutathione peroxidase and levels of malondialdehyde and carbonyls in the basal ganglia, diencephalon plus midbrain of brain compared with control mouse brain. Coadministration of harmalol (48 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. Harmaline, harmalol, and harmine attenuated both the 500 μM MPP+-induced inhibition of electron flow and membrane potential formation and the 100 μM dopamine-induced thiol oxidation and carbonyl formation in mitochondria. The scavenging action of β-carbolines on hydroxyl radicals was represented by inhibition of 2-deoxy-d-ribose degradation. Harmaline and harmalol (100 μM) attenuated 200 μM dopamine-induced viability loss in PC12 cells. The β-carbolines (50 μM) attenuated 50 μM dopamine-induced apoptosis in PC12 cells. The compounds alone did not exhibit significant cytotoxic effects. The results indicate that β-carbolines attenuate brain damage in mice treated with MPTP and MPP+-induced mitochondrial damage. The compounds may prevent dopamine-induced mitochondrial damage and PC12 cell death through a scavenging action on reactive oxygen species and inhibition of monoamine oxidase and thiol oxidation.
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Recent literature indicates that low-dose Methylene Blue (MB), an autoxidizable dye with powerful antioxidant and metabolic enhancing properties, might prevent neurotoxin-induced neural damage and associated functional deficits. This study evaluated whether local MB may counteract the anatomical and functional effects of the intrastriatal infusion of the neurotoxin rotenone (Rot) in the rat. To this end, stereological analyses of striatal lesion volumes were performed and changes in oxidative energy metabolism in the striatum and related motor regions were mapped using cytochrome oxidase histochemistry. The influence of MB on striatal levels of oxidative stress induced by Rot was determined, and behavioral tests were used to investigate the effect of unilateral MB coadministration on motor asymmetry. Rot induced large anatomical lesions resembling “metabolic strokes,” whose size was greatly reduced in MB-treated rats. Moreover, MB prevented the decrease in cytochrome oxidase activity and the perilesional increase in oxidative stress associated with Rot infusion in the striatum. MB also prevented the indirect effects of the Rot-induced lesion on cytochrome oxidase activity in related motor regions, such as the striatal regions rostral and caudal to the lesion, the substantia nigra compacta and reticulata, and the pedunculopontine nucleus. At a network level, MB maintained a global strengthening of functional connectivity in basal ganglia–thalamocortical motor circuits, as opposed to the functional decoupling observed in Rot-alone subjects. Finally, MB partially prevented the behavioral sensorimotor asymmetries elicited by Rot. These results are consistent with protective effects of MB against neurotoxic damage in the brain parenchyma. This study provides the first demonstration of the anatomical, metabolic and behavioral neuroprotective effects of MB in the striatum in vivo, and supports the notion that MB could be a valuable intervention against neural damage associated with oxidative stress and energy hypometabolism.
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The present study investigated in vivo the kinetics of the changes in rat striatal extracellular concentrations of dopamine (DA), and its monoamine oxidase (MAO)-derived metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), following administration either of nitric oxide (NO) synthase inhibitors 7-nitroindazole (7-NI) and Nω-nitro-l-arginine methyl ester (l-NAME) or of the widely used MAO inhibitor pargyline. DA and DOPAC concentrations were determined every 4 min by microdialysis combined with capillary zone electrophoresis coupled with laser-induced fluorescence detection (CZE-LIFD) and by differential normal pulse voltammetry (DNPV), respectively. Administration of 7-NI, both systemic (30 mg/kg, i.p.) or intrastriatal (1 mM through the microdialysis probe), as well as administration of pargyline (75 mg/kg, i.p.), induced simultaneously in the striatum a significant increase in extracellular DA and a significant decrease in extracellular DOPAC. On the other hand, administration of l-NAME (200 mg/kg, i.p.) produced a significant increase in striatal extracellular DA without changes in extracellular DOPAC. These data suggest a possible MAO inhibitory effect of 7-NI which seems to be restricted to this NOS inhibitor. These results may be of special interest for the studies on the functional role of NO in the brain, particularly in dopaminergic transmission.
Article
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a newly described neurotoxin which selectively destroys cells in the substantia nigra when administered systemically to primates. Because the substance creates a condition in humans which is virtually indistinguishable from Parkinson's disease, interest has focused on its mechanism of action. We now report that MPTP appears to be rapidly metabolized after systemic administration in toxic amounts, and identify 1-methyl-4-phenylpyridinium ion (MPP+) as a probable major metabolite.
Article
Enzymatic β-carboline N-methyltransferase activities generate N-methylated β-carbolinium cations that are analogs of the parkinsonian-producing neurotoxin MPP+. We measured β-carboline-2N-methyltransferase and β-carboline-9N-methyltransferase activities in the supernatant and particulate fractions from postmortem human brains. These N-methyltransferase activities were assessed in the substantia nigra, putamen, and frontal cortex from control and Parkinson's disease cases. No significant differences were measured in any brain region in particulate and supernatant fraction β-carboline 2N-methyltransferase activity or particulate fraction β-carboline 9N-methyltransferase activity. Likewise, supernatant fraction β-carboline 9N-methyltransferase activity was similar in the putamen and substantia nigra from Parkinson's disease and control cases. Unexpectedly, supernatant fraction β-carboline 9N-methyltransferase activity was increased fourfold in Parkinson's disease frontal cortex (P < 0.05), suggesting that β-carboline N-methylation may play a role in Parkinson's disease.
Article
Monoamine oxidases A/B (EC 1.4.3.4, MAO), flavoenzymes located on the outer mitochondrial membrane, catalyze the oxidative deamination of biogenic amines, such as dopamine, serotonin, and norepinephrine. In this study, we examined whether the H2O2formed during the two-electron oxidation of tyramine [4-(2-aminoethyl)phenol] (a substrate for monoamine oxidases A/B) may contribute to the intramitochondrial steady-state concentration of H2O2([H2O2]ss) and, thus, be involved in the oxidative impairment of mitochondrial matrix components. Supplementation of intact, coupled rat brain mitochondria with benzylamine, β-phenylethylamine, or tyramine showed initial rates of H2O2production ranging from 0.4- to 1.6 nmol H2O2/min/mg protein. ESR analysis of the oxidative deamination of tyramine by intact rat brain mitochondria revealed the formation of hydroxyl (HO) and carbon-centered radical adducts—the latter probably originating by the HO-mediated oxidation of mannitol. The signals were substantially enhanced upon addition of FeSO4and were abolished by catalase. The intramitochondrial [H2O2]sscalculated in terms of glutathione peroxidase activity during the metabolism of tyramine was 48-fold higher (7.71 ± 0.25 × 10−7M) than that obtained during the oxidation of succinate via complex II in the presence of antimycin A (1.64 ± 0.2 × 10−8M). Oxidative damage to the brain mtDNA was assessed by single strand breakage. The ratio of nicked DNA for the preparations treated with tyramine and those without the amine was 1.5 ± 0.29 (n= 4), 2.12 ± 0.28 (n= 8,P≤ 0.05), and 3.12 ± 0.69 (n= 3,P≤ 0.05) at 15, 30, and 60 min, respectively. Preincubation of mitochondria with tranylcypromine (trans-2-phenylcyclopropylamine), an inhibitor to MAO A/B, abolished mtDNA oxidative damage. Catalase inhibited mtDNA strand breakage by approximately 60%. Incubation of intact, coupled rat brain mitochondria with chlorodinitrobenzene (CDNB) depleted mitochondrial GSH by 72%. Tyramine-dependent damage of mtDNA was decreased by 68% in CDNB-treated mitochondria (with 28% remaining GSH). The [H2O2]sswas slightly increased in CDNB-treated mitochondria: 1.38- and 1.28-fold increase during the oxidation of succinate in the presence of antimycin A and during the oxidation of tyramine, respectively. These results suggest that the H2O2generated during the MAO-catalyzed oxidation of biogenic amines and possibly certain neurotransmitters at the outer mitochondrial membrane contributes to the intramitochondrial [H2O2]ssand may cause oxidative damage to mtDNA. This is effected by the intramitochondrial concentration of GSH and might have potential implications for aging and neurodegenerative processes.
Article
MPP+ has been reported to inhibit reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase in mitochondria, which results in the formation of O2.−. The current report demonstrates that H2O2 and HO. are also products of MPP+ interaction with NADH dehydrogenase. It is possible that MPP. formation precedes the formation of some of these active oxygen species. Reducing equivalents for radical formation come from NADH. MPP+ may be capable of interacting with submitochondrial particles at a site other than the rotenone site, which results in some formation of oxygen radicals. Plasma amine oxidase incubations with MPDP+ resulted in O2.−, H2O2, and perhaps HO. formation. This is probably due to MPP. formation from the oxidation of MPDP+. This study presents new findings that indicate the potential importance of oxygen radical formation in mitochondria during MPTP toxicity.
Article
α-Synuclein (α-syn) is a presynaptic protein that is widely implicated in the pathophysiology of Parkinson's disease (PD). Emerging evidence indicates a strong correlation between α-syn aggregation and proteasomal dysfunction as one of the major pathways responsible for destruction of the dopamine neurons. Using parkinsonism mimetics (MPP+, rotenone) and related oxidants, we have identified an oxidant-induced alternative splicing of α-syn mRNA, generating a shorter isoform of α-syn with deleted exon-5 (112-syn). This spliced isoform has an altered localization and profoundly inhibits proteasomal function. The generation of 112-syn was suppressed by constitutively active MEK-1 and enhanced by inhibition of the Erk-MAP kinase pathway. Overexpression of 112-syn exacerbated cell death in a human dopaminergic cell line compared to full-length protein. Expression of 112-syn and proteasomal dysfunction were also evident in the substantia nigra and to a lesser extent in striatum, but not in the cortex of MPTP-treated mice. We conclude that oxidant-induced alternative splicing of α-syn plays a crucial role in the mechanism of dopamine neuron cell death and thus contributes to PD.
Article
Parkinson's disease is a neurodegenerative disorder characterized mainly by damage to the dopaminergic nigrostriatal system. Recently, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce damage in the nigrostriatal system, accompanied by Parkinson-like symptoms in humans. We present here evidence that MPTP treatment in aged 21-month-old mice produced a marked reduction in the presence and intensity of fluorescence in noradrenergic neurons of the locus coeruleus and in dopaminergic neurons of the ventral tegmental area in addition to extensive damage to the substantia nigra. Aged mice treated with MPTP also showed physical signs of movement disability characterized by marked akinesia, rigidity of the hind limbs, and an initial resting tremor of the entire body. Such symptoms were less evident in young mice treated with MPTP. These remarkable initial behavioral effects of MPTP treatment in aged mice and evidence of reduced catecholamine fluorescence in the locus coeruleus and ventral tegmental area suggest that aged mice are more sensitive to, and more severely affected by MPTP treatment than young mice. We suggest that these MPTP-treated aged mice provide a useful animal model for studying both anatomical and functional characteristics of Parkinson's disease.
Article
Astaxanthin (AST) is a powerful antioxidant that occurs naturally in a wide variety of living organisms. We have investigated the role of AST in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of the substantia nigra (SN) neurons in the mouse model of Parkinson's disease (PD) and 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity of SH-SY5Y human neuroblastoma cells. In in vitro study, AST inhibits MPP+-induced production of intracellular reactive oxygen species (ROS) and cytotoxicity in SH-SY5Y human neuroblastoma cells. Preincubation of AST (50 μM) significantly attenuates MPP+-induced oxidative damage. Furthermore, AST is able to enhance the expression of Bcl-2 protein but reduce the expression of α-synuclein and Bax, and suppress the cleavage of caspase-3. Our results suggest that the protective effects of AST on MPP+-induced apoptosis may be due to its anti-oxidative properties and anti-apoptotic activity via induction of expression of superoxide dismutase (SOD) and catalase and regulating the expression of Bcl-2 and Bax. Pretreatment with AST (30 mg/kg) markedly increases tyrosine hydroxylase (TH)-positive neurons and decreases the argyrophilic neurons compared with the MPTP model group. In summary, AST shows protection from MPP+/MPTP-induced apoptosis in the SH-SY5Y cells and PD model mouse SN neurons, and this effect may be attributable to upregulation of the expression of Bcl-2 protein, downregulation of the expression of Bax and α-synuclein, and inhibition of the activation of caspase-3. These data indicate that AST may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson's disease.
Article
Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines. Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity). Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels. MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal.
Article
Background: The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson's disease (PD). Objective: Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (-)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism. Methods/results: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail. Conclusion: These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG.
Article
Peganum harmala L. is a multipurpose medicinal plant increasingly used for psychoactive recreational purposes (Ayahuasca analog). Harmaline, harmine, harmalol, harmol and tetrahydroharmine were identified and quantified as the main beta-carboline alkaloids in P. harmala extracts. Seeds and roots contained the highest levels of alkaloids with low levels in stems and leaves, and absence in flowers. Harmine and harmaline accumulated in dry seeds at 4.3% and 5.6% (w/w), respectively, harmalol at 0.6%, and tetrahydroharmine at 0.1% (w/w). Roots contained harmine and harmol with 2.0% and 1.4% (w/w), respectively. Seed extracts were potent reversible and competitive inhibitors of human monoamine oxidase (MAO-A) with an IC(50) of 27 microg/l whereas root extracts strongly inhibited MAO-A with an IC(50) of 159 microg/l. In contrast, they were poor inhibitors of MAO-B. Inhibition of MAO-A by seed extracts was quantitatively attributed to harmaline and harmine whereas inhibition by root extracts came from harmine with no additional interferences. Stems and leaves extracts were poor inhibitors of MAO. The potent inhibition of MAO-A by seed and root extracts of P. harmala containing beta-carbolines should contribute to the psychopharmacological and toxicological effects of this plant and could be the basis for its purported antidepressant actions.
Article
Oxidative damage has been implicated in the pathogenesis of Parkinson disease (PD) but the literature data are confusing. Using products of lipid and DNA oxidation measured by accurate methods, we assessed the extent of oxidative damage in PD patients. The levels of plasma F(2)-isoprostanes (F(2)-IsoPs), hydroxyeicosatetraenoic acid products (HETEs), cholesterol oxidation products, neuroprostanes (F(4)-NPs), phospholipase A(2) (PLA(2)) and platelet activating factor-acetylhydrolase (PAF-AH) activities, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), and serum high-sensitivity C-reactive protein were compared in 61 PD patients and 61 age-matched controls. The levels of plasma F(2)-IsoPs, HETEs, 7beta-and 27-hydroxycholesterol, 7-ketocholesterol, F(4)-NPs, and urinary 8-OHdG were elevated, whereas the levels of plasma PLA(2) and PAF-AH activities were lower, in PD patients compared to controls (p< 0.05). The levels of plasma F(2)-IsoPs, HETEs, and urinary 8-OHdG were higher in the early stages of PD (p trend< 0.05). There was a significant negative correlation between the cumulative intake of levodopa and urinary 8-OHdG (r= -0.305, p= 0.023) and plasma total HETEs (r= -0.285, p= 0.043). Oxidative damage markers are systemically elevated in PD, which may give clues about the relation of oxidative damage to the onset and progression of PD.
Article
Zonisamide is an FDA-approved antiepileptic drug that blocks voltage-dependent Na(+) channels and T-type Ca(2+) channels and improves clinical outcome in Parkinson's disease (PD) patients when used as an adjunct to other PD therapies. Zonisamide also modifies dopamine (DA) activity, provides protection in ischemia models and influences antioxidant systems. Thus, we tested it for its ability to protect DA neurons in a mouse model of PD and investigated mechanisms underlying its protection. Concurrent treatment of mice with zonisamide and 1-methyl-4-phenyl-1,2,3,6-tetraydropyridine (MPTP) attenuated the reduction in striatal contents of DA, its metabolite DOPAC and tyrosine hydroxylase (TH). We also discovered that zonisamide inhibited monoamine oxidase B (MAO-B) activity in vitro with an IC(50) of 25 muM, a concentration that is well within the therapeutic range used for treating epilepsy in humans. Moreover, the irreversible binding of systemically administered selegiline to MAO-B in mouse brain was attenuated by zonisamide as measured by ex vivo assays. Zonisamide treatment alone did not produce any lasting effects on ex vivo MAO-B activity, indicating that it is a reversible inhibitor of the enzyme. Consistent with the effects of zonisamide on MAO-B, the striatal content of 1-methyl-4-phenylpyridinium (MPP(+)), which is derived from the administered MPTP via MAO-B actions, was substantially reduced in mice treated with MPTP and zonisamide. The potency and reversibility with which zonisamide blocks MAO-B may contribute to the ability of the drug to improve clinical symptoms in PD patients. The results also suggest that caution in its use may be necessary, especially when administered with other drugs, in the treatment of epilepsy or PD.
Article
We tested the hypothesis that melatonin regulates formation of 6-hydroxydopamine (6-OHDA) in the brain and thereby protects animals from dopaminergic neurotoxicity and the development of parkinsonism in animals. Employing a ferrous-ascorbate-dopamine (FAD) hydroxyl radical ((*)OH) generating system, in the present study we demonstrate a dose-dependent attenuation of 6-OHDA generation by melatonin in vitro. Intra-median forebrain bundle infusion of FAD caused significant depletion of striatal dopamine (DA), which was blocked by melatonin. Per-oral administration of l-3,4-dihydroxyphenylalanine (L-DOPA) for 7 days caused a dose-dependent increase in the formation of 6-OHDA in the mouse striatum, which was increased synergistically by the systemic administration of the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the 7th day of L-DOPA treatment. Melatonin treatment significantly attenuated both the L-DOPA and MPTP-induced increases in the levels of striatal 6-OHDA, and protected against striatal DA depletion caused by the neurotoxin. These observations suggest a novel mode of melatonin-induced dopaminergic neuroprotection in two models of Parkinson's disease, and suggest the possible therapeutic use of this well-known antioxidant indoleamine neurohormone in parkinsonism.
Article
Monoamine oxidase (MAO) B is a mitochondrial enzyme selectively involved in the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to toxic pyridinium cations producing Parkinsonism in animal models. Various synthesized 5-nitroindazoles, 6-nitroindazole and the neuroprotectant 7-nitroindazole were examined as inhibitors of MAO and as antioxidants and radical scavengers. The oxidation of MPTP by human MAO-B and mitochondria was assessed by HPLC. Simple nitroindazoles inhibited MPTP oxidation to 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) in a competitive and reversible manner. 5-Nitroindazole (IC(50)=0.99 microM, K(i)=0.102 microM) and 6-nitroindazole (IC(50)=2.5 microM) were better inhibitors of human MAO-B than 7-nitroindazole (IC(50)=27.8 microM). 6-Nitroindazole also inhibited MAO-A. Nitroindazole isomers were good hydroxyl radical (OH(*)) scavengers, with 5-nitro-, 6-nitro- and 7-nitroindazole showing similar activity (k approximately 10(10) M(-1) s(-1)). Neuroprotective actions of nitroindazoles (7-nitroindazole) could be linked to their MAO-inhibitory and antiradical properties besides inhibition on nitric oxide synthase (NOS). 5-Nitro- and 6-nitroindazole, previously reported as weak NOS inhibitors, were better inhibitors of human MAO-B and more active against MPTP neurotoxin oxidation (lower MPDP(+) and MPP(+) levels) than 7-nitroindazole and acted as good radical scavengers and could be potential neuroprotective agents in addition to MAO-B inhibitors.
Article
Monoamine oxidases (MAO) are mitochondrial enzymes that catalyze the oxidation of monoamines in multiple tissues, including the brain. Elevated MAO activity has long been implicated in the etiology of depression, anxiety, and neurodegenerative disease, fuelling the search for inhibitors in the prevention and treatment of these disorders. We hypothesized that emerging neuroprotective effects of anthocyanins from berry fruits may be explained by an affinity of these polyphenols for MAO isoforms A or B. Using a luminometric MAO assay, 25 anthocyanidins, anthocyanidin-3-glycosides, anthocyanidin-3,5-diglucosides, proanthocyanidins, and phenolic metabolites were examined. For MAO A and B, IC(50) values in the low micromolar range were reached by anthocyanidins and anthocyanidin-3-glycosides, as opposed to values in the low millimolar range for phenolic acids. Kinetic analyses, performed with cyanidin and cyanidin-3-glucoside, indicated a competitive interaction of cyanidin with MAO A plus a mixed competitive and non-competitive mode of interaction of cyanidin with MAO B and of cyanidin-3-glucoside with both enzyme isoforms. Thus anthocyanins and their aglycons achieve MAO inhibition in vitro that is compatible with central nervous functionalities. For extrapolation of the present findings to in vivo effects, future studies will need to address in more detail the bioavailability of these dietary constituents.
Article
This study investigated MAO-A inhibitory activity of methanol extract of Calluna vulgaris (L.) Hull., which traditionally has been used as a nerve calming remedy. A methanolic extract of Calluna vulgaris was partitioned against heptane, ethyl acetate and water. The three fractions were tested in a photometric peroxidase linked MAO-A bioassay. The ethyl acetate phase showed the highest MAO-A inhibitory activity. Quercetin was isolated by VLC through bioassay-guided fractionation and purified by re-crystallisation. The structure was elucidated by LC-MS and (1)H NMR. The IC(50)-value for MAO-A inhibition by quercetin was 18+/-0.2 microM in an assay where the IC(50)-value for MAO-A inhibition by clorgylin was 0.2+/-0.02 microM. The content of quercetin in Calluna vulgaris might explain the reported nerve calming effect of the plant.
Article
Parkinson disease (PD) is associated with progressive loss of dopaminergic neurons in the substantia nigra, as well as with more-widespread neuronal changes that cause complex and variable motor and nonmotor symptoms. Recent rapid advances in PD genetics have revealed a prominent role for mitochondrial dysfunction in the pathogenesis of the disease, and the products of several PD-associated genes, including SNCA, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, show a degree of localization to the mitochondria under certain conditions. Impaired mitochondrial function is likely to increase oxidative stress and might render cells more vulnerable to this and other related processes, including excitotoxicity. The mitochondria, therefore, represent a highly promising target for the development of disease biomarkers by use of genetic, biochemical and bioimaging approaches. Novel therapeutic interventions that modify mitochondrial function are currently under development, and a large phase III clinical trial is underway to examine whether high-dose oral coenzyme Q10 will slow disease progression. In this Review, we examine evidence for the roles of mitochondrial dysfunction and increased oxidative stress in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient management and aid in the development of 'mitochondrial therapy' for PD.
Article
The cause of dopamine cell death in Parkinson's disease remains unknown. Present interest centres on the possible involvement of a toxin mediated mechanism such as that produced, by MPTP. In post-mortem studies there is evidence in the substantia nigra for an on-going toxic process involving increased lipid peroxidation, altered iron metabolism and impairment of mitochondrial function at the level of complex I. Although the precise relationship between these biochemical changes is not known, present evidence points to oxidative stress as an important factor contributing to neuronal loss. Altered mitochondrial function and increased iron levels may not initiate Parkinson's disease but rather act to accelerate cell death. Future strategies for the treatment of Parkinson's disease should be aimed at preventing oxidative stress and stopping or slowing the progression of the underlying pathology.
Article
Methylene blue, 15 mg/day, was compared with placebo in treatment of severe depressive illness. The 3-week trial was designed to avoid bias by placebo response and also to avoid observer bias. Improvement in patients receiving methylene blue was significantly greater than in those receiving placebo. Methylene blue at a dose of 15 mg/day appears to be a potent antidepressant, and further clinical evaluation is essential.
Article
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) hydrochloride injected s.c. at 20 mg/kg once daily for four days resulted in marked depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in mouse striatum one week after the last dose. Pretreatment with MD 240928, (R)-[4-((3-chlorophenyl)-methoxy)phenyl]-5-[(methylamino)methyl]-2- oxazolidinone methanesulfonate, prevented the depletion of striatal dopamine, DOPAC and HVA, whereas pretreatment with harmaline did not. MD 240928 selectively inhibited type B not type A monoamine oxidase (MAO), whereas harmaline selectively inhibited type A MAO in mouse striatum. Acutely after injection of harmaline, DOPAC and HVA concentrations were decreased in mouse striatum; these changes were not produced by MD 240928. The acute changes in dopamine metabolites reveal that MAO-A not MAO-B is responsible for the oxidation of dopamine in mouse striatum. Protection against the neurotoxic effects of MPTP by MD 240928 but not by harmaline indicates that prevention of dopamine oxidation is not the mechanism of the protective effect; instead the protection probably is due to prevention of MPTP metabolism by MAO-B, this metabolism having been shown to occur by other workers. The results with these reversible, competitive inhibitors of the two types of MAO are in agreement with previously reported results from studies using irreversible inhibitors of MAO.
Article
1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes degeneration of the dopaminergic nigrostriatal pathway in several animal species, including humans, monkeys and mice. Changes observed after MPTP administration include marked decrements in the neostriatal content of dopamine and its major metabolites, dihydroxyphenylacetic acid and homovanillic acid, and a greatly diminished capacity of neostriatal synaptosomes to take up 3H-dopamine. In contrast, there is no pronounced loss of serotonin in the neostriatum or of dopamine and its metabolites in other brain areas in MPTP-treated animals. The oxidative metabolism of MPTP to 1-methyl-4-phenyl pyridine, a positively charged species, has been suggested as a critical feature in the neurotoxic process. Moreover, in rat brain preparations, the monoamine oxidase (MAO) inhibitor pargyline and the specific MAO-B inhibitor deprenil can prevent the formation of 1-methyl-4-phenyl-pyridine from MPTP, while the specific MAO-A inhibitor clorgyline has no such effect, suggesting that MAO, and specifically MAO-B, is responsible for the oxidative metabolism of MPTP. We now report that pargyline, nialamide and tranylcypromine, which inhibit both MAO-A and MAO-B, when administered to mice before MPTP, protect against MPTP-induced dopaminergic neurotoxicity. Deprenil is also protective, but clorgyline is not. Our data are consistent with the premise that MAO-B has a crucial role in MPTP-induced degeneration of the nigrostriatal dopaminergic neuronal pathway.
Article
The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces an irreversible neurological syndrome in man and monkey which is similar to idiopathic Parkinson's disease in its clinical, pathological, neurochemical and pharmacological response properties. MPTP is selectively neurotoxic to the dopaminergic regions of the brain, destroying neurones in the substantia nigra (A8 and A9 cells, nigrostriatal system) but not the ventral tegmental area (A10 cells, mesolimbic system). Selective dopamine depletion and nigral cell loss after MPTP treatment has also been reported recently in the mouse. The mechanism by which a peripherally administered, low-molecular weight compound exerts permanent but selective toxic effects on dopamine systems in the brain may be relevant to parkinsonian syndromes induced by other toxins and to the disease process in idiopathic Parkinson's disease. We report here that MPTP is oxidized in the brain to a pyridinium species (a compound with potent herbicidal activity) and, in the monkey, is trapped intraneuronally. Furthermore, we demonstrate that this enzymatic oxidation is blocked in vivo in the mouse by a monoamine oxidase inhibitor, a condition which also blocks the neurotoxicity, indicating that the oxidative metabolism of MPTP is required for its neurotoxic effect.
Article
The neurotoxic chemical MPTP (1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine) is metabolized by rat brain mitochondrial fractions at a rate of 0.91 +/- 0.02 nmoles/mg protein/min. The major metabolite has been identified as the 1-methyl-4- phenylpyridinium species. This biotransformation process is blocked by 10(-7) M deprenyl and pargyline. MPTP itself inhibited the metabolism of benzylamine by brain mitochondrial fractions. These results are discussed in terms of possible bioactivation mechanisms that may be associated with the neurodegenerative properties of MPTP .
Article
Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.
Article
In the absence of identification of either an endogenously or an exogenously derived dopaminergic neurotoxin, the most valid hypothesis currently envisaged for etiopathology of Parkinson's disease (PD) is selective oxidative stress (OS) in substantia nigra (SN). Although OS is not proven, a significant body of evidence from studies on animal and Parkinsonian brain neurochemistry supports it. This hypothesis is based on excessive formation of reactive oxygen species (O2 and OH.) and demise of systems involved with scavenging or preventing the formation of such radicals from H2O2, generated as a consequence of dopamine oxidation (autoxidation and deamination). Since MAO (monoamine oxidase A and B are the major H2O2 generating enzymes in the SN much attention has been paid to their selective inhibitors as symptomatic and neuroprotective agents in PD. Attention should also be given to radical scavengers (e.g. iron chelators, lipid peroxidative inhibitors and Vitamin E derivatives) as therapeutic neuroprotective agents in PD. This is considered valid since a significant elevation of iron is known to occur selectively in SN zone compacta and within the remaining melanized dopamine neurons of Parkinsonian brains. Although all the mechanism of iron induced oxygen free radical formation is not fully known there is no doubt that it participates with H2O2 (Fenton chemistry) to generate cytotoxic hydroxyl radical (OH.) and induce tissue OS and neurodegeneration in 6-hydroxydopamine model of PD. The dramatic proliferation of reactive amoeboid macrophages and microglia seen in SN of PD brains together with OS is highly compatible with an inflammatory process, similar to what has been observed in Alzheimer's disease and multiple sclerosis brains. This has led us to examine the ability of reactive macrophages to produce oxygen free radicals in response to nitric oxide (NO) production. The latter radical has been implicated in the excitotoxicity of glutaminergic neurons innervating the striatum and SN. Indeed we have now observed that in reactive macrophages NO acts as a signal transducer of O2 production which can synergize with dopamine oxidation.
Article
The massive health problem associated with cigarette smoking is exacerbated by the addictive properties of tobacco smoke and the limited success of current approaches to cessation of smoking. Yet little is known about the neuropharmacological actions of cigarette smoke that contribute to smoking behaviour, or why smoking is so prevalent in psychiatric disorders and is associated with a decreased risk of Parkinson's disease. Here we report that brains of living smokers show a 40% decrease in the level of monoamine oxidase B (MAO B; EC 1.4.3.4) relative to non-smokers or former smokers. MAO B is involved in the breakdown of dopamine, a neurotransmitter implicated in reinforcing and motivating behaviours as well as movement. MAO B inhibition is therefore associated with enhanced activity of dopamine, as well as with decreased production of hydrogen peroxide, a source of reactive oxygen species. We propose that reduction of MAO B activity may synergize with nicotine to produce the diverse behavioural and epidemiological effects of smoking.
Article
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.
Article
Production of hydrogen peroxide as a by-product of the breakdown of catecholamines by the enzyme monoamine oxidase (MAO) has been hypothesized to contribute to the increased proclivity of dopaminergic neurons for oxidative injury. We established clonal dopaminergic PC12 cell lines which have elevated MAO activity levels resulting from transgenic expression of the B isoform of the enzyme. Both MAO-A and MAO-B have relatively equivalent affinities for dopamine, and since PC12 primarily express the A and not the B form of the enzyme, this allowed us to distinguish the transgenic MAO activity in these cells from endogenous using the MAO-B specific substrate PEA. Elevation of MAO activity levels in the MAO-B+ cells resulted in higher levels of both free radicals and free radical damage compared with controls. In addition, increased MAO-B levels within PC12 cells caused a dose-dependent increase in sensitivity to the toxin MPTP. Our data suggests that oxidation of catecholamines by MAO can contribute to free radical damage in catecholaminergic neurons and that the low MAO-B activity levels found endogenously in these cells likely accounts for their relative resistance to MPTP toxicity.
Article
The neurodegenerative properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are thought to result from inhibition of complex I of the mitochondrial respiratory chain by the monoamine oxidase-B (MAO-B) generated 1-methyl-4-phenylpyridinium metabolite MPP+. Treatment with 7-nitroindazole (7-NI) protects rodents and baboons against MPTP's neurotoxicity, presumably as a consequence of its inhibition of neuronal nitric oxide synthase (nNOS). The results reported in the present communication, while not in conflict with the proposed role of nNOS, raise the possibility that the inhibition of MAO-B by 7-NI also may contribute to the observed neuroprotection.
Article
Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO). Here we show that the two are linked. Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport. MAO inhibitors prevent this action. Mitochondrial damage is also reversed during electron flow. A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function. In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport. In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria. These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover. The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.
Article
Mitochondrial electron transport chain (ETC) function is selectively reduced in multiple tissues, including brain, from patients with Parkinson's disease (PD) and Alzheimer's disease (AD). The ETC defects are specific to each illness, involve complex I in PD and complex IV in AD, are transferable with mitochondrial DNA (mtDNA) and lead to increased production of reactive oxygen species (ROS) in mtDNA-deficient clonal neuronal cells hybridized with mtDNA ('cybrids') from PD or AD patients. C57BL/6 mice treated with MPTP developed elevated tissue hydroxyl radical ('OH) levels in striatum and ventral midbrain but not cerebellum. In brain microdialysis in awake rats, striatal 'OH output increased 3-5-fold after infusion of methylpyridinium ion (MPP+), a complex I inhibitor, or sodium azide, a complex IV inhibitor. Elevated 'OH after MPP+ was blocked stereospecifically by infusion of the nitric oxide synthase (NOS) inhibitor nitro-L-arginine or by the NMDA channel blocker MK801. Neither NOS inhibition nor NMDA blockade altered azide-induced 'OH production. ETC inhibition in vivo increases production of toxic 'OH, but the underlying mechanisms vary as a function of which ETC complex is inhibited. These results support the concept of developing oxygen free radical scavengers for both AD and PD and further suggest that inhibition of NOS and blockade of NMDA receptor function may alter progression of idiopathic PD.
Article
The ability of 7-nitroindazole (7-NI) to protect against MPTP-induced neurotoxicity has been attributed to its inhibition of neuronal nitric oxide synthase. In the present study, 7-NI was found to counteract almost completely striatal dopamine depletion caused by a single subcutaneus injection of 20 mg/kg MPTP in mice. This effect, however, was accompanied by a significant reduction in the striatal levels of MPP+, the toxic metabolite generated via monoamine oxidase B-catalyzed MPTP oxidation. In the presence of 7-NI, a dose of 40 mg/kg MPTP produced MPP concentrations similar to those measured after treatment with 20 mg/kg MPTP alone. A comparison of neurotoxicity in these two experimental conditions (i.e., mice treated with 20 mg/kg alone versus 40 mg/kg MPTP plus 7-NI) revealed only a slight (20%), but statistically significant, protection of dopamine depletion with 7-NI. These data indicate that the mechanism by which 7-NI counteracts MPTP neurotoxicity in mice is not due solely to inhibition of neuronal nitric oxide synthase, but involves a reduction in MPP+ formation.
Article
To examine whether simple beta-carbolines induce parkinsonian-like symptoms in vivo via N-methylation, the simple beta-carbolines norharman (NH), 2-mono-N-methylated norharmanium cation (2-MeNH+), and 9-mono-N'-methylnorharman (9-MeNH) were systematically administered to C57BL/6 mice for 7 days. These substances induced bradykinesia with reduction of locomotion activity. NH or 2-MeNH+ decreased dopamine (DA) contents to 50-70% of values in controls in the striatum and midbrain. 9-MeNH potently decreased not only DA but also serotonin content in various regions. Immunohistochemical examination revealed that the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta of NH- and 9-MeNH-treated mice were diminished to 76 and 66% of values in control mice, respectively. The formation of a toxic metabolite, 2,9-di-N,N'-methylated norharmanium cation (2,9-Me2NH+), was 14 and eight times higher in the brain of mice receiving 9-MeNH than that in NH- and 2-MeNH+-treated mice, respectively. In cultured mesencephalic cells from rat embryo, 2,9-Me2NH+ selectively killed TH-positive neurons only at a lower dose but was toxic to all neurons at higher doses. Thus, the excess formation of 2,9-Me2NH+ would induce nonspecific neurotoxicity. These results indicated that 9-indole nitrogen methylation should be the limiting step in the development of the toxicity. NH, a selective dopaminergic toxin precursor, is sequentially methylated to form 2,9-Me2NH+, which could be an underlying factor in idiopathic Parkinson's disease.
Article
The mitochondrial enzyme monoamine oxidase (MAO) A and B catalyze the oxidative deamination of various endogenous and exogenous biogenic amines. In the present study, we used human embryonic kidney 293 (HEK 293) cells stably transfected with human MAO-B cDNA to investigate the potential role of hydrogen peroxide (H(2)O(2)) produced by MAO-B isoform as an intracellular messenger involved in regulation of cell signaling and function. The MAO substrate tyramine induced tyrosine phosphorylation of Shc, ERK activation, and an increase in DNA synthesis in HEK 293 expressing MAO-B, but not in wild type HEK 293 cells, which do not express MAO. Tyramine effects were fully prevented by cell pretreatment with the MAO inhibitor pargyline or the antioxidant N-acetylcysteine. These results show that MAO-B induces MAPK/ERK activation and cell mitogenesis through H(2)O(2) production.
Article
Epidemiological studies suggest that smoking reduces the risk for Parkinson's disease. It has been hypothesized that inhibition of monoamineoxidase contributes to this action. The present study examined the contribution of the beta-carbolines norharman, an inhibitor of monoamineoxidase B, and harman, an inhibitor of monoamineoxidase A, which are present in high concentrations in tobacco smoke to the protective action. Nineteen active smokers and five nonsmokers smoked one and two cigarettes. The levels of norharman and harman increased in plasma from smokers and nonsmokers. Ex vivo saturation kinetic experiments revealed that the baseline affinity constant of monoamineoxidase in platelets from smokers was higher than that of nonsmokers in contrast to the maximum turnover rate, which did not differ. Acute smoking affected the monoamineoxidase in nonsmokers only. It is discussed that inhibition of both isoforms of monoamineoxidase is necessary for the neuroprotection and that both norharman and harman play an important role.
Article
Tetrahydro-beta-carboline alkaloids that occur in foods such as wine, seasonings, vinegar and fruit products juices, jams) acted as good radical scavengers (hydrogen- or electron donating) in the ABTS (2,2'-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) assay, and therefore, they could contribute to the beneficial antioxidant capacity attributed to foods. In contrast, the fully aromatic beta-carbolines norharman and harman did not show any radical scavenger activity in the same assay. During the reaction with ABTS.+ radical cation, tetrahydro-beta-carboline-3-carboxylic acid such as 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) and 1-methyl-1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylic acid (MTCA-COOH) were converted to harman, whereas 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (THCA) and 1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylic acid (THCA-COOH) afforded norharman. These results suggest that food and naturally-occurring tetrahydro-beta-carboline alkaloids if accumulated in tissues, as reported elsewhere, might exhibit antioxidant activity.
Article
Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death.
Article
The potential neuroprotective properties of monoamine oxidase B (MAO-B) inhibitors have been of interest in part because of the role that this enzyme plays in the bioactivation of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Interestingly, tobacco smokers have lowered levels of brain and blood platelet MAO-B activity and a well documented lowered incidence of Parkinson's disease (PD) compared to non-smokers. This correlation has led to the intriguing question of whether there are possible relationships between smoking, MAO-B activity and PD. Recent studies have evaluated specific components of tobacco smoke for their MAO inhibiting and neuroprotective properties. This chapter summarizes the relevant literature relating to the basic questions in these areas. We have undertaken studies to identify possible inhibitors of MAO-B in the tobacco leaf and tobacco smoke and have evaluated one such compound in the MPTP PD mouse model. In this chapter we report on the results of these studies and present a discussion of potential avenues of research and their implication with respect to PD, smoking and monoamine oxidase.
Article
In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson's disease, and Alzheimer's disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called "cheese effect." Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.
Article
The neuropathology associated with Parkinson's disease (PD) is thought to involve excessive production of free radicals, dopamine autoxidation, defects in glutathione peroxidase expression, attenuated levels of reduced glutathione, altered calcium homeostasis, excitotoxicity and genetic defects in mitochondrial complex I activity. While the neurotoxic mechanisms are vastly different for excitotoxins and 1-methyl-4-phenylpyridinium ion (MPP(+)), both are thought to involve free radical production, compromised mitochondrial activity and excessive lipid peroxidation. We show here that the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) increased significantly after treatment of cultured cerebellar granule cells (CGCs) with 50 microM MPP(+). Co-treatment with antioxidants such as ascorbate (ASC), catalase, alpha-tocopherol (alpha-TOH), coenzyme Q(10) (CoQ(10)) or superoxide dismutase (SOD) rescued the cells from MPP(+)-induced death. MPP(+)-induced cell death was also abolished by co-treatment with nitric oxide synthase (NOS) inhibitors such as 7-nitroindazole (7-NI), 2-ethyl-2-thiopseudourea hydrobromide (EPTU) or S-methylisothiourea sulphate (MPTU). We also tested the protective effects of an iron chelator (deferoxamine mesylate, DFx) and a peroxynitrite scavenger (FeTTPS) and the results lend further support to the view that the free radical cytotoxicity plays an essential role in MPP(+)-induced death in primary cultures of CGC.