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1.
J Neurochem ; 45(4): 1049-54, 1985 Oct.
Article in English | MEDLINE | ID: mdl-3928814

ABSTRACT

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a chemical that, after injection into experimental animals, including mice and monkeys, causes a degeneration of the nigrostriatal pathway. We carried out experiments designed to study the in vitro oxidation of MPTP by mouse brain mitochondrial preparations. MPTP was actively oxidized by the mitochondrial preparations, with Km and Vmax values very similar to those of benzylamine, a typical substrate for MAO-B. MPTP was oxidized considerably better than many of its analogs, even those with relatively minor structural changes. Several monoamine oxidase inhibitors (MAOI) were potent inhibitors of MPTP oxidation, and there was a highly significant correlation between the capacity of the MAOI tested to inhibit MPTP oxidation and benzylamine oxidation. There was no correlation between the capacity of the MAOI to inhibit MPTP oxidation and their capacity to inhibit the oxidation of tryptamine, a substrate for MAO-A. In other experiments, MPTP was an excellent substrate for pure MAO-B, prepared from bovine liver. All of these data, combined with the fact that MAO-B inhibitors can protect against MPTP-induced dopaminergic neurotoxicity in vivo, point to an important role for MAO-B in MPTP metabolism in vivo.


Subject(s)
Monoamine Oxidase/metabolism , Pyridines/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Allylamine/analogs & derivatives , Allylamine/pharmacology , Animals , Benzylamines/metabolism , Brain/ultrastructure , Clorgyline/pharmacology , Indans/pharmacology , Kinetics , Mice , Mice, Inbred C57BL , Mitochondria/enzymology , Oxidation-Reduction , Selegiline/pharmacology , Tryptamines/metabolism
2.
Neurosci Lett ; 58(1): 133-7, 1985 Jul 04.
Article in English | MEDLINE | ID: mdl-3876523

ABSTRACT

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a recently discovered neurotoxin, caused extensive losses of dopamine and its major metabolites after its administration to male Swiss-Webster mice. In contrast, under identical conditions, several MPTP analogues, even those with relatively minor structural changes, were without toxicity. These include compounds with a 1-ethyl and 1-propyl substituent rather than the 1-methyl, the compound lacking the double bond in the tetrahydropyridine ring, as well as the compound with no phenyl substituent. It follows that each part of the MPTP molecule is important in determining its neurotoxic activity.


Subject(s)
Corpus Striatum/physiology , Dopamine/metabolism , Pyridines/pharmacology , Substantia Nigra/physiology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Corpus Striatum/metabolism , Male , Mice , Mice, Inbred Strains , Neural Pathways/drug effects , Neural Pathways/metabolism , Substantia Nigra/metabolism
3.
Res Commun Chem Pathol Pharmacol ; 47(3): 333-43, 1985 Mar.
Article in English | MEDLINE | ID: mdl-3922020

ABSTRACT

The rates of decomposition of 3H-dopamine (3H-DA), 3H-apomorphine and 3H-ADTN were determined in Tris buffer at pH 7.4 and in a Tris buffer containing a neostriatal membrane preparation representative of that used in binding experiments. In both the Tris buffer alone and in the neostriatal membrane preparation, 3H-DA was the most stable, 3H-ADTN was intermediate and 3H-apomorphine was the least stable. In the Tris buffer, the extent of decomposition of all three 3H-catechols was greatly retarded by sodium ascorbate. In contrast, in the neostriatal membrane preparation pronounced inhibitory effects of ascorbate were obtained only with 3H-ADTN. Even in the presence of high concentrations of sodium ascorbate (i.e., 0.5 mM), there was an extensive decomposition of 3H-apomorphine in the neostriatal membrane preparation. The data suggest that one exercise great caution in choosing appropriate conditions for binding experiments with these unstable ligands.


Subject(s)
Apomorphine , Ascorbic Acid , Dopamine , Edetic Acid , Naphthalenes , Tetrahydronaphthalenes , Animals , Apomorphine/metabolism , Ascorbic Acid/pharmacology , Brain/metabolism , Buffers , Dopamine/metabolism , Drug Stability , Edetic Acid/pharmacology , Male , Membranes/metabolism , Naphthalenes/metabolism , Rats , Temperature , Tetrahydronaphthalenes/metabolism , Time Factors
4.
J Neurochem ; 44(1): 310-3, 1985 Jan.
Article in English | MEDLINE | ID: mdl-3871120

ABSTRACT

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is known to cause a destruction of the dopaminergic nigrostriatal pathway in certain animal species including mice. MPTP and some structurally related analogs were tested in vitro for their capacity to inhibit the uptake of [3H]3,4-dihydroxyphenylethylamine-([3H]DA), [3H]5-hydroxytryptamine ([3H]5-HT), and [3H]gamma-aminobutyric acid [( 3H]GABA) in mouse neostriatal synaptosomal preparations. MPTP was a very potent inhibitor of [3H]5-HT uptake (IC50 value 0.14 microM), a moderate inhibitor of [3H]DA uptake (IC50 value 2.6 microM), and a very weak inhibitor of [3H]GABA uptake (no significant inhibition observed at 10 microM MPTP). In other experiments, MPTP caused some release of previously accumulated [3H]DA and [3H]5-HT, but in each case MPTP was considerably better as an uptake inhibitor than as a releasing agent. The 4-electron oxidation product of MPTP, i.e., 1-methyl-4-phenyl-pyridinium iodide (MPP+), was a very potent inhibitor of [3H]DA uptake (IC50 value 0.45 microM) and of [3H]5-HT uptake (IC50 value 0.78 microM) but MPP+ was a very weak inhibitor of [3H]GABA uptake. These data may have relevance to the neurotoxic actions of MPTP.


Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Pyridines/pharmacology , Serotonin/metabolism , Synaptosomes/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Corpus Striatum/drug effects , Dose-Response Relationship, Drug , Male , Mice , Synaptosomes/drug effects , gamma-Aminobutyric Acid/metabolism
5.
Nature ; 311(5985): 467-9, 1984.
Article in English | MEDLINE | ID: mdl-6332989

ABSTRACT

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.


Subject(s)
Dopamine/physiology , Monoamine Oxidase Inhibitors/pharmacology , Neurons/drug effects , Pyridines/antagonists & inhibitors , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Biotransformation/drug effects , Corpus Striatum/drug effects , Dopamine/metabolism , Homovanillic Acid/metabolism , Male , Mice , Substantia Nigra/drug effects
6.
Neuropharmacology ; 23(6): 711-3, 1984 Jun.
Article in English | MEDLINE | ID: mdl-6611514

ABSTRACT

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes a destruction of the nigrostriatal dopamine pathway in humans as well as in monkeys. However, it has been reported that MPTP is inert in several small animal species. We now report that MPTP, given to mice at 30 mg/kg intraperitoneally, causes severe and long-lasting depletions of dopamine and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum.


Subject(s)
Corpus Striatum/drug effects , Dopamine/analysis , Pyridines/pharmacology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , 3,4-Dihydroxyphenylacetic Acid/analysis , Animals , Corpus Striatum/analysis , Homovanillic Acid/analysis , Male , Mice , Mice, Inbred Strains
7.
J Neurochem ; 41(5): 1384-92, 1983 Nov.
Article in English | MEDLINE | ID: mdl-6619873

ABSTRACT

Sodium ascorbate caused an increased lipid peroxidation and a large decrement in [3H]spiroperidol binding in a rat neostriatal membrane preparation (preparation C). Both effects were greater at intermediate (0.05 and 0.5 mM) than at higher or lower ascorbate concentrations. In contrast, in another neostriatal membrane preparation (preparation A), there was no loss of [3H]spiroperidol binding and only a small increase in lipid peroxidation caused by ascorbate. However, both the ascorbate-induced increase in lipid peroxidation and loss of [3H]spiroperidol binding were greatly enhanced in preparation A by the addition of iron salts. In experiments designed to explore reasons for these apparent discrepancies, we discovered that the method of tissue preparation was a critical factor. The ascorbate effects were consistently greater in a tissue preparation which was originally homogenized in an isotonic sucrose medium and centrifuged, and the cell debris discarded (as was done in preparation C), than in one in which the tissue was homogenized in a hypotonic medium and in which no low-speed centrifugation was done (as was done in preparation A). In other experiments, of several cations tested, only ferrous and ferric potentiated the above-described effects of ascorbate. Some ascorbic acid derivatives (e.g., isoascorbic acid) had properties similar to those of ascorbic acid, whereas several reducing agents could, in the presence of added iron salts, cause both a lipid peroxidation and a loss of [3H]spiroperidol binding.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Ascorbic Acid/pharmacology , Butyrophenones/metabolism , Corpus Striatum/metabolism , Lipid Peroxides/metabolism , Spiperone/metabolism , Animals , Corpus Striatum/drug effects , Ferrous Compounds/pharmacology , Male , Rats , Rats, Inbred Strains
8.
Life Sci ; 32(19): 2183-91, 1983 May 09.
Article in English | MEDLINE | ID: mdl-6843291

ABSTRACT

It has been pointed out by several different groups of investigators in the past several years that ascorbic acid was a potent inhibitor of the binding of dopamine (DA) agonists including 3H-DA itself and 3H-ADTN, 3H-apomorphine and 3H-norpropylapomorphine to neostriatal membrane preparations. However, the significance of this effect of ascorbic acid has been controversial. For example, it has recently been claimed that the stereospecific binding of DA agonists is facilitated by ascorbic acid and can be measured only in its presence. In the present study in neostriatal membrane preparations in the absence of ascorbic acid, the binding of 3H-DA was very potently inhibited by potent DA agonists (DA, ADTN, apomorphine). Considerably weaker effects were obtained with norepinephrine, isoproterenol, serotonin, catechol and pyrogallol. Stereospecific effects were clearly observed in that the binding of 3H-DA was inhibited to a much greater extent by several biologically active enantiomers than by their less active counterparts. For example, (-)-2-hydroxyapomorphine and (-)-norpropylapomorphine were much more potent inhibitors than their corresponding (+) isomers. This binding of 3H-DA was also very strongly inhibited by sodium ascorbate and several other reducing agents. In control experiments in the neostriatal membrane preparation in the absence of ascorbic acid, there was no detectable decomposition of 3H-DA. The data suggest that 3H-DA can, in the absence of sodium ascorbate, bind stereospecifically to a site that has the properties of a DA receptor. Furthermore, sodium ascorbate is a potent inhibitor of this stereospecific binding.


Subject(s)
Ascorbic Acid/pharmacology , Corpus Striatum/metabolism , Dopamine/metabolism , Animals , Catechols/pharmacology , Corpus Striatum/drug effects , Dose-Response Relationship, Drug , Male , Membranes/metabolism , Pyrogallol/pharmacology , Rats , Rats, Inbred Strains , Stereoisomerism
9.
Life Sci ; 32(8): 847-53, 1983 Feb 21.
Article in English | MEDLINE | ID: mdl-6827915

ABSTRACT

The rate of 3H-dopamine decomposition was determined in buffers and in neostriatal membrane preparations that are commonly used in binding experiments. The rate of decomposition of 3H-dopamine was inhibited considerably by the membrane preparation and by ascorbic acid. Under conditions in which the binding of 3H-dopamine is routinely measured in neostriatal membrane preparations, there was almost no 3H-dopamine decomposition. The data would seem to suggest that the routine addition of very high concentrations of antioxidants is unnecessary when 3H-dopamine binding is being determined.


Subject(s)
Ascorbic Acid/pharmacology , Corpus Striatum/ultrastructure , Dopamine/metabolism , Animals , Binding, Competitive/drug effects , Biotransformation , Cell Fractionation , Cell Membrane/metabolism , Male , Rats , Rats, Inbred Strains , Tritium
10.
Neuropharmacology ; 22(1): 135-7, 1983 Jan.
Article in English | MEDLINE | ID: mdl-6843783

ABSTRACT

A considerable controversy exists over whether ascorbic acid should or should not be used in experiments in which the binding of DA agonists to neostriatal membrane preparations is being determined. Some authors claim that its presence is required. In the present study we have determined that sodium ascorbate was a very potent inhibitor of the specific binding of 3H-DA to a rat neostriatal membrane preparation. Under conditions of these binding experiments, there was no decomposition of the 3H-DA as determined by two separate techniques. These data would seem to suggest that when 3H-DA binding is being measured, ascorbate addition is detrimental.


Subject(s)
Ascorbic Acid/metabolism , Corpus Striatum/ultrastructure , Dopamine/metabolism , Animals , Cell Membrane/metabolism , Tritium
11.
J Neurochem ; 38(4): 1000-6, 1982 Apr.
Article in English | MEDLINE | ID: mdl-7062025

ABSTRACT

Ascorbic acid, sodium ascorbate, and isoascorbic acid (the stereoisomer of ascorbic acid) inhibited the stereospecific binding of [3H]spiroperidol to neostriatal membrane preparations. Greater inhibitory effects were obtained at intermediate concentrations of the three ascorbic acid analogs (i.e., 0.06 and 0.6 mM) than at higher (6 mM) or lower (0.006 mM) concentrations. In parallel experiments, the three ascorbic acid analogs induced lipid peroxidation, which was also greater at the two intermediate than at higher or lower concentrations. Several known inhibitors of lipid peroxidation, including propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, alpha-naphthol, and cobalt chloride, as well as the iron chelating agents EDTA and DETAPAC (diethylenetriaminepentaacetic acid) were able to counteract the effects of the ascorbic acid analogs on both lipid peroxidation and on [3H]spiroperidol binding. These data strongly suggest that an iron-catalyzed lipid peroxidation is responsible for the observed inhibitory effects on binding. In other experiments, neostriatal membrane preparations that were preincubated with ascorbic acid (0.6 mM) and subsequently washed still had greatly diminished capacity to bind [3H]spiroperidol, indicating that ascorbic acid need not be physically present during the binding assay in order to affect binding. This experimental procedure also appears to be a way in which [3H]spiroperidol binding sites can be inactivated and washed free of the inactivating agent.


Subject(s)
Ascorbic Acid/pharmacology , Butyrophenones/metabolism , Corpus Striatum/metabolism , Dopamine Antagonists , Lipid Peroxides/metabolism , Spiperone/metabolism , Animals , Cell Membrane/drug effects , Kinetics , Male , Rats , Rats, Inbred Strains
12.
Experientia ; 38(3): 378-9, 1982 Mar 15.
Article in English | MEDLINE | ID: mdl-6804257

ABSTRACT

DETAPAC, an iron-chelating agent, given to male Swiss-Webster mice prior to alloxan, was able to protect the mice from the diabetogenic actions of alloxan. In contrast EDTA, another chelating agent, offered no protection. Possible mechanisms for these effects, including inhibition of hydroxyl radical formation, will be discussed.


Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Pentetic Acid/therapeutic use , Animals , Blood Glucose/analysis , Diabetes Mellitus, Experimental/physiopathology , Edetic Acid/pharmacology , Male , Mice
13.
Res Commun Chem Pathol Pharmacol ; 34(3): 409-21, 1981 Dec.
Article in English | MEDLINE | ID: mdl-7323442

ABSTRACT

Ascorbic acid was a potent inhibitor of the binding of both dopamine agonists (3H-dopamine and 3H-ADTN) and also of dopamine antagonists (3H-spiroperidol and 3H-domperidone) to neostriatal membrane preparations. Against dopamine agonists, ascorbic acid caused a dose-dependent inhibition of binding with about 90% effect at 6 mM ascorbic acid. Against dopamine antagonists there was U-shaped dose response curve for ascorbic acid. That is, 6 mM ascorbic acid caused no significant inhibition, while 0.006 mM caused a slight inhibition, and intermediate concentrations caused extensive inhibition. Almost identical inhibitory effects were obtained with sodium ascorbate. In other experiments, 500 mg/kg of ascorbic acid given to mice 1 hour prior to the dopamine releasing agent d-amphetamine, was able to greatly attenuate the increase in locomotor activity usually seen after amphetamine. These latter data may have important implications for a possible role for ascorbic acid in dopaminergic neurotransmission.


Subject(s)
Ascorbic Acid/pharmacology , Behavior, Animal/drug effects , Corpus Striatum/metabolism , Dopamine/metabolism , Receptors, Dopamine/metabolism , Animals , Cell Membrane/metabolism , Corpus Striatum/drug effects , Domperidone/metabolism , Dopamine Antagonists , Kinetics , Male , Rats , Rats, Inbred Strains , Receptors, Dopamine/drug effects , Spiperone/metabolism
15.
Pharmacol Biochem Behav ; 15(1): 75-9, 1981 Jul.
Article in English | MEDLINE | ID: mdl-6794038

ABSTRACT

1-Deprenil, a potent inhibitor of type B monoamine oxidase, was a weak inhibitor of 3H-dopamine uptake as well as a weak releasing agent for previously accumulated 3H-dopamine in rat neostriatal tissue slices. In similar experiments d-amphetamine as approximately 100 times as potent as 1-deprenil as a releasing agent. When deprenil (20 mg/kg IP) was given to rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra, it brought about a moderate but long-lasting ipsilateral rotational behavior. 1-Dopa (20-40 mg/kg, IP) by itself caused a considerably stronger rotation in the opposite direction (contralateral). When 1-dopa was given to rats 1 hr after 1-deprenil, there was a considerably greater contralateral rotation than after 1-dopa alone. Clorgyline, a type A monoamine oxidase inhibitor, which by itself at 20 mg/kg caused no rotation, also potentiated the contralateral rotation seen after 1-dopa (5-20 mg/kg). In contrast, d-amphetamine, which by itself caused ipsilateral rotation, failed to potentiate the rotation after 1-dopa. Possible mechanisms for these observations will be discussed.


Subject(s)
Levodopa/pharmacology , Phenethylamines/pharmacology , Selegiline/pharmacology , Stereotyped Behavior/drug effects , Substantia Nigra/physiology , Animals , Clorgyline/pharmacology , Dopamine/metabolism , Humans , Hydroxydopamines/pharmacology , Isomerism , Male , Oxidopamine , Rats , Rats, Inbred Strains
16.
J Pharmacol Exp Ther ; 217(3): 745-9, 1981 Jun.
Article in English | MEDLINE | ID: mdl-7194909

ABSTRACT

Mazindol and two homologs of mazindol were tested for their effects as uptake inhibitors in rat tissue slices for [3H]dopamine in the neostriatum, for [3H]norepinephrine in occipital cortex and for [3H]serotonin in whole brain. All three drugs were potent inhibitors of [3H]dopamine uptake (ED50 values between 57 and 280 nM), [3H]norepinephrine uptake (ED50 values less than 19 nM) and were somewhat weaker against [3H]serotonin uptake (ED50 values between 550 and 4100 nM). All three drugs were in contrast very weak as releasing agents for previously accumulated 3H-biogenic amines. Mazindol injection resulted in a large increase in locomotor activity in mice, but its two homologs were without effect. Mazindol was able to counteract amphetamine-induced increases in activity in reserpinized mice, but its homologs were inactive. Mazindol also caused a vigorous ipsilateral rotation in rats with an unilateral 6-hydroxydopamine lesion of the nigrostriatal system, but again the homologs had no such effect. However, all three drugs were potent inhibitors of prolactin secretion in rats (ID50 values 1-2 mg/kg orally). Correlations between the capacities of the drugs to inhibit 3H-biogenic amine uptake and the various in vivo responses are made.


Subject(s)
Behavior, Animal/drug effects , Biogenic Amines/metabolism , Brain Chemistry/drug effects , Indoles/pharmacology , Mazindol/pharmacology , Animals , Dopamine/metabolism , Female , Humans , In Vitro Techniques , Male , Mazindol/analogs & derivatives , Mice , Motor Activity/drug effects , Prolactin/metabolism , Rats , Solubility , Stereotyped Behavior/drug effects
17.
Res Commun Chem Pathol Pharmacol ; 31(1): 163-71, 1981 Jan.
Article in English | MEDLINE | ID: mdl-7196067

ABSTRACT

Azathioprine (1mmole/kg), given to male Swiss-Webster mice one hour prior to 75 mg/kg alloxan, was able to protect against the diabetogenic actions of alloxan. Various potential mechanisms for the protective effects of azathioprine, including its scavenging of the hydroxyl radical, which can be generated from alloxan, will be discussed.


Subject(s)
Azathioprine/therapeutic use , Diabetes Mellitus, Experimental/prevention & control , Alloxan/metabolism , Animals , Azathioprine/metabolism , Glutathione/metabolism , Male , Mercaptopurine/metabolism , Mice
20.
J Pharmacol Exp Ther ; 211(2): 415-8, 1979 Nov.
Article in English | MEDLINE | ID: mdl-501570

ABSTRACT

Several urea derivatives (monomethylurea, monoethylurea and diethylurea) give i.p. to mice 30 min before alloxan (75 mg/kg i.v.) were able to prevent the diabetogenic actions of alloxan. Protection by these agents correlated reasonably well with their capacity to react with (scavenge) the hydroxyl radical. Protection did not correlate with the capacity of the above agents to cause a transient hyperglycemia at the point of alloxan administration, which might have also been a potential means of protection. These data extend previously published data on the capacity of hydroxyl radical scavengers to protect against alloxan and add evidence to the concept that the hydroxyl radical, generated within the beta cells, is the species derived from alloxan responsible for the damage to beta cells.


Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Methylurea Compounds/pharmacology , Urea/analogs & derivatives , Animals , Blood Glucose/metabolism , Free Radicals , Male , Mice , Structure-Activity Relationship , Urea/pharmacology
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