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1

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Neuroprotective Effects of Some Monoamine Oxidase-B Inhibitors Against DSP-4-Induced Noradrenaline Depletion in the Mouse Hippocampus (1994)

Yu, P. H. ; Davis, B. A. ; Fang, J. ; [et al.]

Oxford, UK : Blackwell Science Ltd

Journal of neurochemistry 63 (1994), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a selective noradrenaline (NA) uptake blocker, is capable of inducing long-lasting depletion of NA in some noradrenergic axon terminals and of subsequently causing cell death to NA neuronal cell bodies in rodents. R(−)-Deprenyl, a selective monoamine oxidase (MAO)-B inhibitor, has been shown to be capable of protecting animals against this DSP-4-induced neuronal degeneration. Its action, however, has been claimed to be unrelated to the inhibition of MAO-B activity but rather due to competition for the NA uptake sites. The effects of several types of MAO inhibitors against DSP-4 toxicity, MAO-B activity both in vivo and in vitro, and NA uptake into the hippocampus have been assessed. N-(2-Hexyl)-N-methylpropargylamine (2-HxMP), a potent MAO-B inhibitor, for example, exerts no appreciable effect on NA uptake but is quite potent in counteracting the NA-depleting effect of DSP-4. Such results rule out the possibility that the neuroprotective effect of the MAO-B inhibitors is due mainly to their effect on NA uptake. The in vitro inhibition of MAO-B activity seems to correlate positively with their neuroprotective effects against DSP-4. In comparison to the MAO-B inhibitors, NA uptake blockers, such as desipramine and S(+)-deprenyl, exhibit relatively low efficacy in protecting the NA axon terminals from the effects of DSP-4-induced damage. The restoration of hippocampal NA levels is significantly enhanced with repeated treatments of R(−)-deprenyl or 2-HxMP even at very low doses following the DSP-4 insult. This suggests that in addition to neuroprotection, these MAO-B inhibitors may rescue some of the noradrenergic axon terminals damaged by DSP-4.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1046/j.1471-4159.1994.63051820.x

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Neurochemical and Neuroprotective Effects of Some Aliphatic Propargylamines: New Selective Nonamphetamine-Like Monoamine Oxidase B Inhibitors (1994)

Yu, P. H. ; Davis, B. A. ; Durden, D. A. ; [et al.]

Oxford, UK : Blackwell Science Ltd

Journal of neurochemistry 62 (1994), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: Aliphatic N-propargylamines have recently been discovered to be highly potent, selective, and irreversible monoamine oxidase B (MAO-B) inhibitors. N-Methyl-N-(2-pentyl)propargylamine (M-2-PP) and N-methyl-N-(2-hexyl) propargylamine (2-HxMP), for example, are approximately fivefold more potent than I-deprenyl at inhibiting mouse brain MAO-B activity following oral administration. These inhibitors are nonaromatic compounds and are chemically quite different from other known MAO-B inhibitors. Some of their neurochemical and neuroprotective properties have been evaluated and compared with those of I-deprenyl. We have confirmed that these new inhibitors selectively inhibit MAO-B activity both in vitro and in vivo. 2-Phenylethylamine levels were substantially increased following administration of M-2-PP, but the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were not affected except at high, nonselective doses. Chronic oral administration of I-deprenyl and M-2-PP causes selective inhibition of MAO-B activity and increases dopamine levels in mouse caudate. M-2-PP, like I-deprenyl, has been shown to be potent in protecting against MPTP-induced damage in the mouse. N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a noradrenaline neurotoxin, is not an MAO substrate. Its noradrenaline-depleting effects were substantially mitigated by I-deprenyl as well as by M-2-PP and 2-HxMP in the mouse hippocampus. Administration of 2-phenylethylamine, however, failed to reverse the effect of DSP-4. The neuroprotective effect of M-2-PP and 2-HxMP is apparently unrelated to the uptake of DSP-4.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1046/j.1471-4159.1994.62020697.x

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2-Phenylethylamine: A Modulator of Catecholamine Transmission in the Mammalian Central Nervous System? (1990)

Paterson, I. A. ; Juorio, A. V. ; Boulton, A. A.

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 55 (1990), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Since the identification of 2-phenylethylamine (β-phenylethylamine; PE) as a biogenic amine, there has been much discussion about what role, if any, it may have in the CNS. Indeed, the low endogenous concentration of PE in the brain and its relatively low potency in behavioral and pharmacological experiments have led some researchers to conclude that perhaps PE possessed no physiological role at all but that it was merely a metabolic by-product. Our findings have caused us to conclude otherwise, and in this article we review the neurochemical, neuropharmacological, and neurophysiological findings that lead us to propose that PE is a neuromodulator of catecholamine neurotransmission in the CNS.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1990.tb05764.x

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Deuterium Isotope Effect in γ-Aminobutyric Acid Transamination: Determination of Rate-Limiting Step (1987)

Yu, P. H. ; Durden, D. A. ; Davis, B. A. ; [et al.]

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 48 (1987), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: The rate of transamination of γ-aminobutyric acid (GABA) catalyzed by hog brain γ-aminobutyrate ami-notransferase was substantially reduced when the hydrogen at the γ-carbon position was replaced by deuterium. The deuterium isotope effect of this reaction has been substantiated by fluorometric, radiometric, and mass spectrometric procedures and assessed kinetically. The ratios of Vmax of the nonlabeled substrate/Vmax of the deuterated substrate obtained under different conditions ranged from 6 to 7. This indicates that the cleavage of the hydrogen from the γ-carbon is the rate-determining step in GABA transamination. Similar isotope effects have also been shown to occur in the peripheral system in vivo.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1987.tb04112.x

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Sulfate Conjugation of Monoamines in Human Brain: Purification and Some Properties of an Arylamine Sulfotransferase from Cerebral Cortex (1985)

Yu, P. H. ; Rozdilsky, B. ; Boulton, A. A.

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 45 (1985), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: An arylamine sulfotransferase (PST-M) from human brain cortex that is involved in the formation of O-sulfate esters of monoamines has been purified 272-fold by ammonium sulfate fractionation, gel filtration, DEAE-cellulose ion-exchange chromatography, chromatofocussing, and hydroxyapatite chromatography. A molecular weight of 62,000, pK of pH 5.8, and an optimum pH for the reaction at 7.8–8.0 with respect to tyramines have been determined. This enzyme possesses an extremely high affinity for dopamine and m-tyramine based on the low Km values and is moderately active toward noradrenaline and p-tyramine. Serotonin is a poor substrate. In contrast, another sulfotransferase, PST-P, which has been separated from PST-M and partially purified, exhibited a very high affinity for phenol and nitrophenols but was inactive toward the amine sulfate acceptors. In the human brain the specific activity toward dopamine as well as the ratio of activity toward dopamine/phenol was considerably higher than those for rat, hog, and bovine brains.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1985.tb04070.x

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Regulation of Aromatic l-Amino Acid Decarboxylase by Dopamine Receptors in the Rat Brain (1992)

Zhu, M. Y. ; Juorio, A. V. ; Paterson, I. A. ; [et al.]

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 58 (1992), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: Decarboxylation of phenylalanine by aromatic l-amino acid decarboxylase (AADC) is the rate-limiting step in the synthesis of 2-phenylethylamine (PE), a putative modulator of dopamine transmission. Because neuroleptics increase the rate of accumulation of striatal PE, these studies were performed to determine whether this effect may be mediated by a change in AADC activity. Administration of the D1 antagonist SCH 23390 at doses of 0.01–1 mg/kg significantly increased rat striatal AADC activity in an in vitro assay (by 16–33%). Pimozide, a D2-receptor antagonist, when given at doses of 0.01–3 mg/kg, also increased AADC activity in the rat striatum (by 25–41%). In addition, pimozide at doses of 0.3 and 1 mg/kg increased AADC activity in the nucleus accumbens (by 33% and 45%) and at doses of 0.1, 0.3, and 1 mg/kg increased AADC activity in the olfactory tubercles (by 23%, 30%, and 28%, respectively). Analysis of the enzyme kinetics indicated that the Vmax increased with little change in the Km with l-3,4-dihydroxyphenylalanine as substrate. The AADC activity in the striatum showed a time-dependent response after the administration of SCH 23390 and pimozide: the activity was increased within 30 min and the increases lasted 2–4 h. Inhibition of protein synthesis by cycloheximide (10 mg/kg, 0.5 h) had no effect on the striatal AADC activity or on the increases in striatal AADC activity produced by pimozide or SCH 23390. The results indicate that the increases in AADC activity induced by dopamine-receptor blockers are not due to de novo synthesis of the enzyme. These results show that AADC activity in the striatum is regulated by D1 and D2 receptors and that the activities in the nucleus accumbens and olfactory tubercles are regulated by D2 receptors. The observation that dopamine-receptor antagonists stimulate the synthesis of PE may be explained by the increase in AADC activity.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1992.tb09765.x

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Effects of Deuterium Substitution on the Catabolism of β-Phenylethylamine: An In Vivo Study (1986)

Dyck, L. E. ; Burden, D. A. ; Boulton, A. A.

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 46 (1986), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: β-Phenylethylamine (PE) hydrochloride injected intraperitoneally into rats was distributed evenly throughout the various regions of rat brain. Similarly, when a mixture of PE and α, α, β, β-deuterated PE ([2H4]PE) was injected, no regional differences were observed in the ratios of the amounts of [2H4]PE and PE present; however, significantly more [2H4]PE than PE was present, although a 1:1 mixture had been administered. Further experiments in which the amounts of [2H4]PE and PE in whole rat brain, liver, and plasma were quantified confirmed this finding. The maximum [2H4]PE-to-PE ratios observed were 67 in whole brain 1 h after injection and 8 in liver and in plasma 45 min after injection. The whole brain [2H4]PE-to-PE ratios were decreased by pargyline pretreatment. Subsequent experiments showed that more α, α-[2H4]PE than PE was present in whole brain, liver, and plasma of rats injected with an equimolar mixture of α, α-[2H4]PE and PE. In contrast, β, β-[2H4]PE was not enriched in comparison to PE under the same experimental conditions. We concluded that the basis for the enrichment of [2H4]PE and α, α-[2H4]PE compared to PE was due to protection of the deuterated analogs from the actions of monoamine oxidase and perhaps aldehyde dehydrogenase; this protection led to pronounced deuterium substitution effects in vivo especially in the brain.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1986.tb12982.x

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R-Deprenyl and R-2-Heptyl-N-Methylpropargylamine Prevent Apoptosis in Cerebellar Granule Neurons Induced by Cytosine Arabinoside but Not Low Extracellular Potassium (1998)

Paterson, I. A. ; Zhang, D. ; Warrington, R. C. ; [et al.]

Oxford, UK : Blackwell Science Ltd

Journal of neurochemistry 70 (1998), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: R-Deprenyl and R-2-heptyl-N-methylpropargylamine (R-2-HMP) are compounds that have been shown to reduce neuronal death in various in vitro and in vivo models involving apoptosis but do not always prevent apoptosis. In the present study we have examined the effects of these compounds and their S enantiomers on cytosine arabinoside (ara C)-induced apoptosis and low K+-induced apoptosis in cerebellar granule cells in primary culture. It was found that R-deprenyl and R-2-HMP could prevent ara C-induced apoptosis with an EC50 around 10−9M but could not prevent low K+-induced apoptosis. S-Deprenyl and S-2-HMP did not prevent apoptosis under any conditions but were found to antagonize the antiapoptotic actions of R-deprenyl and R-2-HMP. Using the fluorescent mitochondrial dye chloromethyltetramethylrhodamine methyl ester it was found that there was a loss of mitochondrial function in cerebellar granule cells exposed to ara C but not low K+ medium. R-Deprenyl and R-2-HMP prevented the ara C-induced loss of mitochondrial function. It is concluded that R-deprenyl and R-2-HMP prevent apoptosis of cerebellar granule cells by a mechanism that is independent of monoamine oxidase inhibition and that they act on the same site to prevent specifically apoptosis involving a loss of mitochondrial membrane potential, possibly p53-dependent apoptosis.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1046/j.1471-4159.1998.70020515.x

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The Effect of Some Precursor Amino Acids and Enzyme Inhibitors on the Mouse Striatal Concentration of Tyramines and Homovanillic Acid (1982)

Juorio, A. V. ; Boulton, A. A.

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 39 (1982), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: The parenteral administration of L-phenylalanine or p-tyrosine increases the mouse striatal concentration of p-tyramine, an effect that is enhanced by monoamine oxidase inhibition and reduced by an L-aromatic aminoacid decarboxylase inhibitor. Striatal m-tyramine was increased following administration of L-phenylalanine or m-tyrosine and enhanced further by monoamine oxidase inhibition. It was also observed that m-tyrosine is a better substrate for decarboxylation than p-tyrosine, and that p-tyrosine decarboxylation was blocked by NSD 1055, while that of m-tyrosine was enhanced. The results obtained indicate that both isomers of tyramine are formed in the mouse striatum by hydroxylation of L-phenylalanine to p- or m-tyrosine followed by decarboxylation by a specific decarboxylase; an alternative pathway could be first the decarboxylation of phenylalanine to β-phenylethylamine, followed by its hydroxylation to p- or m-tyramine.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1982.tb07971.x

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THE SUBCELLULAR DISTRIBUTION OF β-PHENYLETHYLAMINE, p-TYRAMINE AND TRYPTAMINE IN RAT BRAIN (1975)

Boulton, A. A. ; Baker, G. B.

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 25 (1975), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: —The quantitative subcellular distribution of β-phenylethylamine, p-tyramine and tryptamine in rat brain was investigated using the mass spectrometric integrated ion current technique. More of the total cellular tryptamine was found to be associated with paniculate fractions than was the case for phenyiethylamine and p-tyramine but a significant amount of this tryptamine was found to be labile. Analysis of the particulate fractions indicated that each of the amines was localized predominantly in the crude P2 pellet and that the bulk of this was associated with the synaptosomal (P2B) fraction. Inhibition of monoamine oxidase systems with pargyline caused an increase in the level of all three amines in all fractions, but the increase was greater in the supernatant than in the combined particulate fractions. This treatment produced changes in the distribution of β-phenylethylamine and p-tyramine between the various particulate subcellular fractions but did not markedly alter the distribution of tryptamine between the same fractions.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1975.tb04353.x

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