Biomedical subjects

P H Yu

Publications and source records attributed to P H Yu.

At least 91 records · Page 5Linked to original sources

PubMed1995

Comparison of cytotoxicity of a quaternary pyridinium metabolite of haloperidol (HP+) with neurotoxin N-methyl-4-phenylpyridinium (MPP+) towards cultured dopaminergic neuroblastoma cells.

Haloperidol has recently been found to be metabolized to its pyridinium ion (HP+). This conversion of haloperidol to HP+ appears to be similar to the activation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to N-methyl-4-phenyl pyridinium ion (MPP+). MPP+ is responsible for the damage of striatal dopaminergic neurons induced by MPTP in humans and animals. It seemed sensible to investigate whether or not HP+ might be toxic towards dopaminergic neurons and perhaps associated with some of the residual moto-function side effects of haloperidol. We therefore investigated the neurotoxicity of HP+ toward cultured human dopamine neuroblastoma cells (SH-SY5Y) and compared it with that of MPP+. HP+ reduced the viability as measured by MTT and [3H]thymidine incorporation methods in SH-SY5Y cells. Cell membrane integrity is reduced by the treatment of HP+ as measured by intracellular LDH levels. The toxicity was concentration and time dependent. Interestingly, HP+ appeared to be more toxic than MPP+ towards the SH-SY5Y cells in early phase in cultures. The toxicity of MPP+ appear to be progressive and subsequently become more than HP+ with prolonged cultivation. In contrary to MPP+, the toxic effect of HP+ towards a dopamine transporter transfected SK-N-MC cell line is not different from its wild type. This indicates that dopamine uptake system is probably not involved in the cytotoxicity caused by HP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1995

Effect of haloperidol and its metabolites on dopamine and noradrenaline uptake in rat brain slices.

The effects of haloperidol and its metabolites on dopamine (DA) and noradrenaline (NA) uptake were investigated. Both direct uptake of [3H]DA and [3H]NA into the rat striatal and hippocampus slices and binding of a specific DA uptake inhibitor [3H]GBR-12935 were employed in the present study. Haloperidol pyridinium (HP+), haloperidol 1,2,3,6-tetrahydropyridine (HTP), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (CPTP) and reduced haloperidol (RHAL) are potent inhibitors of DA uptake. HTP N-oxide (HTPNO) exhibits a relatively weak effect on DA uptake. Other metabolites of haloperidol, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP) and haloperidol N-oxide (HNO), as well as haloperidol itself possess negligible inhibitory effect on DA uptake. HP+ has been shown to be an amine releaser. It is possible that HP+ may induce amphetamine-like neurotoxicity. The effects of the metabolites of haloperidol on [3H]NA uptake are similar to those on [3H]DA uptake. HP+ appears to be different from MPP+, which is a more potent [3H]NA uptake blocker than on [3H]DA uptake. Although haloperidol exhibits no DA uptake inhibitory effect, it has a high affinity for the [3H]GBR-12935 binding site. The possible pharmacological implications such inhibitory effects on amine uptake are discussed.

Animals↗

PubMed1995

Lack of protective effect of R(-)-deprenyl on programmed cell death of mouse thymocytes induced by dexamethasone.

R(-)-Deprenyl, an archetypical MAO-B inhibitor, has been shown to delay the onset of the disabling syndrome of Parkinson's disease and to be useful in the treatment of Alzheimer's disease. Recently, R(-)-deprenyl has been claimed to be capable of preventing apoptosis of PC12 cells, which had been primed with nerve growth factor (NGF) and followed by withdrawal of serum. We investigated the effect of R(-)-deprenyl in a non-neuronal cell model, namely, apoptosis of mouse thymocytes induced by dexamethasone. Trypan blue exclusion and lactate dehydrogenase activity were applied to assess the cell survival. R(-)-Deprenyl did not exhibit any detectable protective effect to the thymocytes from apoptosis. The result is further confirmed by examining the apoptotic DNA fragmentation using gel electrophoresis and assessing the soluble DNA released by a spectrophotometric method.

Animals↗

PubMed1995

Depletion of NOS activity in the rat dentate gyrus neurons by DSP-4 and protection by deprenyl.

DSP-4 is a potent and highly selective neurotoxin of noradrenergic axons of locus coeruleus origin. The authors found that in addition to depletion of the hippocampal noradrenergic terminals the histochemical reactivity of nitric oxide synthase (NOS, NADPH-diaphorase) was lost from neurons in the subgranule zone and hilar region of the dentate gyrus 2 weeks after a systemic administration of this toxin. Pretreatment with R(-)-deprenyl and 2-HxMP (2-hexyl-N-methylpropargylamine, which protects hippocampal noradrenergic axons against DSP-4 neurotoxicity, led to a complete prevention of the loss of NADPH-diaphorase activity.

Animals↗

PubMed1995

Neurochemical, neuroprotective and neurorescue effects of aliphatic N-methylpropargylamines; new MAO-B inhibitors without amphetamine-like properties.

A series of aliphatic N-methylpropargylamine MAO-B inhibitors have been synthesized and their structural and functional relationships have been investigated. 2-Hexyl-N-methylpropargylamine (2-HxMP), for example, has been found to be a highly potent, irreversible, selective, MAO-B inhibitor both in vitro and in vivo. The R-(-)-enantiomers are much more active than the S-(+)-enantiomers at inhibiting MAO-B activity. Some of these compounds protect mouse nigrostriatal dopamine neurons against the neurotoxin MPTP and the mouse hippocampal noradrenergic system against the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). They rescue hippocampal neurons after damage induced by ischemia and kainic acid treatment, as well as motoneurons in young mice following facial nerve axotomy. Such rescue effects are, interestingly, unrelated to inhibition of MAO-B activity. Some of the aliphatic propargylamines enhance the survival of neuroblastoma cells co-cultured with astrocytes following serum depletion. They stimulate the expression of AADC mRNA and inhibit GFAP mRNA expression. They do not possess amphetamine-like properties and exhibit no effect on noradrenaline or dopamine uptake nor do they increase hypertensive effects in the tyramine pressor test. Unlike R(-)-deprenyl, 2-HxMP does not potentiate dopamine toxicity in vitro. These new MAO-B inhibitors may possess significant chemotherapeutic implications for certain psychiatric and neurodegenerative disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1995

Increase of survival of dopaminergic neuroblastoma in co-cultures with C-6 glioma by R-(-)-deprenyl.

We have observed that the survival of dopamine neuroblastoma (SH-SY5Y) cells in co-cultures with C-6 glioma in serum-deprived media is slightly but significantly enhanced by R-(-)-deprenyl, a selective monoamine oxidase B inhibitor. This drug, however, does not directly affect the viability of SH-SY5Y cells or glioma cells in serum or serum-deprived media. The results suggest that R-(-)-deprenyl enhances astroglial trophic support in favor of neuronal survival.

Brain Neoplasms↗

PubMed1994

Characterization of human serum and umbilical artery semicarbazide-sensitive amine oxidase (SSAO). Species heterogeneity and stereoisomeric specificity.

Semicarbazide-sensitive amine oxidases (SSAOs) are located in cardiovascular smooth muscle, cartilage and brown adipose tissues of different species, including human. The enzyme is also present in blood, and its activity appears to be altered under certain pathological conditions. SSAOs from both human umbilical arteries and serum were partially purified, and some of their biochemical properties were investigated. Both human artery and blood SSAO exhibited very similar substrate preference, lack of stereospecificity catalyzing the deamination of pro-R and pro-S benzylamine-deuterated enantiomers, and were very sensitive towards (E)-2-(4-fluorophenethyl)-3-fluoroallylamine (MDL-72974A). It was concluded that circulating serum SSAO is identical to the SSAO from vascular tissues. Human SSAO exhibited distinctly different properties in comparison to bovine and rat SSAOs.

Allyl Compounds↗

PubMed1994

Is brain superoxide dismutase activity increased following chronic treatment with 1-deprenyl?

L-deprenyl, a specific MAO-B inhibitor, has been proposed to possess a neuroprotective effect. The mechanism of such an effect is unclear. L-Deprenyl has been found to increase rat striatal superoxide dismutase (SOD) activity, which inactivates singlet oxygen. It would be very interesting to know how such activation occurs and whether or not other MAO inhibitors also have such an effect. We have analyzed rat striatal SOD activity using a very sensitive nitrite method and an immunological procedure. The effect of different doses and time of treatment with 1-deprenyl and M-2-PP (2-pentyl-N-methyl-propargylamine), a new highly potent, selective and non-amphetamine-like MAO-B inhibitor, on the rat brain has been investigated. We were unable to detect any increase of SOD activity in the rat striata and cerebral cortex nor any increase in the concentration of immunoreactive SOD antibody in the cortex following chronic treatment with 1-deprenyl and M-2-PP. It remains to be substantiated as to whether or not 1-deprenyl can enhance SOD levels.

Animals↗

PubMed1994

Deamination of aliphatic amines by type B monoamine oxidase and semicarbazide-sensitive amine oxidase; pharmacological implications.

Straight and branched chain aliphatic monoamines, which are not normal tissue constituents, are deaminated selectively by type B monoamine oxidase (MAO-B). They exhibit a high affinity towards the active site of MAO-B and this made them very useful pharmacologically. An anticonvulsant prodrug, Milacemide [2-(N-pentyl)glycinamide] is deaminated by MAO-B and this facilitates a mechanism of delivering glycine into the CNS. We have found that 2-propyl-pentylamine (2-propyl-1-aminopentane) and N-(2-propylpentyl)glycinamide are also converted by MAO-B to valproic acid and glycine both in vitro and in vivo; these compounds, however, cause severe tremor. By attaching a propargylamine group the resultant series of aliphatic propargylamine derivatives have been shown to be very potent selective MAO-B inhibitors. They are chemically quite different from most other MAO-B inhibitors, since they do not possess any aromatic structures. The relatively short chain aliphatic propargylamines, i.e. N-2-pentyl-N-methylpropargylamine and N-2-hexyl-N-methylpropargylamine, are 4 to 5 times more potent and more selective than selegiline (1-deprenyl) with respect to the inhibition of MAO-B in brain following oral administration. Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the deamination of not only longer chain aliphatic amines but also short chain aliphatic amines including methylamine. Formaldehyde is produced from methylamine by SSAO. Increased methylamine deamination may cause cellular damage in some pathological conditions, such as uraemia and diabetes. We have observed that cultured human endothelial cells are damaged by methylamine in the presence of SSAO. Inhibition of the SSAO activity completely protects these cells from the methylamine-SSAO induced damage.

Amine Oxidase (Copper-Containing)↗

PubMed1994

Effect of L-deprenyl, its structural analogues and some monoamine oxidase inhibitors on dopamine uptake.

The effect on dopamine uptake by L-deprenyl, its structural analogues and different types of monoamine oxidase (MAO) inhibitors was investigated. Both direct [3H]dopamine uptake into rat striatal slices and binding of a specific dopamine uptake inhibitor [3H]GBR-12935 were used in the present study. L-Deprenyl exhibits a relatively weak dopamine uptake inhibitory effect in vitro, while D-deprenyl possesses a very potent inhibitory effect. The potent effect of D-deprenyl on dopamine uptake may be responsible, at least in part, for its behavioral effects and abuse liability. L-Methamphetamine, a metabolite of L-deprenyl, does not inhibit [3H]GBR-12935 binding but it reduces the retention of [3H]dopamine in striatal tissues, suggesting that it may enhance dopamine release. The MAO-A inhibitors clorgyline and brofaromine also exhibit dopamine uptake inhibitory effects. Irreversible and reversible MAO-B inhibitors, however, such as pargyline, aliphatic N-methylpropargylamines, Ro 19-6327 and MDL-72974A and MAO-A inhibitor moclobemide do not possess any appreciable inhibitory effects on dopamine uptake. Dopamine uptake is probably unrelated to the pharmacological actions of L-deprenyl.

Animals↗

PubMed1994

Chronic L-deprenyl or L-amphetamine: equal cognitive enhancement, unequal MAO inhibition.

The effect of chronic (4 month), subcutaneous injections of saline, L-deprenyl (0.25 mg/kg), or L-amphetamine (0.25 mg/kg) on the acquisition of a learned spatial habit in a modified Morris Water Maze was investigated in middle aged rats. Injections, given three times weekly starting at 6 months of age, were continued during behavioral testing, which occurred at 10 months of age. The cognitive performance of the middle aged rats was compared to that of 2-month-old control rats. Twenty-four hours after the last behavioral test, the rats were sacrificed and their brains were removed, dissected, and frozen in liquid nitrogen. The activities of MAO-A and MAO-B in the lateral cortex were determined. Results indicate that rats in the L-deprenyl group, the L-amphetamine group, and the young control group all learned the water maze task equally rapidly and significantly faster than rats in the saline group. MAO-A did not differ among the saline, amphetamine, and young control rats, but MAO-B was significantly higher in the middle aged saline and L-amphetamine rats than in the young controls. Both MAO-A and MAO-B activities were significantly lower in the L-deprenyl group than in the other three groups. This indicates that low-dose L-deprenyl can also inhibit MAO-A following chronic SC administration. Moreover, the improved cognitive performance produced by L-deprenyl may not be due to its ability to inhibit MAO-B, but rather to some other effect such as the activation of growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗

PubMed1994

Pharmacological and clinical implications of MAO-B inhibitors.

Although the involvement of monoamine oxidase B (MAO-B) in physiological function is not yet well understood, its inhibitors have been shown to be quite useful in the treatment of various neuropsychiatric disorders. Platelet MAO-B activity has been found to be reduced in several psychiatric disorders, related to substance abuse and associated with different personalities. 1-Deprenyl (selegiline), an archetypical MAO-B inhibitor, alone does not seem to exert an antidepressive effect, however, it may become useful when administered in combination with amine neurotransmitter precursors. MAO-B inhibitors are useful adjunct drugs to 1-DOPA in the symptomatic treatment of Parkinson's disease. Interestingly, 1-deprenyl alone can slow down the progress of otherwise disabled syndromes of Parkinson's disease. It has been proposed that 1-deprenyl may play a role in neuroprotection and neurorescue. MAO-B inhibitors can selectively and dramatically increase the level of beta-phenylethylamine, which has been shown to potentiate dopamine and noradrenaline function in the central nervous system. Several new types of highly selective, reversible and irreversible MAO-B inhibitors have recently been developed. The mechanism(s) of neuroprotective and rescue actions of 1-deprenyl and other MAO-B inhibitors will help to shed some light on our understanding of the neurodegenerative process.

Aging↗

PubMed1994

Semicarbazide-sensitive amine oxidase and monoamine oxidase in rat brain microvessels, meninges, retina and eye sclera.

Monoamine oxidase-A and -B (MAO-A and MAO-B) and semicarbazide-sensitive amine oxidase (SSAO) activities were assessed in several rat micro-vascular tissues and eyes using selective substrates and inhibitors. In rat brain microvessels both MAO-A and MAO-B activities are relatively high and the levels of the two types of MAO's are comparable. Retina possesses a similar ratio of MAO-A and B but the activities are much lower. Eye sclera and meninges exhibit mainly MAO-A and MAO-B, respectively. Aorta is the only tissue where SSAO is the predominant amine oxidase. Relatively low, but significant amounts of SSAO were also detected in brain microvessels, meninges, retina and eye sclera. Methylamine was observed to be deaminated by SSAO from different tissues. The physiological and toxicological implications of amine oxidases in these tissues are discussed.

Amine Oxidase (Copper-Containing)↗

PubMed1994

Neurochemical and neuroprotective effects of some aliphatic propargylamines: new selective nonamphetamine-like monoamine oxidase B inhibitors.

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 that l-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 l-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 l-deprenyl and M-2-PP causes selective inhibition of MAO-B activity and increases dopamine levels in mouse caudate. M-2-PP, like l-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 l-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.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1994

Neuroprotective effects of some monoamine oxidase-B inhibitors against DSP-4-induced noradrenaline depletion in the mouse hippocampus.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Phenelzine reduces plasma vitamin B6.

Plasma levels of the active form of vitamin B6 (pyridoxal phosphate) in 19 patients taking phenelzine were found to be reduced on the average to approximately 54% of the value in a control group. There was no correlation of pyridoxal phosphate level with phenelzine daily dosage over the range of 30 mg to 90 mg. No symptoms of vitamin B6 deficiency peripheral neuropathy were found.

Adolescent↗

PubMed1993

Inhibition of tryptophan hydroxylase by 6,7-dihydroxy-N-cyanomethyl-1,2,3,4-tetrahydroisoquinoline, a cyanomethyl derivative of dopamine formed from cigarette smoke.

6,7-Dihydroxy-N-cyanomethyl-1,2,3,4-tetrahydroisoquinoline, a cyanomethyl derivative of dopamine formed from cigarette smoke, was found to inhibit the activity of tryptophan hydroxylase. The inhibition was non-competitive to the substrate L-tryptophan (the Ki value 7.25 +/- 0.81 microM), but not to the biopterin cofactor. The inhibition is irreversible. 6-Hydroxy-N-cyanomethyl-tetrahydro-beta-carboline, a cyanomethyl derivative of serotonin, is inactive towards the hydroxylase. 6,7-Dihydroxy-N-cyanomethyl-1,2,3,4-tetrahydroisoquinoline may affect the serotonin biosynthesis in vivo as a consequence of cigarette smoking.

Animals↗

PubMed1993

Effect of structural modification of alkyl N-propargylamines on the selective inhibition of monoamine oxidase B activity.

A series of alkyl N-methyl-propargylamine derivatives has been discovered recently to be very potent selective irreversible monoamine oxidase B inhibitors (MAO-B). In the present study, we used a simple compound in this series, namely N-2-butyl-N-methylpropargylamine.HCl (2-BuMP), as the basic structure to investigate the effect of structural modification on the effectiveness and selectivity of the inhibition of MAO activities. When the N-methyl group was replaced by a hydrogen atom, an ethyl group or a propargyl group, MAO inhibitory activity was abolished. The modification of the propargyl group, e.g. to 3-butynyl, N-cyanomethyl or to allyl groups, also destroyed the inhibitory activity. The potency of the inhibitors was related to the carbon chain length of the alkyl group as well as to the substitution of the alpha or the terminal carbon atoms. Substitution of hydroxyl, carboxyl or carboethoxyl groups on the terminal carbon of the alkyl chain drastically reduced the inhibitory activity. More potent MAO inhibitory activity was observed for molecules with a single methyl group substitution on the alpha carbon in comparison with those substituted with two hydrogen or two methyl groups. Other branched alkyl N-methylpropargylamines, e.g. N-methyl-N-(3-pentyl)propargylamine, appeared to be slightly less selective in the inhibition of MAO-B activity. Some of these alkyl propargylamine MAO-B inhibitors, which do not possess the amphetamine-like moiety of L-deprenyl, may have significant neuropsychopharmacological implications.

Alkylation↗