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PubMed1982

Comparison of biochemical properties of platelet monoamine oxidase in mentally disordered and healthy individuals.

We have investigated some biochemical properties of platelet monoamine oxidase (MAO) isolated from chronic schizophrenic and agoraphobic patients, nonschizophrenic institutional controls, and healthy volunteers. The enzyme activity level in the healthy population was reasonably constant over at least a 6-week period. High correlations were found between MAO activity assessed for different substrates (p-tyramine, beta-phenylethylamine, and tryptamine). Some heterogeneity of the platelet MAO may exist, however, at least in some of the chronic schizophrenics, since the substrate specificities were changed and the Km values reduced. The half-life of the enzyme at 58 degrees C was 2-3 minutes and the transition temperature derived from Arrhenius plots was 16-17 degrees C with respect to beta-phenylethylamine. Platelet MAO from chronic schizophrenics was not significantly different from control values with respect to temperature effects. SDS-polyacrylamide gel electrophoresis of the 3H-pargyline-MAO adduct revealed that the subunit of platelet MAO is a single band protein with a molar individuals. The adjacent structure of the flavine site of the platelet MAO was chromatographically identical to the penta-peptide isolated from MAOs from other tissues. The response of platelet MAO to thimerosal, a new differential type A MAO inhibitor, could be distinguished not only from type A MAO isolated from human placenta, but also from type B MAO isolated from bovine liver.

Agoraphobia↗
PubMed1986

Effect of maternal methadone administration on the development of multiple forms of monoamine oxidase in rat brain and liver.

The development of total monoamine oxidase (MAO) and MAO-A and MAO-B in the forebrain, brainstem, cerebellum and liver of methadone-treated and normal rats were monitored with tryptamine, serotonin and benzylamine, respectively. Daily administration of methadone (10 mg/kg, s.c.) to pregnant and nursing rats substantially retarded the development of total and the A-form of MAO in the brain regions of pups but had no effect on that of MAO-B. The effect of methadone on the development of total MAO and MAO-A in the liver was only transient and less significant. This finding indicates that the perinatal opiate syndrome associated with maternal exposure to methadone is caused by the inhibition in MAO-A development in monoaminergic neurons in the brain.

Animals↗
PubMed1984

Inhibition of dimethylnitrosamine-induced mutagenesis in Arabidopsis thaliana by diethyldithiocarbamate and carbon monoxide.

Diethyldithiocarbamate and carbon monoxide markedly inhibited the frequency of embryonic and chlorophyll mutations induced by the metabolism-requiring mutagen dimethylnitrosamine in the higher plant Arabidopsis thaliana. In contrast, the monoamine oxidase substrates, tryptamine, benzylamine and 2-phenylethylamine, had no such effect. The mutagenicity of a direct-acting mutagen, N-methyl-N-nitrosourea, was not altered by these inhibitors or substrates.

Carbon Monoxide↗
PubMed1996

Plant hallucinogens: springboards for psychotherapeutic drug discovery.

Medicinal chemists have traditionally looked to the biosynthetic diversity found in nature to provide structural templates for the development of novel therapeutic agents, and the field of hallucinogen chemistry is similar to other fields in this respect. Even LSD, for many psychopharmacologists the prototype hallucinogen, is not itself a natural compound but rather is a semisynthetic analogue of alkaloids found in plants and fungi. A similar statement could be made about the other major structural classes of hallucinogenic agents: the phenylethylamine derivatives, the tryptamine derivatives, and the beta-carboline derivatives. In each case, compounds occurring naturally in some plant, usually associated with a long tradition of ethnomedical or ceremonial use, have been the starting point for the synthesis of numerous analogues. Some of these, such as the methoxylated amphetamine derivatives, display a pharmacological profile that differs in important respects from their natural product templates. In some instances the analogues have proven to be useful tools in the hands of neurobiologists characterizing the structure and function of brain neurotransmitter systems; in other cases, they have led to the development of new psychopharmacological agents with realized or potential clinical utility. This paper gives a brief historical overview of the role of natural products in the history and development of medicinal chemistry and experimental pharmacology, particularly with respect to the development of psychopharmacology and the discovery of CNS-active agents. It discusses the potential for the discovery of new medications with psychotherapeutic and/or research applications though the investigation of plants and natural compounds with serotonergic activities. Finally, consideration is given to some lesser known plant hallucinogens which may provide further useful leads for psychotherapeutic drug discovery.

Animals↗
PubMed1989

Weak inhibition of protein kinase C coupled with various non-specific effects make sphingosine an unsuitable tool in platelet signal transduction studies.

The effects of sphingosine, the newly described inhibitor of the enzyme protein kinase C, on human platelet activation, were studied in order to gain further information on the role of protein kinase in platelet responses. Concentrations of the drug (5-20 microM) which had little effect on protein kinase C activation as measured by the phosphorylation of the 45 kDa and 20 kDa protein substrates induced by phorbol 12-myristate 13-acetate (PMA) and thrombin, strongly inhibited platelet aggregation induced by these agonists, as well as aggregation induced by ADP and ionomycin, which caused no detectable protein kinase C activation or 5-hydroxy[14C]tryptamine[( 14C]5HT) secretion. At approx. 10-fold higher concentrations (150-200 microM), sphingosine had significant inhibitory effects on PMA and thrombin-induced 45 kDa and 20 kDa protein phosphorylation. However, at these high concentrations, the drug caused extensive membrane damage/leakiness as suggested by the substantial release of [14C]5HT and [3H]adenine from pre-loaded platelets (50-70% release of both markers), and the total quenching of quin2 fluorescence by Mn2+ in the presence of the drug. Due to the increased membrane leakiness in the presence of the drug, an apparent potentiation of agonist-induced intracellular Ca2+ elevations in quin2-loaded platelets, as well as an increase in quin2 fluorescence with the drug alone (more than 50 microM) were also observed. Despite this, however, thrombin-induced [3H]arachidonate release was severely reduced in the presence of sphingosine, underlining the inhibitory effects at the membrane level. It is concluded that the weak, if any, inhibitory effects on protein kinase C at concentrations not affecting membrane integrity, as well as the inhibitory effects of sphingosine on platelet aggregation, make it an unsuitable compound as a tool for studies on platelet stimulus-response coupling.

Arachidonic Acid↗
PubMed1988

Immunological studies on paroxetine, a novel anti-depressant drug.

Paroxetine is a novel and selective neuronal 5-hydroxy-tryptamine uptake inhibitor with anti-depressant activity. Paroxetine was examined for its ability to induce adverse immunological reactions, either as a consequence of a specific immune response or by a direct or indirect effect on the immune system. Paroxetine did not react in vitro with protein amino or thiol groups, suggesting that it lacks the capacity to form potentially immunogenic hapten protein conjugates. No anti-paroxetine antibody was detected in plasma or serum samples from patients and rats following oral administration over prolonged periods, or from epicutaneously exposed guinea pigs, or from rabbits given paroxetine in Freund's adjuvant, suggesting that paroxetine does not have the capacity to elicit humoral immune responses. Guinea pigs epicutaneously exposed to paroxetine did not develop contact sensitivity, suggesting that it does not have the capacity to elicit cell-mediated immune responses. These results suggest that paroxetine lacks intrinsic immunogenicity. Anti-SRBC antibody plaque-forming cell responses in mice were unaffected by oral administration of paroxetine, and paroxetine had no significant effect on ex vivo and in vitro murine macrophage phagocytosis of opsonized SRBC or on ex vivo murine splenocyte mitogen responses, suggesting that paroxetine does not exert modulatory effects on the immune system or on macrophage function. These findings, together with the results of pre-clinical safety evaluation studies, suggest that paroxetine is unlikely to have immunotoxic effects.

Adult↗
PubMed1994

The effect of delta sleep-inducing peptide (DSIP) on the changes of body (core) temperature induced by serotonergic agonists in rats.

Hyperthermia induced by high doses of 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT) was diminished and hypothermia induced by low doses of 5-MeODMT was enhanced by pretreatment with delta sleep-inducing peptide (DSIP). Delta sleep-inducing peptide had an enhancing effect of hypothermia induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). This action of DSIP was completely inhibited by ICV injection of anti-DSIP. Pindolol prevented the enhancing action of DSIP on both 8-OH-DPAT- and apomorphine-induced hypothermia. It is suggested that the thermoregulatory action of DSIP is primarily exerted by a 5-HT1A mechanism in the rat.

Animals↗
PubMed1995

Arylamine and arylalkylamine N-acetyltransferases in retina, pineal gland, brain and liver of chicks: a comparative study.

Regulation of arylamine N-acetyltransferase (A-NAT) and arylalkylamine N-acetyltransferase (AA-NAT) was examined in retina, pineal gland, brain and liver of chicks. Enzyme activities were determined using as substrates p-phenetidine and procainamide for A-NAT, tryptamine and phenethylamine for AA-NAT. The activity of A-NAT in all tissues studied does not appear to be regulated by a light-dark cycle. On the other hand, AA-NAT showed distinct light-dark dependent changes (with high values at night) in the retina and pineal gland, but not in brain and liver. The nocturnal increase of retinal and pineal AA-NAT activity was prevented by cycloheximide; the drug did not affect A-NAT activity in these tissues. Treatment of light-adapted chicks with aminophylline significantly increased AA-NAT activity of the retina and pineal gland, without altering the enzyme activity in brain and liver. In these animals, the activity of A-NAT (procainamide) did not change in any tissue studied, whereas the enzyme activity measured using p-phenetidine as a substrate did decrease but only in the retina. A similar pattern of changes in retinal A-NAT and AA-NAT activities was observed after intraocular injection of d,b-cAMP. The rate of inactivation at 4 degrees C was significantly slower for AA-NAT than A-NAT. NATs from brain and liver displayed the highest and lowest, respectively, liability in the cold. The results indicate that the chick retina contains both A-NAT and AA-NAT. The two enzymes have distinct characteristics and the regulation of their activities is different. The retinal A-NAT is similar to A-NAT present in other tested tissues; however, AA-NAT can be induced at night only in the retina and pineal gland. It is suggested that there are two forms of retinal A-NAT, and that, under specified conditions, the activity of one form (A-NAT; p-phenetidine) may be regulated in an opposite manner to AA-NAT activity.

Analysis of Variance↗
PubMed1983

Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT).

In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.

Aged↗
PubMedDate not supplied

Involvement of free radicals in dementia of the Alzheimer type: a hypothesis.

We propose that increased formation of oxygen-derived free radicals, such as the superoxide and hydroxyl species, may be responsible for progressive neural degeneration in dementia of the Alzheimer type (DAT). Several processes increase free radical formation and some of them (e.g., brain trauma, aging) are risk factors for DAT. There is some evidence for increased free radical formation in Down's syndrome which is associated with development of DAT pathology. Free radicals alone may induce cell death by damaging lipids or proteins while reactions between free radicals and neurotransmitters may lead to formation of endogenous neurotoxin(s). Recently, we have demonstrated that partial oxidation of serotonin by exposure to hydroxyl radicals results in formation of a novel neurotoxin, tryptamine-4,5-dione. Elucidation of the role of free radicals in DAT could open new avenues to prevention and treatment of this disease.

Aging↗
PubMed1986

Biological profile of a bioactive aortic substance (BAS), released by vessel rings from indomethacin-treated rats.

The biological activity of a stable unknown material(s), generated by aortic rings (bioactive aortic substance = BAS) isolated from rats injected with a high dose of indomethacin, was explored on contractions of several smooth muscle preparations from normal rats and its effects compared with those elicited by prostacyclin (PGI2) or by 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha). The BAS evoked, as did PGI2 or 6-k-PGF1 alpha, positive inotropism in strips from rat stomach, ileum and urinary bladder, but failed to influence uterine contractions as did prostacyclin or its non-enzymatic metabolite. When tested in rat aortic strips both, PGI2 and the BAS produced relaxation, whereas 6-k-PGF1 alpha was not active. Moreover, lipid substances present in the incubates of aortic rings, were extracted and explored for effects on contractions of rat aortic strips and on arachidonate-evoked human platelet aggregation. These extracts were devoid of influence on both parameters. On the contrary, dried aqueous residues, after the lipid extraction of the supernatants of aortic ring incubates, exhibited human platelet antiaggregatory capacity as well as the ability to evoke positive and negative inotropism similar to those triggered by the BAS in different smooth muscle preparations. Experiments with BAS were also performed employing smooth muscle strips exposed to indomethacin, atropine, propranolol, phentolamine and cyproheptadine. The presence of these antagonists of several neuromodulators and of indomethacin failed to alter de BAS-induced inotropic capacity observed in controls. The findings suggest that the effects attributable to the BAS are not subserved by prostacyclin or other prostanoids, nor by acetylcholine, norepinephrine, histamine or 6-OH-tryptamine.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Photochemical mutagen formation from aerobically treated night-soil effluent and the contributive substances.

Effluents from a night-soil treatment plant, where night-soil was aerobically treated by an activated sludge process, were irradiated with a UV lamp excluding short wavelengths less than 300 nm as a model of exposure to sunlight and the mutagenicities of the ethylacetate extracts from the irradiated effluents were assayed using Salmonella typhimurium TA98. The extracts exhibited mutagenicity toward S. typhimurium TA98 in the absence of rat liver S9 fraction only when the effluents were fortified with nitrite ion (more than 6 ppm) by over aeration or by artificial addition of nitrite, indicating that a limiting factor for mutagen formation is nitrite ion concentration. Nine organic-N-containing compounds as models of the organic components in the effluent were also irradiated and direct-acting potent mutagens were found to be produced from such compounds having indole moiety as indole, oxindole, tryptophan and tryptamine.

Journal Article↗
PubMed1984

Analysis and the effects of some drugs on the metabolism of phenylethylamine and phenylacetic acid.

Phenylethylamine has been reliably measured using radioenzymatic, gas chromatographic, mass spectromatic and gas chromatographic - mass spectrometric methods. Phenylacetic acid has been measured using gas chromatographic and gas chromatographic-mass spectrometric methods. Phenylethylamine concentrations are increased primarily by phenylalanine, its amino acid precursor and by such monoamine oxidase inhibitors as L-deprenyl and pargyline. Phenylethylamine administration influences other neurotransmitters such as dopamine, norepinephrine and 5-hydroxytryptamine. It also effects the tyramines and possibly tryptamine.

Animals↗
PubMed1994

The trace amines and their acidic metabolites in depression--an overview.

1. Investigations of the role of the trace amines (phenylethylamine, tryptamine, m- and p-tyramine) and their acidic metabolites (phenylacetic, indoleacetic, m- and p-hydroxyphenylacetic acids) in depression are reviewed. 2. The evidence for the phenylethylamine hypothesis of depression is mixed. 3. Reduced phenylacetic acid levels in urine, plasma and CSF and changes in those levels during treatment with antidepressants show potential as state markers for depression. 4. Impaired p-tyramine conjugation following a tyramine challenge may be a good trait marker for depression.

Amines↗
PubMed1984

Changes of acetylcholine, catecholamines and amino acid in mice brain following treatment with Nuvacron and Furadan.

The effects of multiple intraperitoneal doses of Nuvacron (0.8 mg/kg) or Furadan (0.25 mg/kg) on the concentrations of brain neurotransmitters in mice were studied. The following were measured: acetylcholine, acetylcholinesterase, gamma-aminobutyric acid, epinephrine, norepinephrine, dopamine and 5-hydroxytryptamine. These pesticides caused a significant decrease in acetylcholinesterase activity and a significant increase in acetylcholine, gamma-amino-butyric acid, epinephrine, norepinephrine, dopamine and 5-hydroxy tryptamine concentrations. The increased concentrations of the neurotransmitters in mouse brain might be associated with CNS depressant action induced by the insecticides.

Acetylcholine↗
PubMed1979

Fast axonal transport in rat sciatic nerve. Inhibition by pineal indoles.

The effect of pineal indoles on fast axoplasmic transport of proteins in the sciatic nerve was examined in rats injected with [3H]leucine in the sixth lumbar dorsal root ganglion. Melatonin (350-1100 nmol) applied locally in the sciatic nerve impaired significantly axonal transport. At a 350-nmol dose all other indoles tested (i.e., 5-hydroxyindoleacetic acid, 5-methoxyindoleacetic acid, serotonin, N-acetylserotonin, tryptamine, 5-methoxytryptamine) were less potent than melatonin to impair fast axonal flow. Vinblastine injected either into the ganglion or in the sciatic nerve markedly inhibited axonal transport.

5-Methoxytryptamine↗
PubMed1982

Nociception is enhanced by the intrathecal injection of 5-methoxy-N,N-dimethyltryptamine in the rat.

The effect of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) at the spinal cord level on nociceptive reflexes was tested using the tail-flick assay in rats. 5-MeODMT was injected directly into the spinal subarachnoid space of conscious rats via a permanently indwelling intrathecal cannula. Administration of 100 micrograms/rat of 5-MeODMT into the thoracic region, using a 4 cm long cannula, reduced the average percent of control reaction time by 14%. The injection of the same dose of 5-MeODMT into the lumbosacral region, via an 8.6 cm long cannula, decreased the average percent of control reaction time by 25%. The ability of 5-MeODMT to mimic the facilitatory (hyperalgesic) effect on nociception of similar doses of tryptamine, in contrast to the antinociceptive (analgesic) effect of serotonin, suggests an interaction of 5-MeODMT with tryptaminergic rather than serotonergic receptors in the spinal cord.

Animals↗
PubMed1985

Beta-carboline analogues of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP): endogenous factors underlying idiopathic parkinsonism?

A remarkable structural similarity exists between the parkinsonian neurotoxin, N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), and 2-[N]-methyl-tetrahydro-beta-carboline (2M-THBC), a tryptamine-derived alkaloid which can be biosynthesized in brain. To explore whether the beta-carboline also has neurotoxic effects, owl monkeys were treated daily with MPTP or 2M-THBC. Acute behavioral similarities were seen, but 2M-THBC did not induce persistent parkinsonism, nor did it cause apparent loss of nigral cells. However, 2M-THBC resembled MPTP in reducing 3,4-dihydroxyphenylacetic acid levels in caudate and in altering levels of serotonin and 5-hydroxyindoleacetic acid in substantia nigra. These limited similarities should be considered in the light of relationships between neurotoxicity, MPTP versus 2M-THBC oxidation, and the chronicity of human Parkinson's disease. We suggest that N-methylated beta-carboline species, possibly accumulating during stress and aging, could well be causative factors in parkinsonism.

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