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Journal ArticleDOI

Effect of selective monoamine oxidase inhibitors on rat pineal melatonin synthesis in vitro.

01 Jan 1988-Journal of Pineal Research (Blackwell Publishing Ltd)-Vol. 5, Iss: 1, pp 99-109
TL;DR: Freshly cultured pineal glands respond to the monoamine oxidase A (MAO A) inhibitor clorgyline and to high concentrations of the MAO B inhibitor, deprenyl, with an increase in serotonin N‐acetyltransferase activity and N-acetylated indoles and a fall in 5‐hydroxylated serotonin degradation products.
Abstract: Freshly cultured pineal glands respond to the monoamine oxidase A (MAO A) inhibitor clorgyline and to high concentrations of the MAO B inhibitor, deprenyl, with an increase in serotonin N-acetyltransferase activity and N-acetylated indoles and a fall in 5-hydroxylated serotonin degradation products. Glands cultured for 48 hours before challenge respond less. Response is absent in glands cultured for 72 hours and in glands from ganglionectomized animals cultured for 48 hours before challenge. These data are consistent with the hypothesis that these MAO inhibitors stimulate melatonin synthesis by protecting norepinephrine from degradation.
Citations
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Journal ArticleDOI
TL;DR: It is hypothesize that the alternate melatonin synthetic pathway may be more important in certain organisms and under certain conditions, and evidence strongly supports that this alternate pathway prevails in some plants, bacteria, and, perhaps, yeast and may also occur in animals.
Abstract: Melatonin is a phylogenetically ancient molecule. It is ubiquitously present in almost all organisms from primitive photosynthetic bacteria to humans. Its original primary function is presumable to be that of an antioxidant with other functions of this molecule having been acquired during evolution. The synthetic pathway of melatonin in vertebrates has been extensively studied. It is common knowledge that serotonin is acetylated to form N-acetylserotonin by arylalkylamine N-acetyltransferase (AANAT) or arylamine N-acetyltransferase (SNAT or NAT) and N-acetylserotonin is, subsequently, methylated to melatonin by N-acetylserotonin O-methyltransferase (ASMT; also known as hydroxyindole-O-methyltransferase, HIOMT). This is referred to as a classic melatonin synthetic pathway. Based on new evidence, we feel that this classic melatonin pathway is not generally the prevailing route of melatonin production. An alternate pathway is known to exist, in which serotonin is first O-methylated to 5-methoxytryptamine (5-MT) and, thereafter, 5-MT is N-acetylated to melatonin. Here, we hypothesize that the alternate melatonin synthetic pathway may be more important in certain organisms and under certain conditions. Evidence strongly supports that this alternate pathway prevails in some plants, bacteria, and, perhaps, yeast and may also occur in animals.

191 citations

Book ChapterDOI
TL;DR: In subjects with Parkinson's disease the MAO-B inhibitor L-deprenyl exerts a L-dopa-sparing effect, prolongs L- dopa action and seems to have a favorable influence regarding on-off disabilities.
Abstract: The development of monoamine oxidase (MAO) inhibitors has followed a winding path. At the origin was the finding of E. A. Zeller that iproniazid, a hydrazine derivative designed to improve the tuberculostatic action of isoniazid, caused potent inhibition of MAO in vitro and in vivo. The inhibitor also exerted in vivo activity in the brain, subsequent pharmacological research indicating that this inhibition led to changes of cerebral functions [1]. Although the drug had no overt behavioral effects in animals when given alone, it modified the action of reserpine, one of the first modern psychotropic drugs. Thus, administration of iproniazid prior to reserpine unexpectedly antagonized the decreases in locomotor activity and in 5-hydroxy-tryptamine (5 HT) levels induced by reserpine in the brain, the animals sometimes even showing locomotor stimulation [1]. Since one serious side effect of reserpine in man was known to be mental depression, the antagonism of reserpine by iproniazid hinted at the possibility that this drug might be of use in the treatment of mood disorders. However, the actual breakthrough for the development of iproniazid as an antidepressant came from clinical observations. Various investigators had reported psychostimulant side effects of the MAO inhibitor in patients with tuberculosis and other chronic diseases.

175 citations

Journal ArticleDOI
TL;DR: This mini-review focuses on the studies of late Prof. IP Lapin and his research team on the role of methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depression and action mechanisms of antidepressant effect.
Abstract: This mini-review focuses on the studies of late Prof. IP Lapin (1903 - 2012) and his research team on the role of methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depression and action mechanisms of antidepressant effect. In the late 60s of the last century Prof. IP Lapin suggested that "intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component" while "activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect". The cause of serotonin deficiency in depression was attributed to the shunt of TRP "metabolism away from serotonin production towards KYN production" due to cortisol-induced activation of liver enzyme, tryptophan 2,3- dioxygenase, the rate-limiting enzyme of TRP - KYN pathway. Prof. Lapin suggested and discovered that KYN and its metabolites affect brain functions, and proposed the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect (kynurenine hypothesis). Further research suggested the antidepressant and cognition- enhancing effects of post-serotonin metabolite, N-acetylserotonin (NAS), an agonist to tyrosine kinase B (TrkB) receptor; and link between depression and chronic inflammation-associated disorders (e.g., insulin resistance, hepatitis C virus) via inflammation-induced activation of indoleamine 2,3- dioxygenase, brain located rate-limiting enzyme of TRY - KYN metabolism. NAS and kynurenines might be the targets for prevention and treatment of depression and associated conditions.

134 citations

Journal ArticleDOI
TL;DR: The results indicate that the IFn-gamma-induced NAT suppression requires the integrity of the sympathetic nerve terminals and the IFN-gamMA-induced enhancement of melatonin production is accomplished through its direct action on pinealocytes.

28 citations

References
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Journal ArticleDOI
TL;DR: The hypothesis that in the enzyme prepared, the MAO is a binary system of enzymes each of which has a detectably different sensitivity to this particular inhibitor, is put forward and evidence after dialysis supports this hypothesis.

1,557 citations

Journal ArticleDOI
TL;DR: Hospitalized bipolar and unipolar endogenously depressed patients who showed an antidepressant response to the monoamine oxidase (MAO) inhibitor, tranylcypromine sulfate, relapsed when relatively small doses of parachlorophenylalanine (PCPA) were added for brief periods, suggesting serotonergic mechanisms are likely involved in the antidepressant effects of both the tricyclic drugs and MAO inhibitors in man.
Abstract: • Hospitalized bipolar and unipolar endogenously depressed patients who showed an antidepressant response to the monoamine oxidase (MAO) inhibitor, tranylcypromine sulfate, relapsed (ie, depression returned) when relatively small doses of parachlorophenylalanine (PCPA) were added for brief periods. Considered together with our findings that PCPA similarly reversed the antidepressant effects of the tricyclic drug, imipramine hydrochloride, implications are (1) serotonergic mechanisms are likely involved in the antidepressant effects of both the tricyclic drugs and MAO inhibitors in man and (2) this indolamine may also play a role in the endogenous clinical state of depression.

266 citations

Journal ArticleDOI
TL;DR: It is established that norepinephrine acting through alpha- and beta-adrenergic receptors stimulates rat pineal N-acetyltransferase activity and, as a result, the production of melatonin, indicating that the widely held belief that melatonin production is regulated exclusively by a postsynaptic beta- adrenergic mechanism must be revised.
Abstract: The role played by postsynaptic alpha-adrenergic receptors in the stimulation of pineal N-acetyltransferase (EC 2.3.1.5) and [3H]melatonin production was investigated in the rat. In vivo studies indicated that phenylephrine, an alpha-adrenergic agonist, potentiated and prolonged the effects of isoproterenol, a beta-adrenergic agonist. Similar observations were made in organ culture with glands devoid of functional nerve endings. In addition, a combination of 1 microM prazosin, an alpha 1-adrenergic blocking agent, and 1 microM propranolol, a beta-adrenergic blocking agent, was many times more potent then either agent alone in blocking the stimulatory effects of norepinephrine on N-acetyltransferase activity and [3H]melatonin production. These findings establish that norepinephrine acting through alpha- and beta-adrenergic receptors stimulates rat pineal N-acetyltransferase activity and, as a result, the production of melatonin. Apparently, beta-adrenergic activation is an absolute requirement, and an alpha-adrenergic receptor mechanism potentiates beta-adrenergic activation. These findings are significant because they demonstrate alpha-adrenergic potentiation of beta-adrenergic effects. In addition, they indicate that the widely held belief that melatonin production is regulated exclusively by a postsynaptic beta-adrenergic mechanism must be revised.

257 citations

Journal ArticleDOI
TL;DR: When rat pineal organ is denervated by ganglionectomy, beta-(3,4-dihydroxyphenyl)-L-alanine induces much more serotonin N-acetyltransferase than in the innervated gland, which appears to be due to changes of the postsynaptic site, probably the beta-adrenergic receptor on the pineal cell.
Abstract: Activity of serotonin N-acetyltransferase (EC 2.3.1.5) in rat pineal organ is rapidly and markedly elevated in vivo after administration of β-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), norepinephrine, epinephrine, isoproterenol, monoamine oxidase inhibitors, or theophylline. Serotonin or 5-hydroxytryptophan has no effect on the increase in activity of this enzyme. Inhibitors of protein synthesis or propranolol, a β-adrenergic blocking agent completely inhibit(s) the increase in activity of serotonin N-acetyltransferase induced by drugs, indicating that new enzyme molecules are formed via stimulation of β-receptors of pineal cells and adenosine 3′:5′-cyclic monophosphate. When rat pineal organ is denervated by ganglionectomy, β-(3,4-dihydroxyphenyl)-L-alanine induces much more serotonin N-acetyltransferase than in the innervated gland. This superinduction by denervation appears to be due to changes of the postsynaptic site, probably the β-adrenergic receptor on the pineal cell.

150 citations