Biomedical subjects

G F Oxenkrug

Publications and source records attributed to G F Oxenkrug.

At least 19 recordsLinked to original sources

PubMed1999

Antidepressive and antihypertensive effects of MAO-A inhibition: role of N-acetylserotonin. A review.

Acute administration of irreversible and reversible selective MAO-A inhibitors and high doses (or chronic administration of low doses) of relatively selective MAO-B inhibitors (but not of highly selective MAO-B inhibitors) suppressed MAO-A activity and stimulated N-acetylation of pineal serotonin into N-acetylserotonin, the immediate precursor of melatonin. Consequent increase of melatonin occurs only in > 21-days-old rats. The effect is strain (spontaneously hypertensive rats > Fisher344N > Wistar Kyoto > Sprague-Dawley) and gender (male > female) dependent. N-acetylserotonin increase after clorgyline was weaker in the light-primed aged (or young animals with lesioned suprachiasmatic nuclei) than in young intact or sham-operated rats. N-acetylserotonin increase after MAO-A inhibitors might mediate their antidepressive (N-acetylserotonin and melatonin exerted antidepressant-like activity in the mouse tail-suspension and frog tests) and antihypertensive effects (N-acetylserotonin, but not melatonin, decreased blood pressure in spontaneously hypertensive rats).

Animals↗

PubMed1998

Clorgyline effect on pineal melatonin biosynthesis in rats with lesioned suprachiasmatic nuclei.

We have reported that clorgyline-induced stimulation of pineal melatonin biosynthesis could be augmented by the exposure to 24h of constant light in young but not in aged rats. Aging is associated with the declined integrity of the suprachiasmatic nuclei (SCN), the major station of the light signal passage from the retina to the pineal gland. The present study aimed to investigate whether SCN integrity is essential for clorgyline effects on pineal melatonin biosynthesis in light-primed rats. Clorgyline (2.5 mg/kg, s.c.) was administered to sham-operated and SCN-lesioned Sprague-Dawley rats kept under regular light/dark cycle or exposed to 24h of constant light. Pineal melatonin and related indoles were evaluated by HPLC-fluorimetric procedure. Clorgyline stimulated pineal melatonin biosynthesis in both SCN-lesioned and sham-operated rats kept under regular light/dark cycle. Exposure to constant light (for 24h) augmented clorgyline-induced stimulation of melatonin biosynthesis in sham-operated rats, but not in SCN-lesioned animals. The obtained results suggest that decline in SCN activity (e.g., age-associated) might contribute to previously reported attenuation of clorgyline-induced stimulation of melatonin biosynthesis in light-primed aged rats.

Animals↗

PubMed1998

The effect of MAO-A inhibition and cold-immobilization stress on N-acetylserotonin and melatonin in SHR and WKY rats.

Selective monoamine oxidase (MAO) A inhibitors and cold-immobilization stress (which increases the production of the endogenous MAO-A inhibitor, tribulin) stimulate rat pineal melatonin biosynthesis in Sprague-Dawley and Fisher 344N rats. Considering the hyperactive sympathetic response of the hypertensive rats, it was interesting to compare the effect of clorgyline and cold-immobilization stress on pineal melatonin and related indoles levels in SHR and WKY rats (HPLC-fluorimetric method). Clorgyline (0.5 mg/kg and 1.5 mg/kg, sc) induced a higher elevation of pineal melatonin and N-acetylserotonin (NAS) in SHR than in WKY rats. Cold immobilization stress resulted in lower serotonin, and higher NAS levels in SHR than in WKY rats with similar elevations in melatonin levels. Our results suggest increased serotonin conversion into NAS and decreased NAS conversion into melatonin with decreased production of tribulin in SHR in comparison with WKY rats.

Animals↗

PubMed1998

Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenetetrazole in mice.

Melatonin was tested in an ongoing attempt to find the endogenous antagonists of quinolinic acid, an endogenous convulsant. Among a great number of metabolites that have been tried before, only a few were found (cerulein and quinaldic acid in mice and kynurenic acid in rats). In SHR (bred from Swiss) male mice, intracerebroventricular (i.c.v.) pretreatment with melatonin (1.25-10.0 microg) attenuated (in the descending order of potency) the convulsant effect of i.c.v. administered kainate, quinolinate, glutamate, N-methyl-D-aspartate, and pentylenetetrazole. Melatonin was ineffective against i.p. administered pentylenetetrazole. Systemically (intraperitoneal, i.p.) administered melatonin (12.5-100.0 mg/kg) attenuated the convulsant effect of quinolinate, while the action of other convulsants used remained unaltered. It is suggested that melatonin could be tried against grand mal seizures in epileptic patients.

Animals↗

PubMed1994

Clorgyline effect on pineal melatonin biosynthesis in adrenalectomized rats pretreated with 6-hydroxydopamine.

The response to administration of the specific monoamine oxidase A (MAO-A) blocker clorgyline was investigated in adult male Sprague-Dawley rats which were adrenalectomized four days prior to treatment or were additionally sympathectomized as newborns by injection of 6-hydroxydopamine. In both groups, the contents of pineal indoles melatonin and N-acetylserotonin were augmented, and the contents of 5-hydroxyindoleacetic acid and 5-hydroxyindoletryptophol decreased 90 min following clorgyline injections when compared to rats receiving saline. The observed responses were less pronounced in rats both adrenalectomized and sympathectomized. The results are in line with the hypothesis that preservation from oxidation of both MAO-A substrates, noradrenaline and serotonin, upon clorgyline administration contributes to the observed increase in melatonin biosynthesis thought to be associated with the anti-depressant effects of MAO inhibition.

Adrenalectomy↗

PubMed1994

Synergistic sedative effect of selective MAO-A, but not MAO-B, inhibitors and melatonin in frogs.

Total suppression of righting reflex in frogs (Rana pipiens, 25-35 mg b.w.) was observed after combined administration of melatonin (12.5 mg/kg) and selective inhibitors of MAO-A: clorgyline (2.5 mg/kg) and moclobemide (50 mg/kg) but not MAO-B: selegiline (25 mg/kg) and Ro-19-6327 (50 mg/kg). None of these drugs alone affected the righting reflex. Clorgyline and selegiline selectively inhibited brain MAO-A and MAO-B activity (by more than 90%), resp. Frogs might represent a convenient model to study the selective MAO-A and B type inhibitors since they provide the opportunity to correlate behaviour and biochemical changes induced by MAO inhibitors.

Animals↗

PubMed1994

Clorgyline effect on pineal melatonin biosynthesis in Roman high- and low-avoidance rats.

Pineal melatonin and related indoles levels were higher in Roman high- than in Roman low-avoidance rats, while 5-HIAA/5-HT ratio, as an index of MAO activity was higher in low- than in high-avoidance rats. Clorgyline stimulated pineal melatonin biosynthesis in both lines of rats. However, melatonin and N-acetylserotonin levels remained higher and 5-HIAA levels remained lower in the high avoidance rats treated with low dose (0.5 mg/kg) while treatment with 1.0 mg/kg of clorgyline eliminated the differences in melatonin production between high- and low-avoidance rats.

Animals↗

PubMed1994

The effect of 6-months l-deprenyl administration on pineal MAO-A and MAO-B activity and on the content of melatonin and related indoles in aged female Fisher 344N rats.

Six months of administration of the selective MAO-B inhibitor, selegiline (l-deprenyl 0.25 mg/kg, s.c.) to aged female Fisher 344N rats suppressed MAO-A as well as MAO-B activity and increased serotonin (substrate for melatonin biosynthesis) and N-acetylserotonin (immediate melatonin precursor) levels in pineal glands taken from the animals during the night. Daytime values were unchanged by the treatment. The data suggest that stimulation of pineal melatonin biosynthesis might be one of the consequences of MAO-A inhibition contributing to life span prolongation induced by chronic selegiline treatment.

Aging↗

PubMed1994

Chronopharmacological study of moclobemide effect on the rat pineal melatonin biosynthesis.

The chronopharmacological hypothesis of the mechanism of the antidepressant effect of MAO-A inhibitors predicts that clinical efficacy depends upon the time of the day at which the drugs are administered. In the present study moclobemide (10 mg/kg, s.c.) injected at the end of the light phase advanced the onset of the nighttime increase of the rat pineal melatonin biosynthesis while the same dose of drug injected at the end of the dark phase delayed the daytime decrease of melatonin biosynthesis. The results obtained suggest that the timing of MAO-A inhibitor administration should be considered in clinical practice.

Animals↗

PubMed1994

The acute effect of the bioprecursor of the selective brain MAO-A inhibitor, MDL 72392, on rat pineal melatonin biosynthesis.

The bioprecursor amino acid MDL 72394 is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392, an irreversible selective MAO-A inhibitor. Pretreatment with the AADC inhibitor carbidopa, which does not penetrate the brain-blood barrier, prevents the liberation of the MAO-A inhibitor outside the brain and results in exclusive inhibition of brain MAO-A. We found that systemic administration of MDL 72394 (0.5 mg/kg, i.p.) stimulated rat pineal melatonin biosynthesis. Carbidopa, in a dose-dependent manner, attenuated or completely prevented MDL-induced stimulation of melatonin biosynthesis in the pineal gland located outside the blood-brain-barrier.

Animals↗

PubMed1994

Chronic effect of the irreversible and reversible selective MAO-A inhibitors on rat pineal melatonin biosynthesis.

Acute administration of the irreversible MAO-A inhibitor, clorgyline (2.0 mg/kg, s.c.) and the reversible MAO-A inhibitor, moclobemide (10 mg/kg, s.c.), increased rat pineal melatonin and related indoles content (HPLC-fluorimetric method). Chronic (21 days) administration of clorgyline attenuated the acute effect of clorgyline on pineal melatonin biosynthesis. The acute effect of moclobemide on melatonin biosynthesis was not affected by chronic moclobemide administration. The observed difference in the chronic effects of irreversible and reversible selective MAO-A inhibitors on melatonin biosynthesis could have clinical implications.

Animals↗

PubMed1994

Calcium, calcification, and melatonin biosynthesis in the human pineal gland: a postmortem study into age-related factors.

It is believed that pineal calcification may be age-associated and that the well-demonstrated age-related decline in melatonin biosynthesis may be an expression of an alteration in calcium homeostasis in the pinealocyte. Prior correlations of melatonin to calcium deposition and age were made on the basis of radiological or semiquantitative analysis. In this postmortem study of 33 subjects (age range 3 months to 65 years) calcium deposits measured by atomic absorption spectrometry correlated positively with age in day and night samples (day: r = 0.56, P < 0.05; night: r = 0.818, P < 0.001). Nighttime (2200 h to 0800 h) pineal melatonin content (HPLC fluorometry) was higher than daytime melatonin levels (nighttime 3.80 +/- 0.3 vs. daytime 0.85 +/- 0.4 ng/mg protein). Nighttime calcium levels in the supernatant correlated negatively with melatonin content (r = -0.59, P < 0.05).

Adolescent↗

PubMed1994

Stimulation of rat pineal melatonin biosynthesis by N-acetylserotonin.

Rat pineal content of melatonin and related indoles (HPLC-fluorimetric procedure) was evaluated after injections of N-acetylserotonin, the immediate precursor of melatonin. The increase of melatonin and NAS but of no other indoles was observed after daytime (but not after nighttime) NAS administration. NAS-induced stimulation of melatonin biosynthesis was dose- and time-dependent. Maximum pineal melatonin levels after NAS injections were similar to physiological night time peak of melatonin levels. It is suggested that NAS-induced stimulation of pineal melatonin biosynthesis might be used as the physiological way of pineal gland stimulation for diagnostic and therapeutic purposes.

Animals↗

PubMed1991

The response of the pineal melatonin biosynthesis to the selective MAO-A inhibitor, clorgyline, in young and middle-aged rats.

1. Clorgyline increased pineal melatonin and N-acetylserotonin (NAS) and decreased 5-hydroxyindoleacetic acid (5-HIAA) content in 3 and 12 months of age male Sprague-Dawley rats kept under 12:12 h light: dark schedule. Exposure to light for 24 h before clorgyline administration resulted in additional elevation of NAS and melatonin. NAS and melatonin levels after clorgyline injections were significantly higher while 5-HIAA levels were significantly lower in young than in middle-aged rats. 2. The 5-HIAA/5-HT ratio (index of monoamine oxidase activity) was higher in middle-aged than in young rats suggesting the lesser degree of clorgyline-induced inhibition of MAO-A in old than in young rats. 3. It is suggested that melatonin response to a single dose of the selective MAO-A inhibitor might be used for the assessment of the aging changes of the rat (and human) pineals.

Aging↗

PubMed1991

Effect of ageing on melatonin synthesis induced by 5-hydroxytryptophan and constant light in rats.

1. This paper describes the effect of the serotonin precursor 5-hydroxytryptophan (5-HTP) on pineal melatonin synthesis young and old rats. 2. 5-HTP itself increased pineal melatonin levels in old rats but did not change melatonin concentrations in young rats kept under 12 hr/12 hr light/dark conditions. 3. After continuous exposure to light for 72 hrs, 5-HTP induced a significant increase in melatonin levels in young rats but did not change the 5-HTP effect on melatonin in old animals. 4. These results are discussed in consideration of previous reports of altered beta-receptor up-regulation by light in old animals, and suggest that the age-related decrease in melatonin synthesis is not entirely related to changes of the enzymatic machine for melatonin synthesis.

5-Hydroxytryptophan↗

PubMed1991

The effects of benzodiazepines on basal and isoproterenol-stimulated N-acetyltransferase activity by the rat pineal gland, in vivo and in vitro.

The present study examined the effects of "peripheral," "central," and "mixed" benzodiazepine agonists and antagonists on the nocturnal rise in rat pineal NAT activity in vivo and the isoproterenol-stimulated NAT activity of pineals in organ culture. Administration of the central agonist clonazepam or the mixed agonist-antagonist diazepam, 4 hr after dark, at a dose of 25 mg/kg each, inhibited nocturnally elevated NAT 20 min later, while this same dose of the peripheral agonist RO 54864 elevated NAT activity. In a second study these agents were administered in vivo 1 hr before dark, at a dose of 3, 10, or 25 mg/kg i.p. and tested 4 hr after dark for in vitro rat pineal NAT activity. None of these agents affected NAT activity at the 3- or 10-mg/kg dose, but RO 54864 25 mg/kg did induce elevated activity. In a third study, all of these agents prolonged the time period for NAT induction by isoproterenol in rat pineals cultured for 48 hr before stimulation. The data suggests that benzodiazepine stimulation of NAT activity in vitro is not specific to "central" or "peripheral" benzodiazepine receptors and that inhibition of melatonin production in vivo occurs either at some step before NAT induction or is involved with the inhibition of pineal HIOMT activity.

Analysis of Variance↗

PubMed1990

Does moclobemide stimulate melatonin synthesis as the other selective MAO-A inhibitors do?

It has been reported that selective MAO-A inhibitors, clorgyline and brofaromine, but not the MAO-B inhibitors, deprenyl and pargyline, stimulated rat pineal melatonin synthesis in humans and animals. Recent studies, however, found no effect of moclobemide, a selective MAO-A inhibitor, on human plasma melatonin levels. Present study found that in vitro moclobemide produced very weak stimulation of rat pineal NAT activity. However, in vivo moclobemide induced a significant increase of rat pineal NAS and melatonin content, and a dramatic decrease of 5-HIAA content (HPLC-fluorimetric procedure). Moclobemide's effect on melatonin and related indoles could be detected as early as 30 min after the injection and lasted, at least, for 2 h. The possible reasons for discrepancies between human and animal data are discussed.

Acetyltransferases↗

PubMed1990

Effect of cocaine on rat pineal melatonin synthesis in vivo and in vitro.

Moderate concentrations (10 microM) of cocaine increased melatonin content and N-acetylserotonin and serotonin-N-acetyltransferase activity in rat pineal glands freshly placed in organ culture. Pineals cultured for 48 hours or taken from ganglionectomized animals did not respond to cocaine. Both procedures markedly reduced pineal noradrenalin (NA). Cocaine (5, 10, 20 mg/kg) given to adult intact rats stimulated pineal melatonin synthesis but only in animals exposed to constant light for 24 hours. Pineal denervation and/or adrenal demedullation neither completely eliminated NA from blood nor prevented cocaine-induced stimulation of melatonin synthesis in these light-primed animals.

Animals↗