Oxygen free radicals, melatonin, and aging.

The recognized peripheral and central biochemical, neuroendocrinological, behavioral, pharmacological, and clinical actions of melatonin are involved at different levels of an overall concept of the pathophysiology of aging. This conceptual approach combines the biochemistry of oxygen free radicals, the social behavior of the individual and the resulting cellular alterations. This has allowed us to propose antioxidant properties of melatonin that we have experimentally demonstrated.

Possible involvement of a gamma-hydroxybutyric acid receptor in startle disease.

Startle disease or hyperreflexia is an autosomal dominant neurological disorder, with a neonatal onset, characterized by muscular hypertonia and myoclonic jerks, exaggerated by the slightest stimulus. Low concentrations of free gamma-aminobutyric acid (GABA) have been found in the cerebrospinal fluid of two affected infants. The involvement of GABA or its receptors has been raised and the use of GABA-agonist drugs has been suggested.

Anxiolytic activity of melatonin in mice: involvement of benzodiazepine receptors.

The anxiolytic properties of melatonin are revealed by two behavioral studies. In a free exploratory situation, the holeboard test, melatonin decreased head-dip performance. In an unconditioned conflict test, the light/dark box choice situation, melatonin increased the time spent in the lit box as well as the number of transitions between the two compartments.

Antioxidant activity of melatonin in mice.

Melatonin (in gum tragacanth as solvent) was administered to mice in the dose range of 100 to 450 mg/kg intraperitoneally. It prevented the increase in plasma glucose resulting from pancreatic toxicity caused by the intravenous administration of alloxan at 40 mg/kg. This action of melatonin was significant and dose-dependent.

Carnitine action on neuromuscular disturbances in the fasting rat: potentiation by L-lysine.

L-Carnitine (oral route) significantly corrects the muscle hypocontractility and hypoexcitability induced in the rat after 5 consecutive days of fasting. This effect is interpreted on the basis of the dual role of L-carnitine as cofactor in the transport of long-chain fatty acids into the mitochondria and as a detoxifying agent of intracellular acyl-CoA. The activity of L-carnitine is increased with the concomitant administration (oral route) of an equimolar dose of L-lysine.

Variations of lipid profile in animals caused by adenosine analogs: N6 (amido-3-propyl) adenosine hydrochloride and (carboxamido-3-propylamino)-6-(triproprionyl) 2',3',5'beta (D-ribosyl)-9-purine.

N6-substituted adenosine analogues are powerful inhibitors of lipolysis in the adipose tissues of animals and humans, because of their agonist effect on A1 purine receptors. Using a model of hypertriglyceridemia provoked by intravenous injection of Triton WR 1339, we observed that Agr 529 [N6(amido-3-propyl)adenosine hydrochloride] at 2 mg.kg-1 intravenous in rabbits, and intraperitoneally and orally in rats led to a return of the levels of circulating triglycerides to normal values.

Protective effects of gamma-hydroxybutyrate on alloxan induced diabetes in mice.

Gamma-hydroxybutyrate (GHB) administered to mice prior to alloxan antagonizes its diabetogenic action in a dose dependent fashion and up to 96 hours after injection. Results are discussed on the basis of free radical formation by alloxan and of the metabolic property of GHB which is known to increase the rate of operation of the pentose phosphate pathway.

Chronic stress and memory: implication of the central cholinergic system.

Restraint stress for ten days (two times two hours daily) induces a hypersensitivity of the central cholinergic system, reflected by antagonism to amnesia induced by scopolamine at 0.1 mg/kg in a passive avoidance test and by hypersensitivity to the hypothermic effect of oxotremorine at 1 mg/kg. A restraint stress for 30 days, on the other hand, diminishes animal retention in the passive avoidance test and causes a hyposensitivity to oxotremorine-induced hypothermia, reflecting a hypoactivity of the central cholinergic system.

Changes in plasma catecholamine levels after the intraperitoneal and intracerebroventricular administration of adenosine analogues and of clonidine in conscious rats.

When an adenosine analogue, N6-(amido-3-propyl) adenosine hydrochloride (Agr 529) is administered systemically, it causes a substantial release of epinephrine (E) by the adrenal medulla with no change in plasma norepinephrine (NE) levels. Low doses of N6-R-phenylisopropyl adenosine (L-PIA), an agonist of adenosine A1 receptors, has no significant effect on plasma epinephrine levels, which are increased by high doses of the analogue. Low doses of 5'-N-ethylcarboxamido-adenosine (NECA), an agonist of adenosine A2 receptors, however, lead to increases.

Action of N6(amido-3-propyl) adenosine hydrochloride (Agr 529) on plasma corticosterone levels in rats.

N6(amido-3-propyl) adenosine (Agr 529) has central properties analogous to those of adenosine. It increases plasma corticosterone levels in rats as a function of dose and of time. A plateau is reached at the dose of 10 mg.

[New route of 2-N-(carboxypropylamino)-2-deoxy-D-glucopyranose synthesis].

A new route to 2-N-(carboxypropylamino)-2-deoxy-D-glucopyranose synthesis is reported, involving the Schiff-base derivative of beta-D-glucosamine with benzyl 4-oxobutyrate. Improvement in the synthesis of benzyl-4-oxobutyrate is also described. Biological compounds action was investigated by evaluating sedative and dopaminergic activities on male mice.

Brain tyrosine increases after treating with prodrugs: comparison with tyrosine.

After mice had been treated with L-tyrosine, O-phospho-L-tyrosine, L-tyrosine methyl ester or N-acetyl-L-tyrosine, tyrosine was assayed by HPLC coupled with fluorometric detection. O-Phospho-L-tyrosine behaved as a tyrosine prodrug after its hydrolysis by acid and alkaline phosphatases. After the intraperitoneal administration of O-phospho-L-tyrosine or the methyl ester, there was a substantial increase in bioavailability in terms of the effect of tyrosine.

[Action of PMA (phorbol myristate acetate), scopolamine, propranolol, and oxotremorine on memorization of an active or passive avoidance test].

The role of various second messengers in the learning and retention of a passive or active avoidance has been investigated in mice. Scopolamine at 3 mg/kg i.p.

[The inhibition of action. Interdisciplinary approach of its mechanisms and physiopathology].

The author recalls his group's work during the three past decades and how, starting from the study of traumatic states, he established the distinction between shock and stress, physiologically and biologically speaking. According to him, stress supposes a memory process, i.e.

Hepatic tyrosine aminotransferase inhibitor affects the bioavailability of exogenous tyrosine.

This study demonstrates the importance of controlling the activity of hepatic tyrosine aminotransferase when tyrosine is administered orally. The specific inhibition of this enzyme is proposed in the clinical use of tyrosine in syndromes related to deficient catecholaminergic transmission.

Effect of 3-(2-morpholinoethylamino)-4-methyl-6-phenyl pyridazine dihydrochloride (minaprine) on plasma cortisone levels of physostigmine treated rats.

3-(2- morpholinoethylamino )-4-methyl-6-phenyl pyridazine dihydrochloride (minaprine), has recognized clinical activity against inhibition of action. In rats, this substance antagonizes the increase of plasma corticosterone levels caused by physostigmine injection. The mechanism of this action is discussed.

Action of adenosine on energy metabolism and on glucose-6-phosphate dehydrogenase in rat brains.

The Warburg method was used to study the action of adenosine on several phases of rat cerebral cortex metabolism, using cortex slices or homogenates. In the presence of exogenous glucose in vitro, oxygen consumption and lactate production are not affected by adenosine in sections. In vivo, there is an increase of oxygen consumption and of lactate production but which are not significant.

Assay of cerebral catecholamines, serotonin and their metabolites in experimental hemorrhagic shock in rats.

Rats were subjected to standard conditions of hemorrhagic shock. Animals were sacrificed 5 minutes and two hours after reinjection of blood which had effused into a syringe. The extent of shock was determined by measuring the acid base balance of the serum.

Action of certain pharmacological associations on the level of cerebral biogenic amines and some metabolites in the curative treatment of hemorrhagic shock in rats.

Different associations of pharmacological agents were tested in the curative treatment of hemorrhagic shock, using as criteria the variations of cerebral biogenic amines (NE, DA, 5-HT) and some of their metabolites (DOPAC, HVA, 5-HIAA). These values were compared to those observed in controls two hours after the reinjection of effused blood. Prior work had led to the use of each component of these therapeutic associations and the reasons having suggested their association are summarized.