Pirlindole and dehydropirlindole protect rat cultured neuronal cells against oxidative stress-induced cell death through a mechanism unrelated to MAO-A inhibition.

It has been shown that the MAO (monoamine oxidase)-B inhibitor deprenyl (DPR, selegiline) protects some cell types against oxidative stress. By decreasing H(2)O(2) production, MAO-A inhibitors could also reduce oxidative stress. This study reports the effect of the MAO-A inhibitors, pirlindole (PIR), dehydropirlindole (DHP), brofaromine (BRO) and moclobemide (MCL) on primary-cultured brain cells exposed to iron-mediated toxicity. A comparison with trolox (TRO), a hydrosoluble vitamin-E analogue that protects against such an induced stress, was performed. Rat hippocampal or cortical cultured cells were exposed either to 2 microM FeSO(4) alone or in the presence of PIR, DHP, BRO, DPR, MCL or TRO. Cell survival (lactate-dehydrogenase measurements, 16 h incubation), intracellular peroxide production (DCF-fluorescence, 1 h incubation), lipoperoxidation (TBARS-fluorescence, 6 h incubation) and mitochondrial function (MTT-test, 16 h incubation) were assessed. PIR, DHP and TRO significantly protected cultures (P<0.05) against Fe(2+)-induced toxicity in a concentration-dependent manner. The EC(50s) of these compounds were 6, 12 and 19 microM, respectively, in hippocampal cells. For cortical cell cultures incubated in the presence of iron and PIR or DHP, EC(50s) were 5 and 6 microM respectively. All Hill coefficients were close to unity. BRO, MCL and DPR were not protective in any type of culture. The IC(50s) for the inhibition of MAO-A were 2, 2 and 0.2 microM for PIR, DHP and BRO, respectively. PIR, DHP and TRO, but not DPR, induced a significant decrease in both intracellular peroxide production and lipoperoxidation. They also improved mitochondrial function. These experiments show that PIR and DHP can protect hippocampal and cortical neurons against oxidative stress at pharmacologically relevant concentrations. This protective effect seems unrelated to inhibition of MAO-A, but possibly involves free radical scavenging.

Regional action of brofaromine on rat brain MAO-A and MAO-B.

1. Brofaromine (CGP 11,305 A) belongs to a new generation of monoamine oxidase (MAO) inhibitors. These compounds induce short, reversible and selective inhibition of brain MAO of type A. 2. The aim of this work is to study monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) activities of several rat brain regions after increasing doses of brofaromine. 3. Brofaromine inhibits MAO-A activities in a dose dependent manner in all brain regions examined. 4. The largest reduction was found in hippocampal formation, striatum and prefrontal cortex respectively. ID50 is 2 times lower in hippocampus than in remaining brain. 5. Brofaromine does not inhibit MAO-B activities in the different regions examined. 6. Brofaromine is a very selective inhibitor of rat brain MAO-A with a preferential action on telencephalic monoaminergic nerve terminals.

Comparative study of pirlindole, a selective RIMA, and its two enantiomers using biochemical and behavioural techniques.

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data.

Effect of moclobemide on rat brain monoamine oxidase A and B: comparison with harmaline and clorgyline.

1. Effects of moclobemide (12.5, 25 and 50 mg/kg), harmaline (10 mg/kg) and clorgyline (10 mg/kg) on monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) were examined ex vivo by a fluorometric method with tyramine (T) and phenylethylamine (PEA) as substrates. Six rat brain areas were dissected for this purpose. 2. Moclobemide had decreased MAO-A activity in all areas examined by a dose-dependent manner; the largest decrease was observed in tuberculum olfactorium and striatum. MAO-B activity after moclobemide had presented some dose-dependently inhibition (about 30 percent at a dose of 50 mg/kg). 3. Harmaline was more potent than moclobemide as MAO-A inhibitor but had left MAO-B activity unchanged. 4. Clorgyline was the most potent of the three drug tested for MAO-A inhibition. MAO-B activity was inhibited at the dose used in these experiments. 5. MAO-A inhibitory properties on tuberculum olfactorium and striatum could be of interest according to some animal models of depression.

[Psychopharmacology of GABA]. / Psychopharmacologie du GABA.

In this paper, different aspects of gabaergic neurotransmission are considered, with emphasis on gaba neurones distribution in brain as well as various drugs interferences on these neurones. GABA agonists direct or indirect such as respectively muscimol or progabide and benzodiazepines or sodium valproate show anticonvulsant properties. These data support the hypothesis of the gamma aminobutyric acid implication in several neuro-muscular disorders especially in epileptic syndrome.

Effect of diflunisal on the human plasma levels and on the urinary excretion of naproxen.

A double-blind placebo controlled crossover study was performed in twelve healthy volunteers receiving multiple doses of naproxen (250 mg b.i.d.) and diflunisal (250 mg b.i.d.) to study the effect of diflunisal co-administration on the naproxen levels in plasma and urine. The naproxen steady-state level was reached between the second and the third day. The peak plasma level appeared about 2 hr after drug administration and varied from 68 to 75 microgram/ml. This maximum was not modified by a simultaneous administration of diflunisal neither in its position nor in its intensity. Statistical analysis using a parametric method, did not reveal a significant influence of diflunisal on the plasma kinetics or on the urinary elimination of naproxen.

[Dopamine of the caudate nucleus in Perodictious potto, Macaca mulatta and Macaca fascicularis]. / Dopamine du noyau caudé chez Perodicticus potto, Macaca mulatta et Macaca fascicularis

The dopamine, dopac and tyrosinehydroxylase contents of the caudate nucleus in the prosimian Perodicticus potto and in the simii Macaca mulatta and M. fascicularis have been estimated. The results do not support the hypothesis according to which the sluggishness of the potto is somehow related to a low dopamine content of part of the extrapyramidal system as found in the Parkinson-syndrome.