Irreversible Monoamine oxidase-B Inhibitor Research Articles

L-deprenyl-induced increase in IL-2 and NK cell activity accompanies restoration of noradrenergic nerve fibers in the spleens of old F344 rats

Previously, we have hypothesized a causal relationship between some measures of immunosenescence and the age-related decline in sympathetic noradrenergic (NA) nerve fibers in spleen and lymph nodes of F344 rats. In the present study, we investigated this interrelationship further by measuring NK cell activity, Con A-induced IL-2 production, norepinephrine (NE) concentration, and morphological localization of NA and neuropeptide-Y (NPY) nerve fibers in the spleens of old (21 months old) male F344 rats after 10 weeks of daily treatment with low doses of l-deprenyl, an irreversible monoamine oxidase-B inhibitor, followed by a 9-day wash-out period. NK cell activity and Con A-induced IL-2 production were increased in deprenyl-treated old rats in comparison to untreated and saline-treated old rats. Deprenyl treatment did not alter the percentage of CD5+ T-cells, but moderately increased the percentage of sIgM + B-cells in the spleens of old rats. In addition to changes in immune responses, NE content and the volume density of NA and NPY nerve fibers were partially augmented in the spleens of deprenyl-treated old rats. In a separate study, various concentrations of deprenyl were added in vitro to spleen cells from young and old F344 rats to examine the direct effects of the drug on Con A-induced IL-2 production. In contrast to in vivo treatment, in vitro addition of deprenyl did not alter the Con A-induced IL-2 production by splenocytes from old rats. Together, these results suggest that the ability of deprenyl to enhance certain immune responses are interlinked to the restoration of sympathetic NA and NPY nerve fibers in the spleens of old rats.

The effect of l-deprenyl, d-deprenyl and MDL72974 on mitochondrial respiration: a possible mechanism leading to an adaptive increase in superoxide dismutase activity

l-Deprenyl is an irreversible monoamine oxidase-B inhibitor with a complex pharmacological profile. For instance, l-deprenyl administration to rat and mice increases cytosolic CuZn- and mitochondrial Mn-superoxide dismutase activities in the striatum. CuZn- and Mn-superoxide dismutase are enzymes involved in defense against superoxide (O 2 ⋅) radicals. Hence, an increase in CuZn- and Mn-superoxide dismutase activities is suggestive of oxidative stress. The major intracellular site of O 2 ⋅ radicals formation is the mitochondrial respiratory chain. Several reports indicated that alterations in mitochondrial respiratory functions enhances O 2 ⋅ production. We observed that l-deprenyl induced a dose-dependent inhibition of oxygen (O 2) consumption (state 3) during ATP synthesis in presence of complex I (pyruvate and malate) and complex II (succinate) substrates in fresh mitochondrial preparations. d-Deprenyl produced a similar inhibitory profile whereas MDL72974, a selective monoamine oxidase-B inhibitor, was less effective. Administration of d-deprenyl or MDL72974 to mice resulted in an increase in both striatal CuZn- and -Mn-superoxide dismutase activities. Accordingly, we propose that the impairment of mitochondrial respiratory functions which stimulates O 2 ⋅ formation could modulate CuZn- and Mn-superoxide dismutase activities, through a mechanism that appears to be independent of monoamine oxidase-B inhibition.

Enantioselective gas chromatographic assay of 2-alkylamines using N-(trifluoroacetyl)prolyl derivatives and a chiral capillary column

The chromatographic properties of (R)-(+)-N-(trifluoroacetyl)prolyl and (S)-(-)-N-(trifluoroacetyl)prolyl derivatives on a chiral gas chromatography capillary column were assessed for the measurement of enantiomeric purities of 2-butylamine, 2-pentylamine, 2-hexylamine, 2-heptylamine and 2-octylamine and their N-methyl analogues, which are used as precursors in the synthesis of some selective, specific, irreversible monoamine oxidase-B inhibitors. Using a Chirasil-Val column it was possible to separate all four diastereomers of the primary amines, and three of the four isomers of the secondary amines. Quantitation of the enantiomers is facilitated even with enantiomerically impure reagent when compared to the use of an achiral phase.

Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo.

Acute inhibition of monoamine oxidase B (MAO-B) in the rat does not affect striatal dopamine (DA) metabolism, but chronic MAO-B inhibition with deprenyl has been reported to increase the release of striatal DA, as shown using in vitro techniques. To see whether chronic MAO-B inhibition also causes an increase in DA release in vivo, rats were treated for 21 days with either deprenyl (0.25 mg/kg), TVP-1012 [R(+)-N-propargyl-1-aminoindan mesylate; 0.05 mg/kg], an irreversible inhibitor of MAO-B that is not metabolized to amphetamines, clorgyline (0.2 mg/kg), or saline (all doses once daily by subcutaneous injection). Concentric 4-mm-long microdialysis probes were implanted in the left striatum under pentobarbital/chloral hydrate anesthesia on day 21, and microdialysate DA, 3,4, dihydroxyacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenyl acetic acid (HVA) were determined in the conscious animals on day 22. Baseline levels of DA were as follows: control, 0.34 +/- 0.04 (n = 13); deprenyl, 0.88 +/- 0.10 (n = 8, p < 0.01); TVP-1012, 0.94 +/- 0.20 (n = 7, p < 0.01); clorgyline, 0.90 +/- 0.12 (n = 7, p < 0.01) pmol/20 min. Levels of DOPAC and HVA were reduced only in the clorgyline-treated group. The incremental release of DA induced by depolarizing concentration of K+ (100 mM bolus of KCl in perfusate) was significantly greater in clorgyline- and deprenyl-treated rats and elevated (nonsignificantly) in TVP-1012-treated rats. Chronic treatment with the MAO-B inhibitors reduced striatal MAO-B activity by 90%, with 15% (TVP-1012) or 40% (deprenyl) inhibition of MAO-A. Clorgyline inhibited MAO-A by 95%, with 30% inhibition of MAO-B. A single dose of deprenyl (0.25 mg/kg, 24 h before microdialysis) had no significant effect on striatal efflux of DA. The results show that DA metabolism was reduced only by clorgyline, whereas neuronal release of DA was enhanced by both MAO-A and MAO-B inhibitors on chronic administration. The enhanced DA release by chronic MAO-B inhibition does not appear to be dependent on production of amphetamine-like metabolites of the inhibitor. Possible mechanisms for the release-enhancing effect of the MAO-B inhibitors include elevation in levels of endogenous beta-phenylethylamine, or an inhibition of DA reuptake, which develops only on chronic administration, because both deprenyl and TVP-1012 have only very weak effects on amine uptake in acute experiments.

In vitro effects on monoamine uptake and release by the reversible monoamine oxidase-B inhibitors Lazabemide and N-(2-aminoethyl)- p-chlorobenzamide: A comparison with l-deprenyl

To investigate whether the reversible monoamine oxidase-B (MAO-B) inhibitors lazabemide and Ro 16–6491 have any additional effect on monoamine uptake and release, in vitro experiments were performed on rat forebrain synaptosomes and blood platelets. The effects of the two drugs were compared with those of l-deprenyl, the well-known irreversible MAO-B inhibitor which is reported to affect amine uptake. Both lazabemide and Ro 16–6491 behaved as weak inhibitors of [ 3H]monoamine uptake by synaptosomes, with a similar rank order of potency for amine uptake inhibition (noradrenaline (NA) ⩾ 5-hydroxytryptamine (5 HT) dopamine (DA)). The ic 50 values for lazabemide and Ro 16–6491, respectively, were: 86 μM and 90 μM for NA uptake; 123 μM and 90 μM for 5HT uptake; > 500 μM and > 1000 μM for DA uptake. l-Deprenyl (rank order of inhibitory potency: NA > DA > 5 HT) was four to 10 times more potent than either compound in inhibiting [ 3H]catecholamine uptake (IC 50 = NA 23 μM, DA 109 μM), and two to three times less potent in inhibiting 5 HT uptake ( ic 50 233 μM). Lazabemide and Ro 16–6491 also differed from l-deprenyl in their ability to induce release of endogenous monoamines from synaptosomes. Thus, Ro 16–6491 (500 μM) induced a greater 5 HT release than did l-deprenyl, but was less effective than l-deprenyl in releasing DA. On the contrary, lazabemide was almost completely inactive on either 5 HT and DA release. The differential effect of the three MAO-B inhibitors on synaptosome 5 HT uptake and release was confirmed by [ 14C]5HT uptake and liberation experiments with isolated rat platelets. The data indicate that the reversible MAO-B inhibitors lazabemide and Ro 16–6491 at relatively high concentrations possess amine uptake-inhibiting properties. With regard to the effects examined, lazabemide markedly differs from l-deprenyl since it does not interfere with DA uptake nor induce amine release from synaptosomes.

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia.

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP+), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP+ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 microM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 microM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 microM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.

Monoamines and related metabolite levels in the cerebrospinal fluid of patients with dementia of Alzheimer type. Influence of treatment with L-deprenyl

An impairment of the monoaminergic systems has frequently been reported for Alzheimer's disease (AD) as well as an overactivity of cerebral monoamineoxidase B (MAO-B). L-deprenyl (LD), a selective and irreversible MAO-B inhibitor, has recently been proposed for the treatment of AD. The cerebrospinal fluid (CSF) levels of norepinephrine (NE), epinephrine (E), dopamine (DA), 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were studied in 14 patients suffering from dementia of Alzheimer type (DAT) and in 14 controls. A three-month double-blind study comparing LD with placebo was carried out, in the DAT group, and the influence of the treatment on neurotransmitter levels and cognitive performance was evaluated. The basal study revealed a significant reduction in CSF NE and HVA levels in DAT patients when compared with controls; the treatment with LD determined a significant decrease in HVA levels only and, as to neuropsychological investigation, a global amelioration of cognitive performances.