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The Effects of Phenelzine and Other Monoamine Oxidase Inhibitor

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The Effects of Phenelzine and Other Monoamine Oxidase Inhibitor British Journal of Phammcology (1995) 114. 837-845 B 1995 Stockton Press All rights reserved 0007-1188/95 $9.00 The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver 12 imidazoline-preferring receptors Regina Alemany, Gabriel Olmos & 'Jesu's A. Garcia-Sevilla Laboratory of Neuropharmacology, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07071 Palma de Mallorca, Spain 1 The binding of [3H]-idazoxan in the presence of 106 M (-)-adrenaline was used to quantitate 12 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irre- versible and reversible monoamine oxidase (MAO) inhibitors. 2 Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-', i.p.), isocarboxazid (10 mg kg-', i.p.), clorgyline (3 mg kg-', i.p.) and tranylcypromine (10mg kg-', i.p.) markedly decreased (21-71%) the density of 12 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-', i.p.) or chlordimeform (10 mg kg-', i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-', i.p.) did not alter the density of 12 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3 In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform dis- placed the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. Phenelzine, 3-phenylpropargylamine and tranylcypromine displayed moderate affinity (KiH = 0.3-6 JLM) for brain and liver I2 imidazoline-preferring receptors; whereas chlordimeform displayed high affinity (KiH = 6 nM) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain (KiH = 40 pM) but not for rat liver I2 imidazoline-preferring receptors (KiH = 169 nM). 4 Preincubation of cortical or liver membranes with phenelzine (10-4 M for 30 min) did not alter the total density of I2 imidazoline-preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I2 imidazoline-preferring receptors. In contrast, preincubation with 10-6 M clorgyline reduced by 40% the Bmax of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors. 5 Chronic treatment (7 days) with the inducers of cytochrome P-450 enzymes phenobarbitone (40 or 80 mg kg-', i.p.), 3-methylcholanthrene (20 mg kg-', i.p.) or 2-methylimidazole (40 mg kg-', i.p.) did not alter the binding parameters of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. The compound SKF 525A, a potent inhibitor of cytochrome P-450 enzymes which forms a tight but reversible complex with the haemoprotein, completely displaced with moderate affinity (KiH = 2-10 ;LM) the specific binding of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 x 10-4 M phenelzine in the presence of 10-3 M NADH, a treatment that irreversibly inactivates the haeme group of cytochrome P-450, did not reduce the density of liver I2 imidazoline-preferring receptors. These results discounted a possible interaction of [3H]-idazoxan with the haeme group of cytochrome P-450 enzymes. 6 Together the results indicate that the down-regulation of I2 imidazoline-preferring receptors is associated with an irreversible inactivation of MAO (at least in the brain) that is not related either to the affinity of the MAO inhibitors for I2 imidazoline-preferring receptors or to an irreversible binding to these putative receptors. These findings indicate a novel effect of irreversible MAO inhibitors in the brain and suggest a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of brain I2 imidazoline-preferring receptors has been reported. Keywords: Imidazoline-preferring receptors; phenelzine; clorgyline; tranylcypromine; moclobemide; monoamine oxidase (MAO); [3H]-idazoxan Introduction Several tissues and cell lines express specific and functional mined and identified as agmatine (Li et al., 1994); this sub- binding sites for imidazoli(di)ne/guanidine compounds which stance is bioactive, promoting release of catecholamines from have been termed imidazoline-preferring receptors (Michel & adrenal chromaffin cells and its biosynthetic enzyme, arginine Ernsberger, 1992). The structure of a possible endogenous decarboxylase is expressed in the rat brain (Li et al., 1994). ligand for these receptors (a component of the so-called The imidazoline-preferring receptors appear to comprise at clonidine-displacing substance; CDS) has been recently deter- least two subtypes, recently designated as I, and I2 (Erns- berger,- I 1992), which differ in their pharmacological profiles 'Author for correspondence at: Lab Neurofarmacolgia, Dept. and also in their tissue and subcellular distributions (for a Biologia Fonamental i Ciencies de la Salut, Universitat de les Illes review see Michel & Insel, 1989; Atlas, 1991; Hieble & Balears, Cra, Valldemossa Km 7.5, E-07071 Palma de Mallorca, Ruffolo, 1992; Kilpatrick et al., 1992). Spain. The I, imidazoline-preferring receptors have been found to 838 R. Alemany et al Pheneizine down-regulates 12 imidazoline receptors be increased in platelet membranes from depressed patients with the cytochrome P-450 inducing agents phenobarbitone and down-regulated after desipramine treatment (Piletz et al., (40 or 80 mg kg-', i.p., every 24 h for 7 days), 3- 1990; 1991). The 12 imidazoline-preferring receptors might methylcholanthrene (20 mg kg-', i.p., every 12 h for 7 days) also be increased in the frontal cortex of depressed suicide or 2-methylimidazole (40 mg kg-', i.p. every 24 h for 7 days). victims (Meana et al., 1993) and recently, down-regulation of Both in the acute and chronic treatments the rats were killed these putative receptors after chronic treatment with the 24 h after the last injection. irreversible monoamine oxidase (MAO) inhibitors clorgyline and pargyline has been reported in the rat brain (Olmos et Rat cortical and liver membrane preparation al., 1993). The I2 imidazoline-preferring receptors and the enzyme MAO show some similarities: (1) they are located on The animals were decapitated and the parieto-occipital cortex the mitochondrial outer membrane (Tesson & Parini, 1991; and portions of liver were rapidly removed into ice-cold Tesson et al., 1991); (2) in the rat and human brain the Tris-sucrose buffer (5 mM Tris-HC1; 250 mM sucrose; 1 mM regional distribution of 12 imidazoline-preferring receptors MgCl2; pH 7.4) and frozen at - 80TC until required. Cortical correlates well with that of the B but not A isoform of the and liver membranes (P2 fractions) were prepared by estab- MAO (Sastre & Garcia-Sevilla, 1993); and (3) the density of lished methods with modifications (Giralt & Garcia-Sevilla, 12 imidazoline-preferring receptors and MAO-B increases 1989). Briefly, the tissue samples were homogenized in 5 ml with age in the human brain (Sastre & Garcia-Sevilla, 1993). of ice-cold Tris-sucrose buffer containing 2 mM of the pro- These findings suggest some relationship between these two tease inhibitor, phenylmethylsulphonyl fluoride (PMSF). The proteins; however, a direct interaction of imidazoline ligands homogenates were centrifuged at 1,100 g for 10min, and the with the active centre of MAO-A and B isoenzymes has been supernatants were then recentrifuged at 40,000 g for 10min. previously discounted (Olmos et al., 1993; Sastre & Garcia- The resulting pellet was washed twice with 2 ml of fresh Sevilla, 1993). incubation buffer (50 mM Tris-HCl, 0.1% ascorbic acid, The MAO inhibitors consist of a structurally diverse group pH 7.5). The final pellet was resuspended in an appropriate of compounds whose antidepressant properties have been volume of this buffer to a final protein content of attributed to their common ability to increase synaptic 800-1OOO gml-' for the cortical membranes and 900- availability of certain monoamine neurotransmitters. How- 1600 g ml1' for the liver membranes. Protein was deter- ever, maximal inhibition of MAO activity usually precedes mined by the method of Lowry et al. (1951), with bovine antidepressant effects, suggesting that the therapeutic effects serum albumin as the standard. of these compounds may be mediated by more than one target (for a review see Baker et al., 1992). Thus, interactions of MAO inhibitors with cytochrome P-450 enzymes (Muak- [3H]-idazoxan binding assay kassah & Yang, 1981; Belanger & Atitse-Gbeasson, 1982; Dupont et al., 1987) have been described. The synthesis of Total [3H]-idazoxan binding was measured in 1.1 ml-aliquots different cytochrome P-450 forms can be induced by a variety (50 mM Tris-HCl, 0.1% ascorbic acid, pH 7.5) of the cortical of compounds in the mitochondria and endoplasmic reticu- or liver membranes which were incubated with shaking for lum of the liver and other tissues (Murrey & Reidy, 1990). 30 min at 25C. Binding of [3H]-idazoxan to brain I2 Therefore, if the 12 imidazoline-preferring receptors were a imidazoline-preferring receptors was always done in the form of cytochrome P-450 enzymes, their density in the liver presence of 10-6 M (-)-adrenaline to prevent the binding of and brain might be modulated by chronic
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