Copyright © 2004 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2004, 56, 727–734 ISSN 1230-6002

INHIBITION OF RODENT BRAIN MONOAMINE OXIDASE AND TYROSINE HYDROXYLASE BY ENDOGENOUS COMPOUNDS – 1,2,3,4- ALKALOIDS

Antoni Patsenka, Lucyna Antkiewicz-Michaluk Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Inhibition of rodent brain monoamine oxidase and tyrosine hydroxylase by endogenous compounds – 1,2,3,4-tetrahydroisoquinoline alkaloids. A. PATSENKA, L. ANTKIEWICZ-MICHALUK. Pol. J. Pharmacol., 2004, 56, 727–734.

Four different noncatecholic and one catecholic (TIQs), cyclic condensation derivatives of b-phenylethylamine and dopa- mine with aldehydes or keto acids, were examined for the inhibition of rat and mouse brain monoamine oxidase (MAO) and rat striatum tyrosine hy- droxylase (TH) activity. Simple noncatecholic TIQs were found to act as moderate (TIQ, N-methyl-TIQ, 1-methyl-TIQ) or weak (1-benzyl-TIQ), MAO B and MAO A inhibitors. 1-Methyl-TIQ inhibited more potently MAO-A than MAO-B; the similar but more modest effect was exerted by salsolinol. Only salsolinol markedly inhibited TH activity, being competitive with the enzyme biopterin cofactor. The inhibition of MAO and TH by TIQs is discussed in relation to their ability to regulate monoamine .

Key words: monoamine oxidase, tyrosine hydroxylase, inhibition of en- zyme activity, tetrahydroisoquinoline derivatives

 correspondence; e-mail: [email protected] A. Patsenka, L. Antkiewicz-Michaluk

Abbreviations: BBB – blood-brain barrier,BH" been found to be toxic to neurons – 5,6,7,8-tetrahydrobiopterin, CSF – cerebrospinal and their concentration has been shown to increase fluid, 5-HT – 5-hydroxytryptamine, MAO – mono- in parkinsonian brains or cerebrospinal fluid (CSF) amine oxidase, MPTP – 1-methyl-4-phenyl-1,2,3,6- [12]. Others, such as 1MeTIQ, show a neuroprotec- tetrahydropyridine, b-PEA – 2-phenylethylamine, tive effect against the -induced neurode- TH – tyrosine hydroxylase, THP – 1,2,3,4-tetrahydro- generation and mortality in rats [1, 5]. papaveroline, TIQ 1,2,3,4- tetrahydroisoquinoline Tyrosine hydroxylase (TH) and MAO are cru- cial enzymes for catecholaminergic neurons. The first step of catecholamines synthesis is catalyzed INTRODUCTION by TH, a rate-limiting regulatory enzyme. TH is an iron-containing 3-monooxygenase (tyrosine-tetra- In physiological conditions catecholamines hydrobiopteridine (BH4): oxygen oxidoreductase, condense with a variety of simple and biogenic al- EC 1.14.16.2, TH) expressed in catecholamine- dehydes to form tetrahydroisoquinoline (TIQ) alka- neurons in mammalian brain, adrenal medulla and loids [7, 9]. The presence of TIQs in mammals in- peripheral sympathetic nerve terminals. The main cluding humans has been widely reported [26, 28]. catabolic enzyme for brain monoamines is mono- Using high-performance liquid chromatography amine oxidase (amine: oxygen oxidoreductase, (HPLC) with electrochemical, fluorescence or gas flavin-containing, EC 1.4.3.4, MAO). It occurs chromatography with mass spectrometry detection usually as the dimer and is classified into isoen- many authors have shown the presence of TIQ de- zymes A and B with a different substrates and in- rivatives such as TIQ, 1-methyl-TIQ (1MeTIQ), hibitors, which are encoded by two different genes. N-methyl-TIQ (NMeTIQ), 1-benzyl-TIQ (1BnTIQ), These enzymes can also produce hydrogen perox- 1-methyl-6,7,-dihydroxy-TIQ (salsolinol) and tet- ide and other reactive oxygen species as additional rahydropapaveroline (THP) in rodent and human products of their reactions; oxidative deamination brain (see a review by Nagatsu [24]). On the other also results in the production of very reactive bio- hand, TIQs are also widely distributed in the envi- genic aldehydes [8, 13, 35]. ronment, being present in many plants and food- Salsolinol derivatives have been reported to in- stuffs, such as port wine, bananas, beer and milk hibit the activity of tryptophan hydroxylase and TH [17, 27]. The exogenously administered TIQs eas- [30, 34, 40], some hydroxylated TIQs have shown ily cross the blood-brain barrier (BBB) and migrate to affect MAO activity [6, 22, 23]. into the brain, producing behavioral and biochemi- However, till now it has not been clarified cal effects in monoamine systems [2, 3, 11, 21]. whether TIQs without a catechol structure can dis- Some of them, e.g. salsolinol, a product of the con- turb the monoamine synthesizing and metabolizing densation of (DA) with acetaldehyde enzymes. The aim of the present study was to de- and/or pyruvate, have aroused considerable interest termine the effect of four noncatecholic TIQs (TIQ, as it may be involved in the pathogenesis of alco- 1MeTIQ, NMeTIQ and 1BnTIQ) on the activity of holism and neurodegeneration [24]. Other-than- MAO and TH and compare them with salsolinol. aromatic amines (phenylethylamines) may also un- dergo condensation with aldehydes yielding such TIQs as TIQ and 1MeTIQ. These alkaloids are pre- MATERIALS and METHODS sumably activated via N-methylation and are oxi- Chemicals and animals dized by monoamine oxidase (MAO) to form a neurotoxic N-methylisoquinolinium ion, the same L-[3,5-H] tyrosine (51 Ci/mmol), 5-hydroxy-3-in- as MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropy- dolyl [14C] ethyl-2-amine creatinine sulfate ([14C]- ridinium ion) from 1-methyl-4-phenyl-1,2,3,6-tetra- 5-HT, 56.7 mCi/mmol) and 2-phenyl[14C]ethylami- hydropyridine (MPTP) , which produces ne hydrochloride ([14C-b-PEA, 57 mCi/mmol) was a clinical syndrome similar to Parkinson’s disease. purchased from Amersham (UK). L-tyrosine, 5-HT, Indeed, it has been shown that salsolinol is a weak b-PEA, a-methyl-p-tyrosine, salsolinol. HCl, TIQ, substrate for N-methyltransferase in the rat sub- THP, BH4, dithiotreitol, bovine serum albumin stantia nigra, but its endogenous concentration is (BSA) and catalase were obtained from Sigma- minute [26]. Some TIQs, such as 1BnTIQ, have Aldrich Chemical Co. (St. Louis, MO, USA). Clor-

728 Pol. J. Pharmacol., 2004, 56, 727–734 INHIBITION OF MAO AND TH BY TETRAHYDROISOQUINOLINES giline and L-deprenyl came from RBI (MA, USA). ethyl acetate/toluene (1:1, v/v) (POCH, Poland) 1MeTIQ, NMeTIQ and 1BnTIQ were synthesized and 1 ml of the organic layer was withdrawn and in the Department of Medicinal Chemistry of the mixed with 4 ml of the scintillation fluid. Radioac- Institute of Pharmacology, Polish Academy of Sci- tivity was determined by liquid scintillation spec- ences in Kraków. All other reagents were of ana- trometry (Beckman LS 6500 counter). Data were lytical grade. expressed in nmol/min/mg of protein of 5-TH- and Male mice (18–20 g) and Wistar rats (240–280 g) b-PEA-oxidized products for MAO-A and B, were used for tissue preparation. All the procedures respectively. were carried out according to the National Institutes of Health Guide for Care and Use of Laboratory Animals, and were approved by the Institute’s In- Determination of tyrosine hydroxylase activity ternal Bioethics Commission. TH activity was determined by a radiochemical assay according to the method of Rejnhard et al. [33] with further modifications. Determination of monoamine oxidase activity The tissue was prepared in the same way as for MAO-A and MAO-B activities were deter- the MAO assay. After the last centrifugation, the mined by a radiochemical assay according to the supernatant was used in TH assay and the protein method of Tipton and Yodim [38], with further concentration was about 3.0 mg/ml. TH reactions modifications. were carried out at a total volume of 100 mlin 5-Hydroxy-3-indolyl [14C] ethyl-2-amine cre- Brand 1.5 ml polyethylene tubes. Reaction mixture atinine sulfate and 2-phenyl[14C]ethylamine hydro- contained the following components: 75–80 mgof chloride were used as the substrates for MAO-A protein; MES buffer, 50 mM, pH 6.0; dithiothreitol, and MAO-B, respectively. Animals (rats or mice) 5 mM; catalase (Sigma C-100, 47 000 U/mg), 90 mg; 3 were sacrificed by decapitation, brain tissue was re- L-tyrosine/L-[ring-3,5- H]tyrosine, 50 mM/1 mCi moved, dissected and frozen till further assayed. per sample; (6R)-L-erythro-5,6,7,8,-tetrahydrobio- Pieces of the frontal cortex, striatum and brainstem pterin(BH4), 125–500 mM. Blank values, obtained of rats or whole brains, except for the cerebellum of by omitting BH, equaled the blank values when tis- mice, were homogenized in 50 mM phosphate sue was discarded. Thus, the last blank was rou- buffer (pH 7.4, 10% w/v) using a Teflon ho- tinely used. The reaction was initiated by adding mogenizer. All manipulations were carried out at BH4, incubated at 37°C for 20 min, and was termi- 4°C. Homogenates were centrifuged at 1000 × g nated with 0.7 ml of a stirred suspension of 7.5% for 5 min; the sediment was discarded and the su- (w/v) charcoal (POCh, Poland) in 0.1 M HCl. The pernatant was recentrifuged at 11800 × g for mixtures were then rapidly stirred for 20 s and cen- 30 min, at +4°C. The pellet (mitochondrial fraction) trifuged at 10 000g for 3 min. Aliquots 0.4 ml of was resuspended in the same buffer to final protein the clear supernatant were transferred to 5 ml scin- concentration of 1.0–1.5 mg/ml, determined by tillation vials, and 4.0 ml of Aquascint (BIOCARE, Lowry’s et al. method [15]. Poland) were added. TH utilizes O2 to produce 3 3 The preincubation medium (50 mM phosphate DOPA and H-H2O from H-tyrosine. Unreacted ty- buffer, pH 7.4) contained 100 ml of displacing solu- rosine and catecholamines were absorbed with an tion with TIQ-alkaloids, ranging from 1.0 mMto aqueous slurry of activated charcoal, and the re- 3 1.0 mM, or the MAO inhibitors clorgiline or leased H-H2O was analyzed by liquid scintillation L-deprenyl (0.1 nM–0.5 mM) and 100 ml of resus- counting. Data were normalized for total protein pended pellet. After 10 min of preincubation at and were expressed as nanomoles of DOPA formed 37°C with shaking, the reaction was started by add- per minute per milligram of protein. The protein ing 50 ml of a radioactive substrate, 100 mMof was assayed using bovine serum albumin as a stan- [14C]-5-HT or 10 mMof[14C]- b-PEA (final con- dard by the method of Lowry et al. [15]. centrations), and was carried out at 37°C for 30 and The data are expressed as means ± SE from 10 min, respectively. The reaction was terminated three independent experiments. The results (IC50) by adding 50 mlof4MHClandcooling. Reaction were assayed using the Prism Pad 4 program (non- products were extracted by vortex with 2 ml of linear regression).

ISSN 1230-6002 729 A. Patsenka, L. Antkiewicz-Michaluk

RESULTS were the most potent MAO-B inhibitors in com- parison with other alkaloids, but IC50 values were Enzyme activity the same in both MAO-A and B only for TIQ. The m Figure 1 shows the chemical structure of TIQs range of IC50 values at 30 M may be recordered as used in this study. In order to optimize the analyti- a moderate inhibition potency [6, 37]. 1MeTIQ had m cal assay for the determination of MAO-A, B and the same IC50 values with MAO-A (29–32, 33 M) TH activity, we studied previously different reac- but five-fold higher IC50 values with MAO-B m tion times and different substrate concentration. (164-230, 160 M) in rat and mouse brains. Salso- The optimal conditions were used, and V values linol produced similar but modest effects compared max m were summarized in Table 1. The regional distribu- to 1MeTIQ (IC50 = 62–230, 170 M and m tion of MAO-A activity was the same in the stria- 582–1000, 1000 M, with MAO-A and B of rat and tum, frontal cortex and the brainstem of rat brain. mouse brain, respectively). It was assumed that sal- MAO-B activity was increased in the brainstem. solinol lacked the inhibition potency in relation to MAO-A activity was more than twice as high as MAO-B. High IC50 of 1BnTIQ pointed to its weak that of MAO-B in rat and mouse brain. inhibition potency in relation to both MAO isoen- In addition, the effects of specific isoenzyme in- zymes. hibitors were analyzed. Clorgiline inhibited MAO-A TIQ MAO-A at IC50 = 2.2 nM and 1.95 nM, and L- 1MeTIQ 125 deprenyl inhibited MAO-B at IC50 =14 nM and NMeTIQ 15 nM for mouse and rat brain, respectively. 100 1BnTIQ a-Methyl-p-tyrosine potently inhibited striatal TH SAL activity (67.8% of the inhibition in a 0.01 mM con- 75 centration). Effects of tetrahydroisoquinoline alkaloids on 50

MAO activity % of Control 25 TIQs inhibited enzyme activity in a dose- 0 dependent manner as shown in Figure 2. IC50 val- -7 -6 -5 -4 -3 -2 ues (the compound concentration that produced Concentration (M) 50% inhibition of the enzyme activity) for each al- kaloid were almost identical in mouse and rat brain and in the structures of rat brain studied (Tab. 2). MAO-B Salsolinol inhibited MAO-A activity the most ef- 125 fectively in rat striatum, and less efficiently in other rat and mouse brain structures. TIQ and NMeTIQ 100 75 R6 50 R N 7 % of Control R2 25 R1 0 R1 R2 R6 R7 -7 -6 -5 -4 -3 -2 TIQ H H HH Concentration (M) 1 Me TIQ CH H HHFig. 2. Inhibition of mouse brain monoamine oxidase (MAO) A 3 and B by tetrahydroisoquinoline (TIQ) alkaloids. IC (mM): CH # N Me TIQ H 3 HHTIQ – 50 (MAO-A) and 35 (MAO-B); N-methyl-TIQ – 1 Bn TIQ CH2-C6H6 H HH(NMeTIQ) 29 and 62; 1-methyl-TIQ (1MeTIQ) = 33 and 160; Salsolinol CH H OH OH 1-benzyl-TIQ – (1BnTIQ) 375 and 470; salsolinol – (SAL)170 3 and > 1000, respectively. Values are the means of three inde- Fig. 1. Chemical structures of tetrahydroisoquinoline (TIQ) al- pendent experiments. TIQs concentrations were used from 1 mM kaloids to1mM

730 Pol. J. Pharmacol., 2004, 56, 727–734 INHIBITION OF MAO AND TH BY TETRAHYDROISOQUINOLINES

Table 1. Monoamine oxidase (MAO) and tyrosine hydroxylase (TH) activity in rodent (Vmax, nmol/min/mg of protein)

MAO-A MAO-B TH

Rat brain striatum 2.17 ± 0.11 0.48 ± 0.03 0.23 ± 0.02 frontal cortex 2.34 ± 0.13 0.68 ± 0.07 – brain stem 2.30 ± 0.09 0.98 ± 0.06 – Mouse brain (without cerebellum) 1.46 ± 0.06 0.58 ± 0.03

Table 2. Monoamine oxidase (MAO) A and B inhibitory activ- Effects of tetrahydroisoquinoline alkaloids on ity (IC50 values, M) of tetrahydroisoquinolines (TIQ) in rat TH activity brain regions

MAO-A MAO-B Only salsolinol was effective as an inhibitor of TH activity. IC50 values for all four nonhydroxy- Striatum TIQ 23 34 lated TIQs exceeded 1000 mM (data not shown). 1 Me TIQ 31 164 Figure 3 shows the curves of TH activity inhibition N Me TIQ 38 67 by salsolinol at two different concentrations of tet- m m 1 Bn TIQ 350 548 rahydrobiopterin (500 M and 250 M) and IC50 for salsolinol (35.4 and 4.1 mM, respectively). Ad- Salsolinol 62 585 ditionally, we tested an other hydroxylated complex Frontal cortex TIQ 47 40 alkaloid THP, a product of DA and dopaldehyde 1 Me TIQ 32 230 condensation. The obtained results show the same N Me TIQ 39 95 inhibition potency of THP (IC50 =7.5 mM) in rela- 1 Bn TIQ 235 420 tion to rat striatum TH. Salsolinol 230 1000 Brainstem TIQ 27 43 DISCUSSION 1 Me TIQ 29 171 N Me TIQ 37 76 In this report, we consider the possibility that TIQs derived from m-PEA can affect catecholamine 1 Bn TIQ 320 640 biosynthesis and catabolism by different way with Salsolinol 195 1000 well-known DA-derived alkaloids. The inhibition of MAO by hydroxylated TIQs and their N-methylated products has been examined by several authors in 125 in vitro and in vivo experiments [6, 18, 22, 23]. Thull et al. [37] tested a few noncatecholic TIQs 100 SAL 1 (TIQ, NMeTIQ), and demonstrated a reversible SAL 2 and competitive type of the inhibition of MAO ac- 75 tivity in rat brain. They confirmed earlier study [6] and indicated that TIQ-alkaloids were not sub- 50 strates of MAO-A or B, even when they were used of inhibition in relatively high concentrations. In our report, we % 25 have compared effects of salsolinol with those of noncatecholic, simple and substituted TIQs. Simple 0 noncatecholic TIQs were similarly active towards -7 -6 -5 -4 -3 -2 mouse and rat MAO isoenzymes. In contrast to Concentration, log M Thull et al. [37], our results revealed more potent Fig. 3. Inhibition of rat striatum tyrosine hydroxylase by salsoli- inhibition of MAO-A and B by TIQ and NMeTIQ nol (SAL) with different concentrations of tetrahydrobiopterin (IC values were not higher than 29–39 and (BH ). SAL 1: 250 mMBH,IC (mM) = 4.1; SAL 2: 500 mM 50 " " # 34–95 mM, with MAO-A and MAO-B, respectively). BH",IC# (mM) = 35.4. Values are the means of three independ- ent experiments. TIQs concentrations were used from 1 mMto The presence of hydroxyl groups at position 6 and 1mM 7 of aromatic ring is not required for an inhibitory

ISSN 1230-6002 731 A. Patsenka, L. Antkiewicz-Michaluk effect, as was assumed by Naoi et al. [26] on the ba- it possesses distinct neuroprotective properties [1, sis of Thull’s et al. results. The above discrepancy 2, 11]. may be explained by the different methods used. It has been proposed also that cyano-products We used a high specific radiochemical method with of TIQ interaction with cigarette smoke may act as different labeled substrates for each form of the MAO inhibitors and may contribute in neuropro- isoenzyme. Kynuramine fluorimetric assay used by tective effect of tobacco smoking against Parkin- Thull et al. needs to inhibit part of enzyme activity son’s disease [20, 36]. Another interesting applica- by specific irreversible inhibitor to analyze another tion is the use of preferential reversible MAO-A in- part of isoenzyme (clorgiline for MAO-B and sele- hibitors to attenuate the reward and dependence of giline for MAO-A). It is very difficult to calculate drug abuse [19]. 1MeTIQ may be one of them. the appropriate concentrations of these compounds. Our results corroborate the inhibition of TH ac- Thus, administration of a low dose of L-deprenyl tivity and competitive interaction of salsolinol with (2.5 mg/kg) inhibited MAO-B activity by 90%, but binding site for pteridine cofactor, which was dem- also MAO-A activity by 40–60% [41]. In addition, onstrated earlier for TH and tryptophan hydroxy- the inhibition of MAO-B is attenuated when the lase [30, 34]. Noncatecholic TIQs are inactive in hydrogen at position 1 is substituted with methyl relation to TH. Possibly, the availability of hy- group (in 1MeTIQ and salsolinol) or with a more droxyl and/or carboxyl groups in the chemical complex group (1BnTIQ). This is in agreement structure are necessary to develop inhibitory activ- with a recent study into MAO molecular structure ity. This have been confirmed by our experiment [16], whose authors determined the crystal struc- with THP and by other studies with norsalsolinol derivatives [34]. In view of the fact that the physio- ture of rat enzyme, compared isoforms A and B, m and explained the role of MAO-B Tyr326 in block- logical concentration of brain BH4 is about 100 M [13], in vivo salsolinol may potentiate its effect on ing the access of the hydroxyl group of substrate to TH. However, there remains a problem of its en- the binding pocket. dogenous brain concentration and BBB permeabil- It is well known that MAO-A plays a leading ity. In contrast to noncatecholic TIQs which easily role in rodent monoamine catabolism. MAO-A penetrate BBB, hydrophilic chemical structure and knock-out (KO) mice exhibited aggressive behav- fast metabolism of salsolinol remain the question ior and increased levels of 5-HT, norepinephrine opened [29]. The fact that salsolinol interacts with and DA, whereas MAO-B KO mice showed an in- b BH4 needs to be further investigate, because of the creased -PEA level only [10, 31]. However, a high pivotal role of the pteridine cofactor in the func- dose of L-DOPA (100 mg/kg, ip) injected to MAO-B tioning of not only monoamine synthesizing en- KO mice produced a higher level of DA than that in zymes, but also nitric oxide synthase, and due to its wild-type mice, that difference being abolished by being a crucial factor in the resistance of dopamin- pretreating the wild-type animals with L-deprenyl ergic neurons [25]. [10]. It is assumed that MAO-B is involved in In conclusion, the role of TIQs as moderate to monoamine metabolism if monoamine levels are low reversible inhibitors of both MAO isoenzymes abnormally elevated. The elevated turnover of cate- may present the group of endogenous compounds cholamines, in particular DA, is regarded as oxida- with very profitable mechanism of action, as neuro- tive stress factor which contributes to the progres- protective activity what was presented for 1MeTIQ sion of neurodegenerative disorders. The conse- [1, 5]. This hypothesis is in agreement with other quence of MAO activity is the exposure of neuronal reports which have shown the lack of neurotoxicity cells to an increased flux of hydrogen peroxide and of TIQ in rodents [14, 32]. However, it should be aldehyde/quinone products of MAO reaction [8]. In mentioned, that some of TIQ derivatives as 1BnTIQ turn, elevated reactive oxygen species may inacti- or salsolinol, the compounds with low affinity to vate the enzyme itself [35]. On the other hand, the MAO and inhibitory activity to TH (salsolinol) inhibition of MAO-B produces a “cheese” effect may produce moderate neurotoxic effect presented and potentiates the evoked stereotypic behavior both in in vitro and in vivo studies [4, 12, 26]. [41]. From the above viewpoint 1MeTIQ seems to Finally, the results obtained in the present study be of interest as a compound with moderate affinity confirm our concept that endogenous TIQ alkaloids for MAO-A and lower affinity for MAO-B. Indeed, may act as physiological regulators and feed-back

732 Pol. J. Pharmacol., 2004, 56, 727–734 INHIBITION OF MAO AND TH BY TETRAHYDROISOQUINOLINES controllers of brain monoamines, in particular DA 11. Kikuchi K, Nagatsu Y, Makino Y, Mashino T, Ohta S, neurotransmitter system [2, 3, 4, 39 ]. Hirobe M: Metabolism and penetration through the blood-brain barrier of parkinsonism-related compounds: 1,2,3,4-tetrahydroisoquinoline and 1-methyl-1,2,3,4- Acknowlegments. Thanks are due to Ms El¿bieta Smo- tetrahydroisoquinoline. Drug Metab Dispos, 1991, 19, lak for the English correction of the paper. This study was 257–262. supported by the statutory funds of the Institute of Pharma- 12. Kotake Y, Ohta S, Kanazawa I, Saurai M: Neurotoxic- cology, Polish Academy of Sciences Kraków, Poland. ity of an endogenous brain amine, 1-benzyl-1,2,3,4- tetrahydroisoquinoline, in organotypic slice co-culture of mesencefalon and striatum. Neuroscience, 2003, REFERENCES 117, 63–70. 13. Levine RA, Kuhn DW, Lovenger W: The regional dis- 1. 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