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D3 receptor agonist rotigotine antihemiparkinsonian actions
European Journal of Pharmacology 599 (2008) 81–85
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European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r
Behavioural Pharmacology
Biperiden enhances L-DOPA methyl ester and dopamine Dl receptor agonist SKF-82958 but antagonizes D2/D3 receptor agonist rotigotine antihemiparkinsonian actions Edward F. Domino ⁎, Lisong Ni Department of Pharmacology, University of Michigan, Ann Arbor, MI 49109-0632, United States
a r t i c l e
i n f o
Article history: Received 8 May 2008 Received in revised form 29 July 2008 Accepted 16 September 2008 Available online 30 September 2008 Keywords: Biperiden Dopamine receptor agonists Hemiparkinsonism L-DOPA methyl ester MPTP M1/M4 cholinergic receptor antagonist N-0923 D1 or D2/D3 receptor agonist Rotigotine SCH-23390 SKF-82958
a b s t r a c t The effects of biperiden (0, 100, and 320 µg/kg), a selective muscarinic M1/M4 receptor cholinergic antagonist, were studied alone and in combination with those of L-DOPA methyl ester (16.7 mg/kg), a selective dopamine D1 receptor agonist SKF-82958 (74.8 µg/kg), or a selective D2/D3 receptor agonist rotigotine (32 µg/kg) on circling behavior in MPTP induced hemiparkinsonian monkeys. The doses selected were given i.m. in approximately equieffective doses to produce contraversive circling. Biperiden alone with 5% dextrose vehicle produced a slight increase in contraversive circling in a dose related manner. When combined with LDOPA methyl ester, it enhanced contraversive circling and decreased ipsiversive circling. When biperiden was combined with SKF-82958, contraversive circling also was enhanced and ipsiversive circling decreased. Exactly the opposite was observed with the combination of biperiden and rotigotine. The results indicate a dramatic difference in effects of a prototypic muscarinic M1/M4 receptor cholinergic antagonist in combination with prototypic full dopamine D1 or D2/D3 receptor agonists. Biperiden interactions with L-DOPA methyl ester were more predominantly Dl than D2/D3 receptor-like in this animal model of hemiparkinsonism. © 2008 Elsevier B.V. All rights reserved.
1. Introduction From a historical perspective, muscarinic cholinergic antagonists dominated the therapy of Parkinson's disease for almost 100 years because of the fortuitous discovery of tinctures of Atropa belladonna and Hyoscyamus niger. They were first used to control the symptoms of excessive salivation. It is now known that Parkinson's disease involves a destruction of dopaminergic neurons. This has led to the use of levodopa and selective dopamine D2/D3 receptor agonists. The role of acetylcholine in the pathophysiologic mechanisms of this disease is still unclear. Since the 1980s, schematic diagrams of the extrapyramidal system and the neural circuits involved, as described by leading neuroscientists/ neurologists, seldom include acetylcholine in their schemes (Young and Penney, 1989; Albin et al., 1995; Crutcher, 1999; Wichmann and DeLong, 1999; Lowe and Leigh, 2002; Squire et al., 2003). According to Marsden (1976), most anticholinergic drugs given alone are only slightly to moderately effective in 10–25% of parkinsonian patients. Both the muscarinic M1/M4 receptor anticholinergic biperiden and the nonselective dopamine agonist apomorphine reduce parkinso⁎ Corresponding author. Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0632, United States. Tel.: +1 734 764 9115; fax: +1 734 763 4450. E-mail address: [email protected] (E.F. Domino). 0014-2999/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2008.09.028
nian tremor, but the former does not improve rigidity or akinesia, as does the latter (Schrag et al., 1999). In view of the cognitive deficits produced by anticholinergic agents, they are seldom used in elderly/cognitively impaired patients. Abrupt withdrawal of anticholinergic medications frequently results in an exacerbation of parkinsonian symptoms (Goetz et al., 1981). Furthermore, long term use of levodopa may increase cholinergic supersensitivity. The review by Hornykiewicz (1989) on the neurochemistry, and that of Lang and Blair (1989) on anticholinergic drugs summarize the literature to that date. After more than 40 years, it is now also well accepted that levodopa and dopamine receptor agonist therapies are not ideal. Obviously, the role of multiple dopamine receptors and their interactions with multiple chemical transmitters/modulators in the basal ganglia need further study. In particular, the specific interactions between multiple selective dopaminergic and muscarinic cholinergic agonists and antagonists need clarification in both neurologically normal and pathological extrapyramidal motor states. Although biperiden is used occasionally in combination with levodopa in patients with Parkinson's disease, it is not known if the effects of the combination are due to an anticholinergic action interaction with either the dopamine D1 or D2 receptor families. Scopolamine, a nonselective muscarinic cholinergic antagonist, attenuates the behavioral effects of neuroleptics with predominant dopamine D2 receptor affinities in mice
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(Christensen et al., 1985; Hyttel et al., 1985). Biperiden, a predominant muscarinic M1/M4 selective cholinergic antagonist, is equally effective in antagonizing the dystonia and oral dyskinesia of sensitized Cebus apella monkeys given SCH-23390 (7-chloro-8-hydroxy-3-methyl-5phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), a selective dopamine Dl receptor antagonist, or raclopride, a selective dopamine D2 receptor antagonist (Juul-Povlsen et al., 1986; Kistrup et al., 1987). Trihexyphenidyl enhances the contraversive effects of L-DOPA methyl ester and the dopamine D1 receptor selective agonist SKF-82958 ((±)6chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide), but reduces such effects of the dopamine D2/ D3 selective agonist (−)-2-(N-propyl-N-2-thienylethylamino)-5hydroxytetralin (N-0923, Güldenpfennig et al., 2005; Reynolds et al., 2005; Domino and Ni, 1998; Boeckler and Gmeiner, 2006). N-0923 is now commonly known as rotigotine, and will be referred to as such in this manuscript (The Parkinson Study Group, 2003; Güldenpfenning et al., 2005; Babic et al., 2006; LeWitt et al., 2007a,b; Watts, 2007). Rotigotine was approved by the FDA in May 2007 as a transdermal patch (Neuropro®) for the treatment of Parkinson's disease. The patch was discontinued in April 2008 due to problems with the delivery system. 2. Methods and materials 2.1. Materials Four adult female Macaca nemestrina (pig tailed macaque) monkeys were studied. Details of their care, induction of MPTP induced hemiparkinsonism, and behavioral observations have been described previously (Bankiewicz et al., 1986; Belluzzi et al., 1994; Domino and Sheng, 1993a,b). Each animal was anesthetized in her own squeeze cage with ketamine HCl given i.m. in a base dose of 5– 10 mg/kg, as needed. Subsequently, each animal was given 30 mg/kg i.v. pentobarbital to maintain deep anesthesia and secured on an operating table in the prone position for exposure of the right common carotid artery at its bifurcation. MPTP was slowly infused unilaterally into the right carotid artery. Surgery lasted approximately
30 min. The wound was then irrigated with H2O2 solution and closed with a continuous nylon suture and skin clips. Each animal was given 300,000 U of sterile penicillin G benzathine and penicillin G procaine in an aqueous suspension. After recovery from surgery and evidence of hemiparkinsonism, the animals were periodically studied for their responses to various antiparkinsonian agents using video camera recordings and subsequent behavioral scoring by persons blinded to the test medication used. The number and duration of complete 360° ipsiversive and contraversive circling were recorded every 5 min 30 min before and 2 h after drug administration. Contraversive circling indicates supersensitive dopamine receptors on the ipsilateral side and vice versa. The protocol was approved by the University of Michigan Institutional Animal Ethics Committee. For this study, the animals were drug free for several months before initiation to establish stable control baseline data. Each animal was previously tested with other dopamine receptor agonists several years after MPTP administration. All agents were reagent, medical, or veterinary grade available from commercial sources. L-DOPA methyl ester was purchased from Sigma-Aldrich, St. Louis, MO 63118. Racemic biperiden hydrochloride was used because of its clinical use. It was obtained from the Knoll Pharmaceutical Company, Wippany, NJ 07981. The selective dopamine Dl receptor agonist SKF-82958 (Weinstock et al., 1980) was purchased from Research Biochemicals, Natick, MA. The selective dopamine D2/D3 receptor agonist N-0923 (rotigotine) was obtained from Dr. D. McAfee, Discovery Therapeutics, Richmond, VA 23261. All drugs were given i.m. in a logarithmic dose fashion in doses of 100 or 320 µg/kg to all four monkeys. The same volume of vehicle (5% glucose in H2O or 0.9% NaCl) was injected i.m. as a control. The experimental design included all four monkeys being given the same treatment on the same day (usually Thursday, once per week). Animals were studied at about 0830 of the experimental day with a vehicle control given i.m. at −30 min. At 0 time, either control vehicle or biperiden was given i.m. and the animals run for an additional 30 min. At +30 min, a dopamine receptor agonist was given and the animals were run for an additional 2 h. The order of each dose of medication was randomized.
Fig. 1. Biperiden enhances the effects of L-DOPA methyl ester on circling behavior in MPTP induced hemiparkinsonian monkeys. The number of mean complete rotations during 120 min plus S.E. is shown for contraversive (C) and ipsiversive (I) circling on the y-axis and the dose of biperiden (vehicle 0, 100 and 320 µg/kg) on the x-axis. All injections were i.m. with biperiden or vehicle at 0 time and L-DOPA methyl ester at +30 min. Rotations were counted immediately after the last injection for another 120 min. Two-way ANOVA with repeated measures indicated that the combination increased contraversive circling (F (1, 24) = 370.57, =p b 0.0001; ⁎⁎p b 0.01, ⁎⁎⁎p b 0.001).
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Fig. 2. Effects of L-DOPA methyl ester, SKF-82958, or rotigotine alone and in combination with biperiden in MPTP induced hemiparkinsonian monkeys. Approximately equivalent, moderately effective doses of each dopamine agonist were given in separate experiments (see Table 1). The data with a vehicle control injection plus each agonist were normalized to the maximum contraversive and ipsiversive circling as 100 in order to better illustrate the effects of each agonist in combination with biperiden. Note the opposite actions of the combination of biperiden with the two selective dopamine agonists and the predominant D1-like response of L-DOPA methyl ester. One-way ANOVA with repeated measures were conducted on the original data for each drug combination with p b 0.0001 to b0.001.
2.2. Statistical analysis Our previous studies using MPTP lesioned hemiparkinsonian monkeys provided data with a normal distribution even though a small N was used. Based on these previous studies, the data were analyzed using parametric studies. Data were subjected to statistical analysis for active drug versus vehicle, or active drug alone versus different dose combinations. Two-way ANOVA with repeated measures was run using SPSS 15.0, followed by the Bonferroni comparison procedure when a significant F ratio was obtained. An alpha level of 0.05 was used for all statistical tests. The Mauchly's Test of Sphericity, under the two-way ANOVA with repeated measures, confirmed our assumption that variations over dose and drug conditions are equal. 3. Results 3.1. Effects of biperiden alone and in combination with L-DOPA methyl ester Compared to a vehicle (D5 W) injection, biperiden in doses of 100 and 320 µg/kg i.m. in a dose related manner increased contraversive circling. It also increased ipsiversive circling but less than contraversive circling, as illustrated in Fig. 1. A two-way ANOVA with repeated measures for the ipsiversive circling was conducted and the change was statistically significant (Pillai's Trace Test, F (1, 24) = 39.11, P b 0.001). The effects were statistically significant on contraversive circling as well. The Pillai's Trace Test indicated F (2, 23) = 30.80, P b 0.0001. These effects lasted for at least 2 h. A 5% dextrose in water (D5 W) control in the A.M. at 0 time, and a dose of 16.7 mg/kg i.m. LDOPA methyl ester given at +30 min, produced a much greater increase in contraversive circling and a decrease in ipsiversive circling (see Fig. 1). The combination of L-DOPA methyl ester plus 100 or 320 µg/kg i.m. biperiden produced a further increase, confirmed by two-way ANOVA with repeated measures (Pillai's Trace Test, F (1, 24) = 370.57, P b 0.0001. The effects were small for potentiation and were
primarily an additive effect. However, the interaction analysis of the two-way ANOVA with repeated measures indicated that a 100 µg/kg dose of biperiden i.m. was much more effective than the control (D5 W) and the larger dose of 320 µg/kg, F (2, 23) = 7.85, P b 0.01. 3.2. Effects of biperiden in combination with a selective dopamine D1 or D2/D3 dopamine agonist An attempt to obtain a dose of a dopamine Dl or D2 receptor agonist alone equally effective to 16.7 mg/kg i.m. L-DOPA methyl ester was unsuccessful. As a result, the dose of either dopamine receptor agonist that produced the closest effect to that of L-DOPA methyl ester was chosen for combination studies with biperiden. In order to compare the results of all three different treatment combinations, the data were normalized based on 100 as the maximal contraversive effect of control vehicle plus L-DOPA methyl ester, control vehicle plus the selective dopamine Dl receptor agonist SKF-82958, or control vehicle plus the selective dopamine D2/D3 receptor agonist rotigotine. The results are illustrated in Fig. 2 and Table 1. With each dopamine receptor agonist in a fixed dose, both contraversive and ipsiversive circling were normalized to 100. Increasing doses of biperiden, in combination with L-DOPA methyl ester, showed a similar increase in
Table 1 Mean data of ipsiversive and contraversive circling with experimental treatments given I.M. Medication
Biperiden dose
Ipsiversive
S.E.M.
Contraversive
S.E.M.
L-DOPA
0 100 320 0 100 320 0 100 320
0.49 0.41 0.43 1.25 1.15 0.91 1.15 1.48 2.10
0.07 0.07 0.15 0.15 0.18 0.13 0.16 0.18 0.16
8.84 12.11 11.38 2.88 6.61 6.86 15.58 12.87 9.69
0.61 0.83 0.50 1.09 1.80 1.21 3.88 2.83 2.46
Methyl Ester (16.7 mg/kg) SKF-83958 (74.8 µg/kg)
Rotigotine (10 µg/kg)
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normalized contraversive and a decrease in normalized ipsiversive circling (compare Fig. 1 to Fig. 2). A dose of 74.8 µg/kg i.m. SKF-82958 given alone and in combination with 100 or 320 µg/kg of biperiden produced a marked increase in contraversive circling and a slight decrease in ipsiversive circling, which were both statistically significant by ANOVA (F (2, 24) = 7.41, P b 0.001). This is illustrated in the normalized data in Fig. 2. In marked contrast to the dopamine Dl agonist combination, biperiden attenuated the effects of the dopamine D2/D3 receptor agonist rotigotine on contraversive circling, and enhanced ipsiversive circling in these hemiparkinsonian monkeys. One-way ANOVA with repeated measures indicated that these decreases (F (2, 24) = 10.79, P b 0.0001) as well as the increases (F (2, 24) = 7.84, P b 0.001) were highly significant. 4. Discussion The striatum contains high concentrations of acetylcholine, acetylcholinesterase, choline acetyltransferase, choline transporters, and multiple muscarinic cholinergic (3H-QNB) binding sites (Fibiger et al., 1987; McGeer et al., 1987). There is considerable evidence, based primarily on histological and lesion studies, that the striatum has many large and some small cholinergic interneurons. The large interneurons represent about 1% of the total number of striatal neurons. It is well known that cholinergic striatal neurons are modulated by dopaminergic afferents. Dopamine and its agonists were first shown to inhibit striatal cholinergic interneuronal activity, thus decreasing striatal acetylcholine release and turnover (Lehmann and Langer, 1983; Stoof and Kebabian, 1984). Subsequently, it became clear that dopamine Dl and D2 receptor activation had different effects on striatal acetylcholine release (Ajima et al., 1990; Consolo et al., 1987). Dopamine D2 receptor agonists inhibit acetylcholine release (Dawson et al., 1990; Scatton, 1982). On the other hand, dopamine Dl receptor agonists increase acetylcholine release (Damsma et al., 1990; Fage and Scatton, 1986; Gorell et al., 1986). Selective dopamine antagonists have the opposite effects on acetylcholine release. Both nonselective (benztropine) and partially selective (biperiden, trihexyphenidyl) muscarinic cholinergic antagonists are used to supplement levodopa therapy in human parkinsonism (Cedarbaum et al., 1990). Burke and Fahn (1984) and Burke (1986) reported on the selectivity of various anticholinergic, antiparkinsonian agents for muscarinic M1 and M2 receptor families of cholinergic receptor subtypes. For a comparison to pirenzepine, which had a selectivity ratio for muscarinic M1 receptors of 8.6, the selectivity ratios for various other anticholinergic agents tested were: biperiden 6.8; trihexiphenidyl 6.4; scopolamine 5.5; dexetimide 4.3; benztropine 4.2; atropine 3.3; procyclidine 2.9; ethopropazine 2.4; orphenadrine 2.1. Syvälahti et al. (1987) also reported that biperiden, like pirenzepine, binds to muscarinic M1 cholinergic receptors selectively. Subsequently, Eltze and Figala (1998) studied the affinity of the (+) and (−) enantiomers of biperiden for different muscarinic cholinergic receptors. They showed that (+)biperiden was highly M1 selective, while (−)biperiden had low binding affinity and did not discriminate between muscarinic M1 and M2 receptor families. The pA2 is the negative logarithm of the molar concentration of an antagonist which produces a two fold shift to the right of the agonist dose response curve. The isomers of biperiden as antagonists of acetylcholine differ considerably. The pA2 of (+) biperiden is 9.15, and of (−)biperiden is 6.36 for muscarinic M1 sites. It is clear that in low doses or concentrations, racemic biperiden will act as a selective muscarinic M1 receptor antagonist. One can conclude that the synergistic effect of racemic biperiden in the present study with L-DOPA methyl ester and SKF-82958 is probably due to a muscarinic M1/M4 cholinergic receptor antagonist action. An especially provocative conclusion from the present study is that in MPTP hemilesioned monkeys, contraversive circling induced by L-DOPA methyl ester is mediated by a predominant dopamine Dl
and not a D2 receptor agonist action. The fact that biperiden had a synergistic action with both L-DOPA methyl ester and SKF-82958, but antagonized the effects of rotigotine, is indeed impressive. The findings with the combination of biperiden and Dl or D2/D3 selective dopamine agonists are in agreement with a previous report that trihexiphenidyl, another muscarinic M1 receptor selective cholinergic antagonist (Giachetti et al., 1986; Tien and Wallace, 1985), enhances the effects of SKF-82958 and antagonizes the effects of rotigotine in MPTP-induced hemiparkinsonian monkeys (Domino and Ni, 1998). The results of these two studies indicate that the muscarinic effects of acetylcholine, by stimulating the direct GABA/substance P pathways, are antagonistic to the D1 receptor actions of dopamine. The muscarinic M1 receptor actions of acetylcholine via Gq/11 increase IP3/DAG. The muscarinic M4 receptor actions of acetylcholine via Gi reduce cAMP, whereas the D1/D5 receptor actions of dopamine stimulate cAMP formation. Therefore, muscarinic M1 receptor antagonism will reduce IP3/DAG, and muscarinic M4 receptor antagonism will enhance cAMP formation by the D1 receptor actions of dopamine. The D2 receptor actions of dopamine to inhibit cAMP formation in the indirect GABA enkephalin pathway will be reduced by muscarinic M4 receptor antagonism of the usual inhibition of cAMP by acetylcholine. Obviously, the conclusion that dopamine Dl but not D2/D3 receptors control the additive cholinergic M1/M4 receptor interactions in lesions of the striatum is the best interpretation of the data. The results with biperiden are similar to those with trihexiphenidyl, another muscarinic cholinergic antagonist, in combination with the same dopamine receptor agonist in hemiparkinsonian monkeys (Domino and Ni, 1998). Studies with highly selective dopamine D1 through D5 receptor agonists (see Alexander et al., 2008) are needed to confirm the specific role of each member of the dopamine family of receptor subtypes. Blocking experiments with very selective dopamine antagonists and correlational analysis of drug potencies with binding affinities must be done. There are now more selective Dl receptor agonists in addition to SKF-82958 (Salmi et al., 2004). Furthermore, rotigotine, like other D2/D3 receptor agonists, has some affinity for other dopamine receptors. Biperiden also inhibits dopamine reuptake (Jackisch et al., 1993). A study of both isomers of biperiden should also be undertaken in the future. Both biperiden and trihexyphenidyl have M1 and M4 cholinergic receptor affinities. Inasmuch as the striatum has a very high abundance of M4 receptors, it may be that the interactions observed involve M4 rather than M1 cholinergic receptors. Further studies with other more highly selective dopamine D3 receptor agonists, and muscarinic cholinergic antagonists, must be conducted to determine the generalization of the provocative conclusions of the present study. Acknowledgments Supported in part by the University of Michigan Psychopharmacology Research Fund 361024, and the Education and Research Development Fund 54010. References Ajima, A., Yamaguchi, T., Kato, T., 1990. Modulation of acetylcholine release by Dl, D2 dopamine receptors in rat striatum under freely moving conditions. Brain Res. 518, 193–198. Albin, R.L., Young, A.B., Penney, J.B., 1995. The functional anatomy of the basal ganglia. Trends Neurosci. 18, 63–64. Alexander, S.P.H., Mathie, A., Peters, J.A., 2008. Guide to Receptors and Channels (GRAC) 3rd Ed. Br. J. Pharmacol. 153 (Suppl (2)), S1–S-209. Babic, T., Boothmann, B., Polivka, J., Rektor, I., Boroojerdi, B., Hack, H.J., Randerath, O., 2006. Rotigotine transdermal patch enables rapid titration to effective doses in advanced-stage idiopathic Parkinson disease: subanalysis of a parallel group, openlabel, dose-escalation study. Clin. Neuropharmacol. 29, 238–242. Bankiewicz, K.S., Oldfield, E.H., Chiueh, C.C., Doppman, J.L., Jacobowitz, D.M., Kopin, U., 1986. Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci. 39, 7–16.
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European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r
Behavioural Pharmacology
Biperiden enhances L-DOPA methyl ester and dopamine Dl receptor agonist SKF-82958 but antagonizes D2/D3 receptor agonist rotigotine antihemiparkinsonian actions Edward F. Domino ⁎, Lisong Ni Department of Pharmacology, University of Michigan, Ann Arbor, MI 49109-0632, United States
a r t i c l e
i n f o
Article history: Received 8 May 2008 Received in revised form 29 July 2008 Accepted 16 September 2008 Available online 30 September 2008 Keywords: Biperiden Dopamine receptor agonists Hemiparkinsonism L-DOPA methyl ester MPTP M1/M4 cholinergic receptor antagonist N-0923 D1 or D2/D3 receptor agonist Rotigotine SCH-23390 SKF-82958
a b s t r a c t The effects of biperiden (0, 100, and 320 µg/kg), a selective muscarinic M1/M4 receptor cholinergic antagonist, were studied alone and in combination with those of L-DOPA methyl ester (16.7 mg/kg), a selective dopamine D1 receptor agonist SKF-82958 (74.8 µg/kg), or a selective D2/D3 receptor agonist rotigotine (32 µg/kg) on circling behavior in MPTP induced hemiparkinsonian monkeys. The doses selected were given i.m. in approximately equieffective doses to produce contraversive circling. Biperiden alone with 5% dextrose vehicle produced a slight increase in contraversive circling in a dose related manner. When combined with LDOPA methyl ester, it enhanced contraversive circling and decreased ipsiversive circling. When biperiden was combined with SKF-82958, contraversive circling also was enhanced and ipsiversive circling decreased. Exactly the opposite was observed with the combination of biperiden and rotigotine. The results indicate a dramatic difference in effects of a prototypic muscarinic M1/M4 receptor cholinergic antagonist in combination with prototypic full dopamine D1 or D2/D3 receptor agonists. Biperiden interactions with L-DOPA methyl ester were more predominantly Dl than D2/D3 receptor-like in this animal model of hemiparkinsonism. © 2008 Elsevier B.V. All rights reserved.
1. Introduction From a historical perspective, muscarinic cholinergic antagonists dominated the therapy of Parkinson's disease for almost 100 years because of the fortuitous discovery of tinctures of Atropa belladonna and Hyoscyamus niger. They were first used to control the symptoms of excessive salivation. It is now known that Parkinson's disease involves a destruction of dopaminergic neurons. This has led to the use of levodopa and selective dopamine D2/D3 receptor agonists. The role of acetylcholine in the pathophysiologic mechanisms of this disease is still unclear. Since the 1980s, schematic diagrams of the extrapyramidal system and the neural circuits involved, as described by leading neuroscientists/ neurologists, seldom include acetylcholine in their schemes (Young and Penney, 1989; Albin et al., 1995; Crutcher, 1999; Wichmann and DeLong, 1999; Lowe and Leigh, 2002; Squire et al., 2003). According to Marsden (1976), most anticholinergic drugs given alone are only slightly to moderately effective in 10–25% of parkinsonian patients. Both the muscarinic M1/M4 receptor anticholinergic biperiden and the nonselective dopamine agonist apomorphine reduce parkinso⁎ Corresponding author. Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0632, United States. Tel.: +1 734 764 9115; fax: +1 734 763 4450. E-mail address: [email protected] (E.F. Domino). 0014-2999/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2008.09.028
nian tremor, but the former does not improve rigidity or akinesia, as does the latter (Schrag et al., 1999). In view of the cognitive deficits produced by anticholinergic agents, they are seldom used in elderly/cognitively impaired patients. Abrupt withdrawal of anticholinergic medications frequently results in an exacerbation of parkinsonian symptoms (Goetz et al., 1981). Furthermore, long term use of levodopa may increase cholinergic supersensitivity. The review by Hornykiewicz (1989) on the neurochemistry, and that of Lang and Blair (1989) on anticholinergic drugs summarize the literature to that date. After more than 40 years, it is now also well accepted that levodopa and dopamine receptor agonist therapies are not ideal. Obviously, the role of multiple dopamine receptors and their interactions with multiple chemical transmitters/modulators in the basal ganglia need further study. In particular, the specific interactions between multiple selective dopaminergic and muscarinic cholinergic agonists and antagonists need clarification in both neurologically normal and pathological extrapyramidal motor states. Although biperiden is used occasionally in combination with levodopa in patients with Parkinson's disease, it is not known if the effects of the combination are due to an anticholinergic action interaction with either the dopamine D1 or D2 receptor families. Scopolamine, a nonselective muscarinic cholinergic antagonist, attenuates the behavioral effects of neuroleptics with predominant dopamine D2 receptor affinities in mice
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(Christensen et al., 1985; Hyttel et al., 1985). Biperiden, a predominant muscarinic M1/M4 selective cholinergic antagonist, is equally effective in antagonizing the dystonia and oral dyskinesia of sensitized Cebus apella monkeys given SCH-23390 (7-chloro-8-hydroxy-3-methyl-5phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), a selective dopamine Dl receptor antagonist, or raclopride, a selective dopamine D2 receptor antagonist (Juul-Povlsen et al., 1986; Kistrup et al., 1987). Trihexyphenidyl enhances the contraversive effects of L-DOPA methyl ester and the dopamine D1 receptor selective agonist SKF-82958 ((±)6chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide), but reduces such effects of the dopamine D2/ D3 selective agonist (−)-2-(N-propyl-N-2-thienylethylamino)-5hydroxytetralin (N-0923, Güldenpfennig et al., 2005; Reynolds et al., 2005; Domino and Ni, 1998; Boeckler and Gmeiner, 2006). N-0923 is now commonly known as rotigotine, and will be referred to as such in this manuscript (The Parkinson Study Group, 2003; Güldenpfenning et al., 2005; Babic et al., 2006; LeWitt et al., 2007a,b; Watts, 2007). Rotigotine was approved by the FDA in May 2007 as a transdermal patch (Neuropro®) for the treatment of Parkinson's disease. The patch was discontinued in April 2008 due to problems with the delivery system. 2. Methods and materials 2.1. Materials Four adult female Macaca nemestrina (pig tailed macaque) monkeys were studied. Details of their care, induction of MPTP induced hemiparkinsonism, and behavioral observations have been described previously (Bankiewicz et al., 1986; Belluzzi et al., 1994; Domino and Sheng, 1993a,b). Each animal was anesthetized in her own squeeze cage with ketamine HCl given i.m. in a base dose of 5– 10 mg/kg, as needed. Subsequently, each animal was given 30 mg/kg i.v. pentobarbital to maintain deep anesthesia and secured on an operating table in the prone position for exposure of the right common carotid artery at its bifurcation. MPTP was slowly infused unilaterally into the right carotid artery. Surgery lasted approximately
30 min. The wound was then irrigated with H2O2 solution and closed with a continuous nylon suture and skin clips. Each animal was given 300,000 U of sterile penicillin G benzathine and penicillin G procaine in an aqueous suspension. After recovery from surgery and evidence of hemiparkinsonism, the animals were periodically studied for their responses to various antiparkinsonian agents using video camera recordings and subsequent behavioral scoring by persons blinded to the test medication used. The number and duration of complete 360° ipsiversive and contraversive circling were recorded every 5 min 30 min before and 2 h after drug administration. Contraversive circling indicates supersensitive dopamine receptors on the ipsilateral side and vice versa. The protocol was approved by the University of Michigan Institutional Animal Ethics Committee. For this study, the animals were drug free for several months before initiation to establish stable control baseline data. Each animal was previously tested with other dopamine receptor agonists several years after MPTP administration. All agents were reagent, medical, or veterinary grade available from commercial sources. L-DOPA methyl ester was purchased from Sigma-Aldrich, St. Louis, MO 63118. Racemic biperiden hydrochloride was used because of its clinical use. It was obtained from the Knoll Pharmaceutical Company, Wippany, NJ 07981. The selective dopamine Dl receptor agonist SKF-82958 (Weinstock et al., 1980) was purchased from Research Biochemicals, Natick, MA. The selective dopamine D2/D3 receptor agonist N-0923 (rotigotine) was obtained from Dr. D. McAfee, Discovery Therapeutics, Richmond, VA 23261. All drugs were given i.m. in a logarithmic dose fashion in doses of 100 or 320 µg/kg to all four monkeys. The same volume of vehicle (5% glucose in H2O or 0.9% NaCl) was injected i.m. as a control. The experimental design included all four monkeys being given the same treatment on the same day (usually Thursday, once per week). Animals were studied at about 0830 of the experimental day with a vehicle control given i.m. at −30 min. At 0 time, either control vehicle or biperiden was given i.m. and the animals run for an additional 30 min. At +30 min, a dopamine receptor agonist was given and the animals were run for an additional 2 h. The order of each dose of medication was randomized.
Fig. 1. Biperiden enhances the effects of L-DOPA methyl ester on circling behavior in MPTP induced hemiparkinsonian monkeys. The number of mean complete rotations during 120 min plus S.E. is shown for contraversive (C) and ipsiversive (I) circling on the y-axis and the dose of biperiden (vehicle 0, 100 and 320 µg/kg) on the x-axis. All injections were i.m. with biperiden or vehicle at 0 time and L-DOPA methyl ester at +30 min. Rotations were counted immediately after the last injection for another 120 min. Two-way ANOVA with repeated measures indicated that the combination increased contraversive circling (F (1, 24) = 370.57, =p b 0.0001; ⁎⁎p b 0.01, ⁎⁎⁎p b 0.001).
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Fig. 2. Effects of L-DOPA methyl ester, SKF-82958, or rotigotine alone and in combination with biperiden in MPTP induced hemiparkinsonian monkeys. Approximately equivalent, moderately effective doses of each dopamine agonist were given in separate experiments (see Table 1). The data with a vehicle control injection plus each agonist were normalized to the maximum contraversive and ipsiversive circling as 100 in order to better illustrate the effects of each agonist in combination with biperiden. Note the opposite actions of the combination of biperiden with the two selective dopamine agonists and the predominant D1-like response of L-DOPA methyl ester. One-way ANOVA with repeated measures were conducted on the original data for each drug combination with p b 0.0001 to b0.001.
2.2. Statistical analysis Our previous studies using MPTP lesioned hemiparkinsonian monkeys provided data with a normal distribution even though a small N was used. Based on these previous studies, the data were analyzed using parametric studies. Data were subjected to statistical analysis for active drug versus vehicle, or active drug alone versus different dose combinations. Two-way ANOVA with repeated measures was run using SPSS 15.0, followed by the Bonferroni comparison procedure when a significant F ratio was obtained. An alpha level of 0.05 was used for all statistical tests. The Mauchly's Test of Sphericity, under the two-way ANOVA with repeated measures, confirmed our assumption that variations over dose and drug conditions are equal. 3. Results 3.1. Effects of biperiden alone and in combination with L-DOPA methyl ester Compared to a vehicle (D5 W) injection, biperiden in doses of 100 and 320 µg/kg i.m. in a dose related manner increased contraversive circling. It also increased ipsiversive circling but less than contraversive circling, as illustrated in Fig. 1. A two-way ANOVA with repeated measures for the ipsiversive circling was conducted and the change was statistically significant (Pillai's Trace Test, F (1, 24) = 39.11, P b 0.001). The effects were statistically significant on contraversive circling as well. The Pillai's Trace Test indicated F (2, 23) = 30.80, P b 0.0001. These effects lasted for at least 2 h. A 5% dextrose in water (D5 W) control in the A.M. at 0 time, and a dose of 16.7 mg/kg i.m. LDOPA methyl ester given at +30 min, produced a much greater increase in contraversive circling and a decrease in ipsiversive circling (see Fig. 1). The combination of L-DOPA methyl ester plus 100 or 320 µg/kg i.m. biperiden produced a further increase, confirmed by two-way ANOVA with repeated measures (Pillai's Trace Test, F (1, 24) = 370.57, P b 0.0001. The effects were small for potentiation and were
primarily an additive effect. However, the interaction analysis of the two-way ANOVA with repeated measures indicated that a 100 µg/kg dose of biperiden i.m. was much more effective than the control (D5 W) and the larger dose of 320 µg/kg, F (2, 23) = 7.85, P b 0.01. 3.2. Effects of biperiden in combination with a selective dopamine D1 or D2/D3 dopamine agonist An attempt to obtain a dose of a dopamine Dl or D2 receptor agonist alone equally effective to 16.7 mg/kg i.m. L-DOPA methyl ester was unsuccessful. As a result, the dose of either dopamine receptor agonist that produced the closest effect to that of L-DOPA methyl ester was chosen for combination studies with biperiden. In order to compare the results of all three different treatment combinations, the data were normalized based on 100 as the maximal contraversive effect of control vehicle plus L-DOPA methyl ester, control vehicle plus the selective dopamine Dl receptor agonist SKF-82958, or control vehicle plus the selective dopamine D2/D3 receptor agonist rotigotine. The results are illustrated in Fig. 2 and Table 1. With each dopamine receptor agonist in a fixed dose, both contraversive and ipsiversive circling were normalized to 100. Increasing doses of biperiden, in combination with L-DOPA methyl ester, showed a similar increase in
Table 1 Mean data of ipsiversive and contraversive circling with experimental treatments given I.M. Medication
Biperiden dose
Ipsiversive
S.E.M.
Contraversive
S.E.M.
L-DOPA
0 100 320 0 100 320 0 100 320
0.49 0.41 0.43 1.25 1.15 0.91 1.15 1.48 2.10
0.07 0.07 0.15 0.15 0.18 0.13 0.16 0.18 0.16
8.84 12.11 11.38 2.88 6.61 6.86 15.58 12.87 9.69
0.61 0.83 0.50 1.09 1.80 1.21 3.88 2.83 2.46
Methyl Ester (16.7 mg/kg) SKF-83958 (74.8 µg/kg)
Rotigotine (10 µg/kg)
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normalized contraversive and a decrease in normalized ipsiversive circling (compare Fig. 1 to Fig. 2). A dose of 74.8 µg/kg i.m. SKF-82958 given alone and in combination with 100 or 320 µg/kg of biperiden produced a marked increase in contraversive circling and a slight decrease in ipsiversive circling, which were both statistically significant by ANOVA (F (2, 24) = 7.41, P b 0.001). This is illustrated in the normalized data in Fig. 2. In marked contrast to the dopamine Dl agonist combination, biperiden attenuated the effects of the dopamine D2/D3 receptor agonist rotigotine on contraversive circling, and enhanced ipsiversive circling in these hemiparkinsonian monkeys. One-way ANOVA with repeated measures indicated that these decreases (F (2, 24) = 10.79, P b 0.0001) as well as the increases (F (2, 24) = 7.84, P b 0.001) were highly significant. 4. Discussion The striatum contains high concentrations of acetylcholine, acetylcholinesterase, choline acetyltransferase, choline transporters, and multiple muscarinic cholinergic (3H-QNB) binding sites (Fibiger et al., 1987; McGeer et al., 1987). There is considerable evidence, based primarily on histological and lesion studies, that the striatum has many large and some small cholinergic interneurons. The large interneurons represent about 1% of the total number of striatal neurons. It is well known that cholinergic striatal neurons are modulated by dopaminergic afferents. Dopamine and its agonists were first shown to inhibit striatal cholinergic interneuronal activity, thus decreasing striatal acetylcholine release and turnover (Lehmann and Langer, 1983; Stoof and Kebabian, 1984). Subsequently, it became clear that dopamine Dl and D2 receptor activation had different effects on striatal acetylcholine release (Ajima et al., 1990; Consolo et al., 1987). Dopamine D2 receptor agonists inhibit acetylcholine release (Dawson et al., 1990; Scatton, 1982). On the other hand, dopamine Dl receptor agonists increase acetylcholine release (Damsma et al., 1990; Fage and Scatton, 1986; Gorell et al., 1986). Selective dopamine antagonists have the opposite effects on acetylcholine release. Both nonselective (benztropine) and partially selective (biperiden, trihexyphenidyl) muscarinic cholinergic antagonists are used to supplement levodopa therapy in human parkinsonism (Cedarbaum et al., 1990). Burke and Fahn (1984) and Burke (1986) reported on the selectivity of various anticholinergic, antiparkinsonian agents for muscarinic M1 and M2 receptor families of cholinergic receptor subtypes. For a comparison to pirenzepine, which had a selectivity ratio for muscarinic M1 receptors of 8.6, the selectivity ratios for various other anticholinergic agents tested were: biperiden 6.8; trihexiphenidyl 6.4; scopolamine 5.5; dexetimide 4.3; benztropine 4.2; atropine 3.3; procyclidine 2.9; ethopropazine 2.4; orphenadrine 2.1. Syvälahti et al. (1987) also reported that biperiden, like pirenzepine, binds to muscarinic M1 cholinergic receptors selectively. Subsequently, Eltze and Figala (1998) studied the affinity of the (+) and (−) enantiomers of biperiden for different muscarinic cholinergic receptors. They showed that (+)biperiden was highly M1 selective, while (−)biperiden had low binding affinity and did not discriminate between muscarinic M1 and M2 receptor families. The pA2 is the negative logarithm of the molar concentration of an antagonist which produces a two fold shift to the right of the agonist dose response curve. The isomers of biperiden as antagonists of acetylcholine differ considerably. The pA2 of (+) biperiden is 9.15, and of (−)biperiden is 6.36 for muscarinic M1 sites. It is clear that in low doses or concentrations, racemic biperiden will act as a selective muscarinic M1 receptor antagonist. One can conclude that the synergistic effect of racemic biperiden in the present study with L-DOPA methyl ester and SKF-82958 is probably due to a muscarinic M1/M4 cholinergic receptor antagonist action. An especially provocative conclusion from the present study is that in MPTP hemilesioned monkeys, contraversive circling induced by L-DOPA methyl ester is mediated by a predominant dopamine Dl
and not a D2 receptor agonist action. The fact that biperiden had a synergistic action with both L-DOPA methyl ester and SKF-82958, but antagonized the effects of rotigotine, is indeed impressive. The findings with the combination of biperiden and Dl or D2/D3 selective dopamine agonists are in agreement with a previous report that trihexiphenidyl, another muscarinic M1 receptor selective cholinergic antagonist (Giachetti et al., 1986; Tien and Wallace, 1985), enhances the effects of SKF-82958 and antagonizes the effects of rotigotine in MPTP-induced hemiparkinsonian monkeys (Domino and Ni, 1998). The results of these two studies indicate that the muscarinic effects of acetylcholine, by stimulating the direct GABA/substance P pathways, are antagonistic to the D1 receptor actions of dopamine. The muscarinic M1 receptor actions of acetylcholine via Gq/11 increase IP3/DAG. The muscarinic M4 receptor actions of acetylcholine via Gi reduce cAMP, whereas the D1/D5 receptor actions of dopamine stimulate cAMP formation. Therefore, muscarinic M1 receptor antagonism will reduce IP3/DAG, and muscarinic M4 receptor antagonism will enhance cAMP formation by the D1 receptor actions of dopamine. The D2 receptor actions of dopamine to inhibit cAMP formation in the indirect GABA enkephalin pathway will be reduced by muscarinic M4 receptor antagonism of the usual inhibition of cAMP by acetylcholine. Obviously, the conclusion that dopamine Dl but not D2/D3 receptors control the additive cholinergic M1/M4 receptor interactions in lesions of the striatum is the best interpretation of the data. The results with biperiden are similar to those with trihexiphenidyl, another muscarinic cholinergic antagonist, in combination with the same dopamine receptor agonist in hemiparkinsonian monkeys (Domino and Ni, 1998). Studies with highly selective dopamine D1 through D5 receptor agonists (see Alexander et al., 2008) are needed to confirm the specific role of each member of the dopamine family of receptor subtypes. Blocking experiments with very selective dopamine antagonists and correlational analysis of drug potencies with binding affinities must be done. There are now more selective Dl receptor agonists in addition to SKF-82958 (Salmi et al., 2004). Furthermore, rotigotine, like other D2/D3 receptor agonists, has some affinity for other dopamine receptors. Biperiden also inhibits dopamine reuptake (Jackisch et al., 1993). A study of both isomers of biperiden should also be undertaken in the future. Both biperiden and trihexyphenidyl have M1 and M4 cholinergic receptor affinities. Inasmuch as the striatum has a very high abundance of M4 receptors, it may be that the interactions observed involve M4 rather than M1 cholinergic receptors. Further studies with other more highly selective dopamine D3 receptor agonists, and muscarinic cholinergic antagonists, must be conducted to determine the generalization of the provocative conclusions of the present study. Acknowledgments Supported in part by the University of Michigan Psychopharmacology Research Fund 361024, and the Education and Research Development Fund 54010. References Ajima, A., Yamaguchi, T., Kato, T., 1990. Modulation of acetylcholine release by Dl, D2 dopamine receptors in rat striatum under freely moving conditions. Brain Res. 518, 193–198. Albin, R.L., Young, A.B., Penney, J.B., 1995. The functional anatomy of the basal ganglia. Trends Neurosci. 18, 63–64. Alexander, S.P.H., Mathie, A., Peters, J.A., 2008. Guide to Receptors and Channels (GRAC) 3rd Ed. Br. J. Pharmacol. 153 (Suppl (2)), S1–S-209. Babic, T., Boothmann, B., Polivka, J., Rektor, I., Boroojerdi, B., Hack, H.J., Randerath, O., 2006. Rotigotine transdermal patch enables rapid titration to effective doses in advanced-stage idiopathic Parkinson disease: subanalysis of a parallel group, openlabel, dose-escalation study. Clin. Neuropharmacol. 29, 238–242. Bankiewicz, K.S., Oldfield, E.H., Chiueh, C.C., Doppman, J.L., Jacobowitz, D.M., Kopin, U., 1986. Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci. 39, 7–16.
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