Subtypes of Muscarinic Receptors as Targets for Treatment of Dystonia

Event Abstract Back to Event Subtypes of Muscarinic Receptors as Targets for Treatment of Dystonia Dominika Klisko1, Peter Jenner1 and Sarah Rose1* 1 King's College London, Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, United Kingdom Background: Anticholinergics are effective in some types of dystonia that do not respond to levodopa, particularly in juveniles (1). However, they produce peripheral and central side effects which reduce compliance due to lack of selectivity. Muscarinic M4 receptors are specifically located in the striatum, and therefore have the potential to improve the treatment without producing unfavourable side effects (2). For this reason, we have investigated whether selective antagonists of the M4 receptor will reduce dystonia without inducing the M1/M3-mediated peripheral side effects. We used pilocarpine-induced perioral movements and saliva production to measure central and peripheral activity respectively. Methods: Male Wistar rats were treated with pilocarpine (0.1 – 32 mg/kg ip) and the number of purposeless perioral movements was recorded for 1 min every 10 min (3). Additionally, the saliva secretion test was performed following administration of pilocarpine (0.1 – 8 mg/kg ip) by oral introduction of a cotton bud for 10 s (4). Subsequently, the effect of non-selective antimuscarinics: trihexyphenidyl (THP; 0.3 – 5 mg/kg ip) and benztropine (BNZ; 0.3 – 5 mg/kg ip), and subtype selective antimuscarinics: pirenzepine (PIR; M1; 2.36 – 377 nmole ICV), darifenacin (DAR; M3; 0.75 – 24 mg/kg ip) and tropicamide (TRP; M4; 1.25 – 20 mg/kg ip) was investigated on pilocarpine-induced (3.4 mg/kg ip) chewing movements and salivation and measured as previously stated. For ICV pirenzepine administration, a stainless steel cannula was stereotaxically implanted into the right lateral ventricle (coordinates AP: -0.8; ML: -1.4; DV: -2.8 mm relative to bregma) (5) under isoflurane anaesthesia. Injections were made via injection needle connected to a microinjection pump (2 µl at a rate 1 µl/min). Data are expressed as mean ± SEM and analysed by non-linear regression (ED50 and ID50), Friedman test followed by Dunn’s test (perioral movements) and one-way ANOVA followed by Dunnett’s test (salivation). Results: Systemic administration of pilocarpine dose-dependently induced purposeless chewing movements (EC50=3.4 mg/kg). The chewing was significantly inhibited by peripheral and central administration of antimuscarinics: (IC50 in mg/kg: THP: 1.6; BNZ: 0.7; DAR: 9.0; TRP: 8.6; PIR: 29 nmole). Pilocarpine-stimulated sialorrhea was also reduced by all antimuscarinics, except pirenzepine (IC50 in mg/kg: THP: >5; BNZ: >5; DAR: 0.3; TRP: >20). Conclusions: All peripherally administered antimuscarinics, regardless of their relative selectivity, inhibited pilocarpine-induced chewing and reduced saliva production. Trihexyphenidyl and benztropine were more potent in preventing chewing than other compounds. Systemic administration of M3 antagonist almost completely inhibited salivation, whereas ICV administration of pirenzepine reduced jaw movements but did not suppress sialorrhea, which could suggest involvement of centrally located muscarinic receptor in perioral movements but not saliva production. However, since none of the compounds were highly selective for the M4 receptor, further investigation with more selective compounds is needed to explain the role of M4 muscarinic receptor in production of involuntary movements. Acknowledgements This study was supported by the Rosetrees Trust. References (1) Jankovic J (2013). Mov Disord 28: 1001 – 1012; (2) Mayorga AJ (1999). Eur J Pharmacol 364: 7 – 11; (3) Stewart B et al. (1988). Psychopharmacology 96: 55 – 62; (4) Flynn FW et al. (1980). Physiol Behav 24: 451 – 455; (5) Paxinos G and Watson C (1986). The rat in stereotaxic coordinates. Academic Press, New York. Keywords: Dystonia, muscarinic receptors, Purposeless chewing, Rats, anticholinergics Conference: 5th Biennial Workshop on Dystonia: “Controversies in Dystonia and Parkinsonism” | Nobile Collegio Chimico Farmaceutico, Rome, May 29-30, 2015, Rome, Italy, 29 May - 30 May, 2015. Presentation Type: Poster presentation Topic: Dystonia Citation: Klisko D, Jenner P and Rose S (2015). Subtypes of Muscarinic Receptors as Targets for Treatment of Dystonia. Front. Neurol. Conference Abstract: 5th Biennial Workshop on Dystonia: “Controversies in Dystonia and Parkinsonism” | Nobile Collegio Chimico Farmaceutico, Rome, May 29-30, 2015. doi: 10.3389/conf.fneur.2015.57.00006 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Apr 2015; Published Online: 30 Apr 2015. * Correspondence: Dr. Sarah Rose, King's College London, Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, London, SE1 1UL, United Kingdom, sarah.salvage@kcl.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Dominika Klisko Peter Jenner Sarah Rose Google Dominika Klisko Peter Jenner Sarah Rose Google Scholar Dominika Klisko Peter Jenner Sarah Rose PubMed Dominika Klisko Peter Jenner Sarah Rose Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.