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A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease.
Exp Neurol. 2005 Feb; 191(2):243-50.EN

Abstract

l-DOPA-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease (PD). Whilst the MPTP-lesioned primate provides an excellent animal model in which to develop new therapies, however, it is logistically difficult to employ widely. Thus, a simple rodent assay to screen multiple compounds as candidates for further study of their potential in LID would be a valuable addition to the drug development process. Here, we investigate how agents with demonstrated ability to reduce LID in man and monkey can regulate l-DOPA-induced behaviours in the reserpine-treated rat. Administration of l-DOPA (125 mg/kg) to reserpine-treated rats elicited high levels of both horizontal and vertical movement. Drugs that have previously been found to reduce LID in parkinsonian primates and PD patients without compromising the anti-parkinsonian efficacy of l-DOPA selectively and dose-dependently reduce vertical components of activity when co-administered with l-DOPA in the reserpine-treated rat. For instance, amantadine (1 mg/kg) and idazoxan (3 mg/kg) reduced vertical activity by 59% and 83%, respectively, while neither drug had significant effects on horizontal activity. In contrast, haloperidol (1 mg/kg), an agent lacking the ability to selectively reduce LID without compromising the anti-parkinsonian actions of l-DOPA, reduced both horizontal and vertical activity, by 98% and 99%, respectively. We also assessed the actions of an NMDA antagonist, a class of compound proposed to have potential as anti-dyskinetic agents. The effects of MK-801 were dose-dependent (0.01-0.5 mg/kg), at some doses (e.g., 0.05 mg/kg), providing selective reduction of vertical activity (90%), at others (e.g., 0.5 mg/kg), non-selective reduction of vertical and horizontal (99% and 77%, respectively). These observations highlight the association between potential anti-dyskinetic action and a selective reduction in l-DOPA-induced vertical activity in the reserpine-treated rat.

Authors+Show Affiliations

Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15649479

Citation

Johnston, Tom H., et al. "A Simple Rodent Assay for the in Vivo Identification of Agents With Potential to Reduce Levodopa-induced Dyskinesia in Parkinson's Disease." Experimental Neurology, vol. 191, no. 2, 2005, pp. 243-50.
Johnston TH, Lee J, Gomez-Ramirez J, et al. A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease. Exp Neurol. 2005;191(2):243-50.
Johnston, T. H., Lee, J., Gomez-Ramirez, J., Fox, S. H., & Brotchie, J. M. (2005). A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease. Experimental Neurology, 191(2), 243-50.
Johnston TH, et al. A Simple Rodent Assay for the in Vivo Identification of Agents With Potential to Reduce Levodopa-induced Dyskinesia in Parkinson's Disease. Exp Neurol. 2005;191(2):243-50. PubMed PMID: 15649479.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease. AU - Johnston,Tom H, AU - Lee,Joohyung, AU - Gomez-Ramirez,Jordi, AU - Fox,Susan H, AU - Brotchie,Jonathan M, PY - 2004/07/20/received PY - 2004/09/20/revised PY - 2004/10/05/accepted PY - 2005/1/15/pubmed PY - 2005/2/19/medline PY - 2005/1/15/entrez SP - 243 EP - 50 JF - Experimental neurology JO - Exp Neurol VL - 191 IS - 2 N2 - l-DOPA-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease (PD). Whilst the MPTP-lesioned primate provides an excellent animal model in which to develop new therapies, however, it is logistically difficult to employ widely. Thus, a simple rodent assay to screen multiple compounds as candidates for further study of their potential in LID would be a valuable addition to the drug development process. Here, we investigate how agents with demonstrated ability to reduce LID in man and monkey can regulate l-DOPA-induced behaviours in the reserpine-treated rat. Administration of l-DOPA (125 mg/kg) to reserpine-treated rats elicited high levels of both horizontal and vertical movement. Drugs that have previously been found to reduce LID in parkinsonian primates and PD patients without compromising the anti-parkinsonian efficacy of l-DOPA selectively and dose-dependently reduce vertical components of activity when co-administered with l-DOPA in the reserpine-treated rat. For instance, amantadine (1 mg/kg) and idazoxan (3 mg/kg) reduced vertical activity by 59% and 83%, respectively, while neither drug had significant effects on horizontal activity. In contrast, haloperidol (1 mg/kg), an agent lacking the ability to selectively reduce LID without compromising the anti-parkinsonian actions of l-DOPA, reduced both horizontal and vertical activity, by 98% and 99%, respectively. We also assessed the actions of an NMDA antagonist, a class of compound proposed to have potential as anti-dyskinetic agents. The effects of MK-801 were dose-dependent (0.01-0.5 mg/kg), at some doses (e.g., 0.05 mg/kg), providing selective reduction of vertical activity (90%), at others (e.g., 0.5 mg/kg), non-selective reduction of vertical and horizontal (99% and 77%, respectively). These observations highlight the association between potential anti-dyskinetic action and a selective reduction in l-DOPA-induced vertical activity in the reserpine-treated rat. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/15649479/A_simple_rodent_assay_for_the_in_vivo_identification_of_agents_with_potential_to_reduce_levodopa_induced_dyskinesia_in_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(04)00395-4 DB - PRIME DP - Unbound Medicine ER -