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2.448 Reversal of motor deficits without dyskinesia induction by continuous delivery of ropinirole in MPTP-treated common marmosets
S140
Tuesday, 11 December 2007
50% and a pA2 (in the presence of quinpirole) of 8.4), and hD3 receptors (pEC50 = 9.2, IA = 67%; pA2 = 9) and a full agonist at h5-HT1A receptors (pEC50 = 6.3). In striatal slices pardoprunox attenuated [3 H]-dopamine release indicating lack of agonism (pD2 < 6), yet antagonized the effect of quinpirole on K+ -stimulated [3 H]-dopamine release (pA2 8.5). The partial agonist terguride and haloperidol also had this effect (pA2 10.2 and 9.3). Conclusion: These data suggest that pardoprunox possesses partial agonist properties at dopamine D2/3 receptors and agonist properties at 5-HT1A receptors in vitro, further in vivo studies will be needed, but these actions differentiate from known dopamine agonists.
2.446 BN82451 and BN83026 reduce L-DOPA-induced dyskinesia in hemiparkinsonian rats B. Spinnewyn1° , C. Charnet, S. Cornet, S. Bernetiere, J. Camara, M. Auguet, P.-E. Chabrier 1 Les Ulis, France Objective: Chronic exposure to L-DOPA, the most efficacious treatment in the management of Parkinson’s disease, is associated with the development of complications such as dyskinesia. In this study the effects of acute or subchronic administration of BN82451 and BN83026, two members of a new family of multitargeting molecules, were evaluated on a model of L-DOPA-induced dyskinesia in rats. Method: Rats were submitted to two unilateral injections of 6-OHDA in the striatum. Four weeks later, the animals were treated chronically with increasing daily doses of L-DOPA. During 4 weeks of treatment, L-DOPA-treated rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia. For quantification of dyskinesia, rats were observed individually every 30 minutes from 30 to 180 min after the injection of L-DOPA or vehicle. At day 1, BN82451 and BN83026 were orally administered just after the first AIM measurement (30 minutes after L-DOPA injection). For subchronic determination, treatment was pursued the 4 consecutive days; once a day for BN83026 and twice a day for BN82451 according to their respective pharmacokinetics. AIMs were measured at Day 1 and Day 5. Results: A single administration (10 and 30 mg/kg) of BN82451 or BN83026 significantly reduced AIMs. However at day 1, the dose of 3 mg/kg was partially active whereas the dose of 1 mg/kg was ineffective. At day 5, treatment with 3 mg/kg, but not with 1 mg/kg, of the two compounds resulted in a fully significant improvement of AIMs score. Conclusion: The results show that a single administration of BN82451 and BN83026 alleviate dyskinesia induced by L-DOPA in hemiparkinsonian rats and demonstrate that subchronic treatments necessitate lower doses to achieve the same antidyskinetic efficacy.
2.447 AMPA antagonists attenuate L-DOPA-induced abnormal involuntary movements in the 6-OHDA-lesioned rat model of Parkinson’s disease C. Kobylecki1° , P. Ravenscroft, A. Crossman United Kingdom
1 Manchester,
Objective: Chronic treatment with L-DOPA in Parkinson’s disease (PD) is associated with motor complications, including L-DOPA-induced dyskinesia (LID). Elevated striatal glutamate transmission has been implicated in the pathophysiology of LID, and the a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor antagonist, talampanel, has been shown to reduce LID in a primate model of PD [1]. Our objective was to evaluate the efficacy of AMPA receptor antagonists in a recently-validated rodent model of LID. Method: Rats were rendered parkinsonian by unilateral 6-hydroxydopamine (6-OHDA) lesion of the right medial forebrain bundle. A stable level of abnormal involuntary movements (AIMs) was induced by chronic L-DOPA treatment, as previously described [2]. Escalating doses of AMPA antagonists were administered together with L-DOPA, and their effect on
L-DOPA-induced AIMs evaluated. Motor performance was assessed using the rotarod; antagonists were evaluated alone and in combination with L-DOPA. Results: The competitive AMPA antagonist, ZK 200775 (6 mg/kg, i.p.) impaired motor performance when compared to vehicle (p < 0.05; paired t test). ZK 200775 (3 and 6 mg/kg, i.p.) did not alter motor performance in combination with L-DOPA. Axial, limb and orolingual AIMs were reduced following ZK 200775 administration (3 and 6 mg/kg, i.p.) when compared to L-DOPA alone (p < 0.01; Friedman ANOVA followed by Dunn post hoc test). Conclusion: These data support the potential use of AMPA receptor antagonists to alleviate LID. These agents have hitherto not been examined in the rodent AIMs model of LID, and further work is required to elucidate the role of antagonists at different subtypes of the AMPA receptor. AMPA receptor antagonists may prove useful to alleviate the disabling motor complications of L-DOPA therapy in PD. References [1] Konitsiotis S et al. Neurology 2000; 54: 1589−95. [2] Lundblad M et al. Eur J Neurosci 2002; 15: 120−32.
2.448 Reversal of motor deficits without dyskinesia induction by continuous delivery of ropinirole in MPTP-treated common marmosets K. Stockwell1° , D. Virley, M. Perren, M. Iravani, M. Jackson, S. Rose, P. Jenner 1 London, United Kingdom Objective: L-dopa treatment for Parkinson’s disease is associated with motor complications, including dyskinesia, postulated to be due to its short half-life and pulsatile effect upon striatal dopamine receptors. Treatment with dopamine agonists, e.g. ropinirole (three-times-daily oral administration), may result in less dyskinesia, compared with L-dopa. Continuous delivery may offer improved reversal of motor deficits and reduced dyskinesia, therefore the effects of repeated oral ropinirole treatment versus continuous infusion were investigated in MPTP-treated common marmosets. Method: Common marmosets were treated with MPTP (2 mg/kg, subcutaneously, daily over 5 days) to induce a stable parkinsonian syndrome. Animals were divided into two groups. During Phase I (14 days), Group 1 (n = 4) received ropinirole (0.4 mg/kg, po, BID, 7 hrs apart), while Group 2 (n = 5) received continuous ropinirole infusion via subcutaneous Alzet osmotic minipumps (0.8 mg/kg/day, 2x M2002). On day 15, Group 2 switched to oral treatment and the minipumps were removed, while Group 1 switched to continuous infusion for 14 days (Phase II). Locomotor activity, motor disability and dyskinesia were assessed on treatment days 1, 4, 8, 11 and 14 (Phase I), and 16, 19, 23, 26 and 29 (Phase II). Results: During Phase I, levels of increased locomotor activity were similar between groups, but the improvement in motor disability was more marked in animals receiving continuous infusion than oral treatment. Ropinirole induced little dyskinesia, but where present, dyskinesia was more marked in animals receiving oral treatment than continuous infusion. During Phase II, the improvement in locomotor activity and reversal of motor deficits were maintained. Motor disability was further improved in animals switched to continuous infusion. Dyskinesia levels were low, but tended to be higher in animals that initially received oral treatment than continuous infusion. Conclusion: These data suggest that continuous infusion of ropinirole reduces motor disability and the risk of dyskinesia compared with oral treatment.
Tuesday, 11 December 2007
50% and a pA2 (in the presence of quinpirole) of 8.4), and hD3 receptors (pEC50 = 9.2, IA = 67%; pA2 = 9) and a full agonist at h5-HT1A receptors (pEC50 = 6.3). In striatal slices pardoprunox attenuated [3 H]-dopamine release indicating lack of agonism (pD2 < 6), yet antagonized the effect of quinpirole on K+ -stimulated [3 H]-dopamine release (pA2 8.5). The partial agonist terguride and haloperidol also had this effect (pA2 10.2 and 9.3). Conclusion: These data suggest that pardoprunox possesses partial agonist properties at dopamine D2/3 receptors and agonist properties at 5-HT1A receptors in vitro, further in vivo studies will be needed, but these actions differentiate from known dopamine agonists.
2.446 BN82451 and BN83026 reduce L-DOPA-induced dyskinesia in hemiparkinsonian rats B. Spinnewyn1° , C. Charnet, S. Cornet, S. Bernetiere, J. Camara, M. Auguet, P.-E. Chabrier 1 Les Ulis, France Objective: Chronic exposure to L-DOPA, the most efficacious treatment in the management of Parkinson’s disease, is associated with the development of complications such as dyskinesia. In this study the effects of acute or subchronic administration of BN82451 and BN83026, two members of a new family of multitargeting molecules, were evaluated on a model of L-DOPA-induced dyskinesia in rats. Method: Rats were submitted to two unilateral injections of 6-OHDA in the striatum. Four weeks later, the animals were treated chronically with increasing daily doses of L-DOPA. During 4 weeks of treatment, L-DOPA-treated rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia. For quantification of dyskinesia, rats were observed individually every 30 minutes from 30 to 180 min after the injection of L-DOPA or vehicle. At day 1, BN82451 and BN83026 were orally administered just after the first AIM measurement (30 minutes after L-DOPA injection). For subchronic determination, treatment was pursued the 4 consecutive days; once a day for BN83026 and twice a day for BN82451 according to their respective pharmacokinetics. AIMs were measured at Day 1 and Day 5. Results: A single administration (10 and 30 mg/kg) of BN82451 or BN83026 significantly reduced AIMs. However at day 1, the dose of 3 mg/kg was partially active whereas the dose of 1 mg/kg was ineffective. At day 5, treatment with 3 mg/kg, but not with 1 mg/kg, of the two compounds resulted in a fully significant improvement of AIMs score. Conclusion: The results show that a single administration of BN82451 and BN83026 alleviate dyskinesia induced by L-DOPA in hemiparkinsonian rats and demonstrate that subchronic treatments necessitate lower doses to achieve the same antidyskinetic efficacy.
2.447 AMPA antagonists attenuate L-DOPA-induced abnormal involuntary movements in the 6-OHDA-lesioned rat model of Parkinson’s disease C. Kobylecki1° , P. Ravenscroft, A. Crossman United Kingdom
1 Manchester,
Objective: Chronic treatment with L-DOPA in Parkinson’s disease (PD) is associated with motor complications, including L-DOPA-induced dyskinesia (LID). Elevated striatal glutamate transmission has been implicated in the pathophysiology of LID, and the a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor antagonist, talampanel, has been shown to reduce LID in a primate model of PD [1]. Our objective was to evaluate the efficacy of AMPA receptor antagonists in a recently-validated rodent model of LID. Method: Rats were rendered parkinsonian by unilateral 6-hydroxydopamine (6-OHDA) lesion of the right medial forebrain bundle. A stable level of abnormal involuntary movements (AIMs) was induced by chronic L-DOPA treatment, as previously described [2]. Escalating doses of AMPA antagonists were administered together with L-DOPA, and their effect on
L-DOPA-induced AIMs evaluated. Motor performance was assessed using the rotarod; antagonists were evaluated alone and in combination with L-DOPA. Results: The competitive AMPA antagonist, ZK 200775 (6 mg/kg, i.p.) impaired motor performance when compared to vehicle (p < 0.05; paired t test). ZK 200775 (3 and 6 mg/kg, i.p.) did not alter motor performance in combination with L-DOPA. Axial, limb and orolingual AIMs were reduced following ZK 200775 administration (3 and 6 mg/kg, i.p.) when compared to L-DOPA alone (p < 0.01; Friedman ANOVA followed by Dunn post hoc test). Conclusion: These data support the potential use of AMPA receptor antagonists to alleviate LID. These agents have hitherto not been examined in the rodent AIMs model of LID, and further work is required to elucidate the role of antagonists at different subtypes of the AMPA receptor. AMPA receptor antagonists may prove useful to alleviate the disabling motor complications of L-DOPA therapy in PD. References [1] Konitsiotis S et al. Neurology 2000; 54: 1589−95. [2] Lundblad M et al. Eur J Neurosci 2002; 15: 120−32.
2.448 Reversal of motor deficits without dyskinesia induction by continuous delivery of ropinirole in MPTP-treated common marmosets K. Stockwell1° , D. Virley, M. Perren, M. Iravani, M. Jackson, S. Rose, P. Jenner 1 London, United Kingdom Objective: L-dopa treatment for Parkinson’s disease is associated with motor complications, including dyskinesia, postulated to be due to its short half-life and pulsatile effect upon striatal dopamine receptors. Treatment with dopamine agonists, e.g. ropinirole (three-times-daily oral administration), may result in less dyskinesia, compared with L-dopa. Continuous delivery may offer improved reversal of motor deficits and reduced dyskinesia, therefore the effects of repeated oral ropinirole treatment versus continuous infusion were investigated in MPTP-treated common marmosets. Method: Common marmosets were treated with MPTP (2 mg/kg, subcutaneously, daily over 5 days) to induce a stable parkinsonian syndrome. Animals were divided into two groups. During Phase I (14 days), Group 1 (n = 4) received ropinirole (0.4 mg/kg, po, BID, 7 hrs apart), while Group 2 (n = 5) received continuous ropinirole infusion via subcutaneous Alzet osmotic minipumps (0.8 mg/kg/day, 2x M2002). On day 15, Group 2 switched to oral treatment and the minipumps were removed, while Group 1 switched to continuous infusion for 14 days (Phase II). Locomotor activity, motor disability and dyskinesia were assessed on treatment days 1, 4, 8, 11 and 14 (Phase I), and 16, 19, 23, 26 and 29 (Phase II). Results: During Phase I, levels of increased locomotor activity were similar between groups, but the improvement in motor disability was more marked in animals receiving continuous infusion than oral treatment. Ropinirole induced little dyskinesia, but where present, dyskinesia was more marked in animals receiving oral treatment than continuous infusion. During Phase II, the improvement in locomotor activity and reversal of motor deficits were maintained. Motor disability was further improved in animals switched to continuous infusion. Dyskinesia levels were low, but tended to be higher in animals that initially received oral treatment than continuous infusion. Conclusion: These data suggest that continuous infusion of ropinirole reduces motor disability and the risk of dyskinesia compared with oral treatment.