Background: Recent evidences obtained in rodent and primate models of PD and preliminary clinical trials, indicate that adenosine A2A receptor antagonists might represent a new valuable therapeutic tool for the treatment of PD. Methods: Unilaterallly 6-hydroxydopamine lesioned rats were used for evaluation of motor impairments, whereas the acetylcholinesterase inhibitor tacrine (2.5 mg/kg i.p.) was administered to rats to induce tremulous jaw movements as a model of parkinsonian tremor. In situ hybridization was utilized to evaluate GAD67 mRNA. Results: In 6-OHDA lesioned rats, acute administration of SCH 58261 counteracted the impairments in the initiation of stepping movements induced by the lesion and increased the turning behavior induced by L-DOPA. Furthermore, in the tacrine model of parkinsonian tremor, SCH58261 antagonised tacrine-induced bursts of tremulous jaw movements. In chronic studies, SCH 58261 L-DOPA in contrast to L-DOPA alone, did not induce long-term increase in GAD67 (the synthesizing enzyme of GABA) mRNA in striatum and globus pallidus whereas the increase in the mRNA of GAD67 produced by the dopaminergic lesion in the substantia nigra was counteracted by SCH 58261 L-DOPA. Conclusion: The data indicate that A2A receptor antagonists may be beneficial in motor impairment and tremor which characterize PD. Furthermore the neuronal modifications observed in rat basal ganglia after chronic treatment with SCH 58261 L-DOPA as compared to L-DOPABackground: Recent evidences obtained in rodent and primate models of PD and preliminary clinical trials, indicate that adenosine A2A receptor antagonists might represent a new valuable therapeutic tool for the treatment of PD. Methods: Unilaterallly 6-hydroxydopamine lesioned rats were used for evaluation of motor impairments, whereas the acetylcholinesterase inhibitor tacrine (2.5 mg/kg i.p.) was administered to rats to induce tremulous jaw movements as a model of parkinsonian tremor. In situ hybridization was utilized to evaluate GAD67 mRNA. Results: In 6-OHDA lesioned rats, acute administration of SCH 58261 counteracted the impairments in the initiation of stepping movements induced by the lesion and increased the turning behavior induced by L-DOPA. Furthermore, in the tacrine model of parkinsonian tremor, SCH58261 antagonised tacrine-induced bursts of tremulous jaw movements. In chronic studies, SCH 58261 L-DOPA in contrast to L-DOPA alone, did not induce long-term increase in GAD67 (the synthesizing enzyme of GABA) mRNA in striatum and globus pallidus whereas the increase in the mRNA of GAD67 produced by the dopaminergic lesion in the substantia nigra was counteracted by SCH 58261 L-DOPA. Conclusion: The data indicate that A2A receptor antagonists may be beneficial in motor impairment and tremor which characterize PD. Furthermore the neuronal modifications observed in rat basal ganglia after chronic treatment with SCH 58261 L-DOPA as compared to L-DOPABackground: Recent evidences obtained in rodent and primate models of PD and preliminary clinical trials, indicate that adenosine A2A receptor antagonists might represent a new valuable therapeutic tool for the treatment of PD. Methods: Unilaterallly 6-hydroxydopamine lesioned rats were used for evaluation of motor impairments, whereas the acetylcholinesterase inhibitor tacrine (2.5 mg/kg i.p.) was administered to rats to induce tremulous jaw movements as a model of parkinsonian tremor. In situ hybridization was utilized to evaluate GAD67 mRNA. Results: In 6-OHDA lesioned rats, acute administration of SCH 58261 counteracted the impairments in the initiation of stepping movements induced by the lesion and increased the turning behavior induced by L-DOPA. Furthermore, in the tacrine model of parkinsonian tremor, SCH58261 antagonised tacrine-induced bursts of tremulous jaw movements. In chronic studies, SCH 58261 L-DOPA in contrast to L-DOPA alone, did not induce long-term increase in GAD67 (the synthesizing enzyme of GABA) mRNA in striatum and globus pallidus whereas the increase in the mRNA of GAD67 produced by the dopaminergic lesion in the substantia nigra was counteracted by SCH 58261 L-DOPA. Conclusion: The data indicate that A2A receptor antagonists may be beneficial in motor impairment and tremor which characterize PD. Furthermore the neuronal modifications observed in rat basal ganglia after chronic treatment with SCH 58261 L-DOPA as compared to L-DOPA alone, suggest that such treatment might not produce detrimental long-term responses in basal ganglia areas.

Modulatory role of adenosine A(2A) receptors in basal ganglia as basis for the use of A(2A) antagonists in the treatment of Parkinson's disease

CARTA, ANNAROSA;FRAU, LUCIA;
2006

Abstract

Background: Recent evidences obtained in rodent and primate models of PD and preliminary clinical trials, indicate that adenosine A2A receptor antagonists might represent a new valuable therapeutic tool for the treatment of PD. Methods: Unilaterallly 6-hydroxydopamine lesioned rats were used for evaluation of motor impairments, whereas the acetylcholinesterase inhibitor tacrine (2.5 mg/kg i.p.) was administered to rats to induce tremulous jaw movements as a model of parkinsonian tremor. In situ hybridization was utilized to evaluate GAD67 mRNA. Results: In 6-OHDA lesioned rats, acute administration of SCH 58261 counteracted the impairments in the initiation of stepping movements induced by the lesion and increased the turning behavior induced by L-DOPA. Furthermore, in the tacrine model of parkinsonian tremor, SCH58261 antagonised tacrine-induced bursts of tremulous jaw movements. In chronic studies, SCH 58261 L-DOPA in contrast to L-DOPA alone, did not induce long-term increase in GAD67 (the synthesizing enzyme of GABA) mRNA in striatum and globus pallidus whereas the increase in the mRNA of GAD67 produced by the dopaminergic lesion in the substantia nigra was counteracted by SCH 58261 L-DOPA. Conclusion: The data indicate that A2A receptor antagonists may be beneficial in motor impairment and tremor which characterize PD. Furthermore the neuronal modifications observed in rat basal ganglia after chronic treatment with SCH 58261 L-DOPA as compared to L-DOPABackground: Recent evidences obtained in rodent and primate models of PD and preliminary clinical trials, indicate that adenosine A2A receptor antagonists might represent a new valuable therapeutic tool for the treatment of PD. Methods: Unilaterallly 6-hydroxydopamine lesioned rats were used for evaluation of motor impairments, whereas the acetylcholinesterase inhibitor tacrine (2.5 mg/kg i.p.) was administered to rats to induce tremulous jaw movements as a model of parkinsonian tremor. In situ hybridization was utilized to evaluate GAD67 mRNA. Results: In 6-OHDA lesioned rats, acute administration of SCH 58261 counteracted the impairments in the initiation of stepping movements induced by the lesion and increased the turning behavior induced by L-DOPA. Furthermore, in the tacrine model of parkinsonian tremor, SCH58261 antagonised tacrine-induced bursts of tremulous jaw movements. In chronic studies, SCH 58261 L-DOPA in contrast to L-DOPA alone, did not induce long-term increase in GAD67 (the synthesizing enzyme of GABA) mRNA in striatum and globus pallidus whereas the increase in the mRNA of GAD67 produced by the dopaminergic lesion in the substantia nigra was counteracted by SCH 58261 L-DOPA. Conclusion: The data indicate that A2A receptor antagonists may be beneficial in motor impairment and tremor which characterize PD. Furthermore the neuronal modifications observed in rat basal ganglia after chronic treatment with SCH 58261 L-DOPA as compared to L-DOPABackground: Recent evidences obtained in rodent and primate models of PD and preliminary clinical trials, indicate that adenosine A2A receptor antagonists might represent a new valuable therapeutic tool for the treatment of PD. Methods: Unilaterallly 6-hydroxydopamine lesioned rats were used for evaluation of motor impairments, whereas the acetylcholinesterase inhibitor tacrine (2.5 mg/kg i.p.) was administered to rats to induce tremulous jaw movements as a model of parkinsonian tremor. In situ hybridization was utilized to evaluate GAD67 mRNA. Results: In 6-OHDA lesioned rats, acute administration of SCH 58261 counteracted the impairments in the initiation of stepping movements induced by the lesion and increased the turning behavior induced by L-DOPA. Furthermore, in the tacrine model of parkinsonian tremor, SCH58261 antagonised tacrine-induced bursts of tremulous jaw movements. In chronic studies, SCH 58261 L-DOPA in contrast to L-DOPA alone, did not induce long-term increase in GAD67 (the synthesizing enzyme of GABA) mRNA in striatum and globus pallidus whereas the increase in the mRNA of GAD67 produced by the dopaminergic lesion in the substantia nigra was counteracted by SCH 58261 L-DOPA. Conclusion: The data indicate that A2A receptor antagonists may be beneficial in motor impairment and tremor which characterize PD. Furthermore the neuronal modifications observed in rat basal ganglia after chronic treatment with SCH 58261 L-DOPA as compared to L-DOPA alone, suggest that such treatment might not produce detrimental long-term responses in basal ganglia areas.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/74232
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