OBJECTIVES: To evaluate the clinical and biological effects of chronic pramipexole (PPX) therapy in a proposed animal model of restless legs syndrome (RLS). METHODS: We developed an animal model of RLS with iron deprivation (ID) plus bilateral 6-hydroxydopamine (6-OHDA) lesions in the A11 nuclei in C57BL/6 mice, which showed increased locomotor activities that lessened by application of the dopamine agonist PPX. The mice were treated with PPX for a period of 28 (short-term observation) and 84 days (long-term observation). We measured the behavioral performances, iron levels, monoamine contents, and dopamine receptor bindings in the spinal cord after treatment. RESULTS: C57BL/6 mice with ID diet plus 6-OHDA lesions in A11 nuclei showed significantly increased movement (Moving Time increased by 186% and total travel distance increased by 162%). Acute and chronic treatment with three doses of PPX (0.1 mg/kg, 0.5 mg/kg, and 2.5 mg/kg) attenuated locomotor activities in the mice. Biochemical assays demonstrated that the ID+6-OHDA mice had significant lower levels of dopamine and HVA, and D2 receptor density in the lumbar cord. Chronic treatment with PPX did not significantly alter dopamine or serotonin metabolites in the lumbar cord. There was a trend to mildly decreased D3, but not D1 or D2 receptor density. PPX treatment also caused a modestly increased D1, but not D2 or D3, receptor affinity. The reduction in spinal cord iron seen in the ID+6-OHDA mice was partially attenuated by long-term PPX treatment compared to untreated animals. CONCLUSIONS: Pramipexole produced long-term improvement of the RLS-like symptoms in our proposed animal model, caused a partial recovery of spinal iron deficiency, and modestly increased D1 receptor affinity.
OBJECTIVES: To evaluate the clinical and biological effects of chronic pramipexole (PPX) therapy in a proposed animal model of restless legs syndrome (RLS). METHODS: We developed an animal model of RLS with iron deprivation (ID) plus bilateral 6-hydroxydopamine (6-OHDA) lesions in the A11 nuclei in C57BL/6 mice, which showed increased locomotor activities that lessened by application of the dopamine agonist PPX. The mice were treated with PPX for a period of 28 (short-term observation) and 84 days (long-term observation). We measured the behavioral performances, iron levels, monoamine contents, and dopamine receptor bindings in the spinal cord after treatment. RESULTS: C57BL/6 mice with ID diet plus 6-OHDA lesions in A11 nuclei showed significantly increased movement (Moving Time increased by 186% and total travel distance increased by 162%). Acute and chronic treatment with three doses of PPX (0.1 mg/kg, 0.5 mg/kg, and 2.5 mg/kg) attenuated locomotor activities in the mice. Biochemical assays demonstrated that the ID+6-OHDAmice had significant lower levels of dopamine and HVA, and D2 receptor density in the lumbar cord. Chronic treatment with PPX did not significantly alter dopamine or serotonin metabolites in the lumbar cord. There was a trend to mildly decreased D3, but not D1 or D2 receptor density. PPX treatment also caused a modestly increased D1, but not D2 or D3, receptor affinity. The reduction in spinal cord iron seen in the ID+6-OHDAmice was partially attenuated by long-term PPX treatment compared to untreated animals. CONCLUSIONS:Pramipexole produced long-term improvement of the RLS-like symptoms in our proposed animal model, caused a partial recovery of spinal iron deficiency, and modestly increased D1 receptor affinity.
Authors: Mark P DeAndrade; Russell L Johnson; Erica L Unger; Li Zhang; Thomas van Groen; Karen L Gamble; Yuqing Li Journal: Hum Mol Genet Date: 2012-06-07 Impact factor: 6.150