The a7 Nicotinic Receptor Agonist ABT-107 Decreases L-Dopa–Induced Dyskinesias in Parkinsonian Monkeys
نویسندگان
چکیده
Previous studies in Parkinsonian rats and monkeys have shown that b2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce L-Dopa–induced dyskinesias (LIDs), a serious complication of L-Dopa therapy for Parkinson’s disease. Since rodent studies also suggested an involvement of a7 nAChRs in LIDs, we tested the effect of the potent, selective a7 agonist ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)1H-indole]. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)lesioned monkeys were gavaged with L-Dopa/carbidopa (10 and 2.5mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03–1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40–60%. LIDs returned to control levels only after a 6-week ABT-107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50–60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance.We next tested ABT-107 together with theb2 agonist ABT-894 [(3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo [3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50–60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, a7 and b2 nAChR–selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either a7 or b2 nAChRs may be useful as antidyskinetic agents in Parkinson’s disease.
منابع مشابه
The α7 nicotinic receptor agonist ABT-107 decreases L-Dopa-induced dyskinesias in parkinsonian monkeys.
Previous studies in Parkinsonian rats and monkeys have shown that β2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce l-Dopa-induced dyskinesias (LIDs), a serious complication of l-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of α7 nAChRs in LIDs, we tested the effect of the potent, selective α7 agonist ABT-107 [5-(6-[(3R)-1-azabicyc...
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