TC-8831, a nicotinic acetylcholine receptor agonist, reduces l-DOPA-induced dyskinesia in the MPTP macaque

Johnston, Tom H.; Fox, Susan H.; Koprich, James B.; Szeliga, Kendall T.; James, J. W.; Graef, John D.; Letchworth, Sharon R.; Jordan, Kristen; Hill, Michael P.; Brotchie, Jonathan M.

doi:10.1016/j.neuropharm.2013.06.005

Cited by 38 publications

(31 citation statements)

References 38 publications

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“…No effects were observed in the antiparkinsonian effects of levodopa. Similar results with nicotine were observed in rats and mice, 74,75 and also when some nicotinic agonists, such as TC-8831, 76 ABT-089 and ABT-894, 77 ABT-107, 78 and AQW051 were tested. 79 …”

Section: Cholinergic Disturbances In Pdsupporting

confidence: 80%

Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease

Pérez-Lloret

Barrantes

2016

npj Parkinson's Disease

168

122

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In view of its ability to explain the most frequent motor symptoms of Parkinson’s Disease (PD), degeneration of dopaminergic neurons has been considered one of the disease’s main pathophysiological features. Several studies have shown that neurodegeneration also affects noradrenergic, serotoninergic, cholinergic and other monoaminergic neuronal populations. In this work, the characteristics of cholinergic deficits in PD and their clinical correlates are reviewed. Important neurophysiological processes at the root of several motor and cognitive functions remit to cholinergic neurotransmission at the synaptic, pathway, and circuital levels. The bulk of evidence highlights the link between cholinergic alterations and PD motor symptoms, gait dysfunction, levodopa-induced dyskinesias, cognitive deterioration, psychosis, sleep abnormalities, autonomic dysfunction, and altered olfactory function. The pathophysiology of these symptoms is related to alteration of the cholinergic tone in the striatum and/or to degeneration of cholinergic nuclei, most importantly the nucleus basalis magnocellularis and the pedunculopontine nucleus. Several results suggest the clinical usefulness of antimuscarinic drugs for treating PD motor symptoms and of inhibitors of the enzyme acetylcholinesterase for the treatment of dementia. Data also suggest that these inhibitors and pedunculopontine nucleus deep-brain stimulation might also be effective in preventing falls. Finally, several drugs acting on nicotinic receptors have proved efficacious for treating levodopa-induced dyskinesias and cognitive impairment and as neuroprotective agents in PD animal models. Results in human patients are still lacking.

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Section: Cholinergic Disturbances In Pdsupporting

confidence: 80%

Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease

Pérez-Lloret

Barrantes

2016

npj Parkinson's Disease

168

122

View full text Add to dashboard Cite

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“…Z. Huang, Campos, Ly, Carroll, & Quik, 2011; Quik, Campos, Bordia, et al, 2013). Additionally, varenicline and TC-8831 decreased LIDs ~50% in nonhuman primates, although a limitation with these drugs was the development of emesis (Johnston, et al, 2013; D. Zhang, et al, 2013).…”

Section: Role For Nicotine and Nachr Agonists In Reducing L-dopa-imentioning

confidence: 99%

Role for the nicotinic cholinergic system in movement disorders; therapeutic implications

Quik¹,

Zhang²,

Perez³

et al. 2014

Pharmacology & Therapeutics

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A large body of evidence using experimental animal models shows that the nicotinic cholinergic system is involved in the control of movement under physiological conditions. This work raised the question whether dysregulation of this system may contribute to motor dysfunction and whether drugs targeting nicotinic acetylcholine receptors (nAChRs) may be of therapeutic benefit in movement disorders. Accumulating preclinical studies now show that drugs acting at nAChRs improve drug-induced dyskinesias. The general nAChR agonist nicotine, as well as several nAChR agonists (varenicline, ABT-089 and ABT-894) reduce L-dopa-induced abnormal involuntary movements or dyskinesias up to 60% in parkinsonian nonhuman primates and rodents. These dyskinesias are potentially debilitating abnormal involuntary movements that arise as a complication of L-dopa therapy for Parkinson’s disease. In addition, nicotine and varenicline decrease antipsychotic-induced abnormal involuntary movements in rodent models of tardive dyskinesia. Antipsychotic-induced dyskinesias frequently arise as a side effect of chronic drug treatment for schizophrenia, psychosis and other psychiatric disorders. Preclinical and clinical studies also show that the nAChR agonist varenicline improves balance and coordination in various ataxias. Lastly, nicotine has been reported to attenuate the dyskinetic symptoms of Tourette’s disorder. Several nAChR subtypes appear to be involved in these beneficial effects of nicotine and nAChR drugs including α4β2*, α6β2* and α7 nAChRs (the asterisk indicates the possible presence of other subunits in the receptor). Overall, the above findings, coupled with nicotine’s neuroprotective effects, suggest that nAChR drugs have potential for future drug development for movement disorders.

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“…These findings suggest that drugs targeting b2* and/or a7 nAChRs may yield therapies to reduce LIDs. In fact, pharmacologic studies show that several b2* nAChR agonists reduce LIDs in both rat and monkey models of LIDs (Huang et al, 2011a;Johnston et al, 2013;Quik et al, 2013a;Zhang et al, 2013aZhang et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Zhang¹,

McGregor²,

Decker³

et al. 2014

J Pharmacol Exp Ther

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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 . MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with L-Dopa/carbidopa (10 and 2.5 mg/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 the b2 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.

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TC-8831, a nicotinic acetylcholine receptor agonist, reduces l-DOPA-induced dyskinesia in the MPTP macaque

Cited by 38 publications

References 38 publications

Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease

Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease

Role for the nicotinic cholinergic system in movement disorders; therapeutic implications

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

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