Emerging drugs for levodopa-induced dyskinesia

Dakheel, Amaal Al; Beaulieu‐Boire, Isabelle; Fox, Susan H.

doi:10.1517/14728214.2014.955014

Cited by 9 publications

(3 citation statements)

References 77 publications

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“…93,96 In addition, numerous other CNS neurotransmitters have been implicated including the serotonergic, glutamatergic, opioid, GABAergic, noradrenergic, histaminergic, and various peptidergic systems. 93,94,96,[106][107][108] More recent work also indicates a role for striatal cholinergic interneurons and the nicotinic cholinergic system. Experimental studies show that ablation of striatal cholinergic interneurons in mice before initiation of L-dopa treatment markedly reduced LIDs without compromising the therapeutic efficacy of L-dopa.…”

Section: L-dopa-induced Dyskinesiasmentioning

confidence: 99%

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders

Quik

Boyd

Bordia

et al. 2018

Nicotine &Amp; Tobacco Research

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Accumulating data from preclinical studies and clinical trials suggest that drugs targeting CNS cholinergic systems may be useful for symptomatic treatment of movement disorders. Nicotinic cholinergic drugs, including nicotine and selective nAChR receptor agonists, reduce L-dopa-induced dyskinesias, as well as antipsychotic-induced tardive dyskinesia, and may be useful in Tourette's syndrome and ataxia. Subtype selective muscarinic cholinergic drugs may also provide effective therapies for Parkinson's disease, dyskinesias and dystonia. Continued studies/trials will help address this important issue.

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Section: L-dopa-induced Dyskinesiasmentioning

confidence: 99%

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders

Quik

Boyd

Bordia

et al. 2018

Nicotine &Amp; Tobacco Research

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“…The striatal pulsatile dopamine receptor stimulation can lead to aberrant signal cascade reactions in dyskinesia rat model. 1,4,19 Previous research have suggested that Src tyrosine kinase was one important protein kinases for intracellular signal transduction related to dopamine receptor reaction. 20,21 Calcium influx dependent on the NMDAR can modulate many downstream signaling pathways after chronic L-DOPA treatment, including Src or CaMKII activation.…”

Section: Discussionmentioning

confidence: 99%

S-nitrosylation of Src by NR2B-nNOS signal causes Src activation and NR2B tyrosine phosphorylation in levodopa-induced dyskinetic rat model

Ding

Guan

et al. 2018

Hum Exp Toxicol

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Abnormality in Src PSD-95 NR2B signaling complex assemble occurs in levodopa-induced dyskinesia (LID). N-methyl-D-aspartate receptor (NMDAR) subunit NR2B tyrosine phosphorylation mediated by Src family protein tyrosine kinases is closely associated with dyskinesia. Src autophosphorylation (p-Src) is an important part of Src-catalyzed phosphorylation of NR2B. In addition, the neuronal nitric oxide synthase (nNOS)-derived NO (nNOS/NO) signal which was also involved in dyskinesia recently was proved to participate in the regulation of Src function. Yet, the detailed signal mechanism about the interactions of NR2B, nNOS, and Src is still unknown. In the present study, we investigated the influences of nNOS on Src activation and NR2B tyrosine phosphorylation in dyskinetic rat model by immunoblotting and immunoprecipitation. The results demonstrated that chronic levodopa treatment resulted in downregulation of p-nNOS-S847, one marker of nNOS overactivation. Coinstantaneously, the S-nitrosylation (SNO-Src) and autophosphorylation (p-Src) of Src and NR2B tyrosine phosphorylation were upregulated in dyskinetic rat model. Conversely, administration of 7-NI, one nNOS inhibitor, reversed all these effects of levodopa treatment. Besides, NR2B-containing NMDAR (NR2B/NMDAR) antagonist CP-101,606 could upregulate p-nNOS-S847 and thus attenuate nNOS activation and simultaneously reduce the SNO-Src, p-Src, and NR2B tyrosine phosphorylation. Taken together, the S-nitrosylation of Src is caused by nNOS/NO signal, which is overactivated via Ca2+ influx dependent on NR2B/NMDAR, and subsequently facilitates Src auto-tyrosine phosphorylation and further phosphorylates NR2B. The “NR2B/NMDAR–nNOS/NO–SNO-Src–p-Src–NR2B/NMDAR” signaling cycle may be the molecular basis of NR2B tyrosine phosphorylation upward positive feedback, which demonstrates the possibility as one latent target for dyskinesia therapy.

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“…Emerging drugs for levodopa (L-Dopa) induced dyskinesias include cholinergic agents [91]. The use of such compounds rests on the balance model, in this case dopamine and acetylcholine in particular [65].…”

Section: Cholinergicmentioning

confidence: 99%

Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials

Lockwood

Remington

2015

Expert Opinion on Emerging Drugs

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Emerging drugs for levodopa-induced dyskinesia

Abstract: The success of future therapeutic approaches will depend on the potential success of translational research.

Cited by 9 publications

References 77 publications

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders

S-nitrosylation of Src by NR2B-nNOS signal causes Src activation and NR2B tyrosine phosphorylation in levodopa-induced dyskinetic rat model

Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials

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