Adenosine antagonists reverse the cataleptic effects of haloperidol: Implications for the treatment of Parkinson's disease

Trevitt, Jennifer; Vallance, Christopher; Harris, Allison; Goode, Tamara

doi:10.1016/j.pbb.2009.02.001

Cited by 41 publications

(26 citation statements)

References 65 publications

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“…Adenosine A 2A -receptor antagonists inhibit motor deficits induced by dopamine antagonists, such as catalepsy and suppressed locomotion [47,48,53,54,55,56,57]. Consistently, adenosine A 2A -receptor antagonists inhibited the motor disability induced by dopaminergic neurotoxins (i.e.…”

Section: Motor Circuitry Of the Basal Gangliamentioning

confidence: 95%

Adenosine A<sub>2A</sub>-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders

Kulisevsky

Poyurovsky

2011

Eur Neurol

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Parkinson’s disease and drug-induced movement disorders (DIMDs) have commonalities in etiology based on impaired dopamine-based neurotransmission. Adenosine A_2A-receptor antagonism may provide a new mechanism through which these disorders can be managed. In the motor circuit, tonic output from the globus pallidus and substantia nigra regulates movement via opposing excitatory and inhibitory inputs to the cerebral cortex through the direct and indirect pathways. Increased activity of the direct pathway increases movement via an inhibitory effect on thalamocortical projection neurons; increased activity of the indirect pathway has the opposite effect. Regulation of these pathways is mediated primarily by reciprocal inhibitory interactions between dopamine and adenosine receptors on neurons of these pathways. Adenosine A_2A receptors are colocalized with dopamine D₂ receptors on the indirect pathway neurons, with A_2A activation opposing the effect of D₂ activation. The A_2A receptors’ role in the pathophysiology of Parkinson’s disease and DIMDs is evidenced by the upregulation of A_2A receptors in patients with Parkinson’s disease and patients receiving long-term administration of dopamine blockers. Further, A_2A-receptor antagonists are effective in reversing parkinsonian motor deficits and extrapyramidal symptoms in animal models of Parkinson’s disease and DIMDs. Understanding the role of A_2A-receptor antagonism in the pathophysiology of Parkinson’s disease and DIMD has therapeutic implications.

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Section: Motor Circuitry Of the Basal Gangliamentioning

confidence: 95%

Adenosine A<sub>2A</sub>-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders

Kulisevsky

Poyurovsky

2011

Eur Neurol

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“…The A 2A antagonists caffeine, theophylline, SCH58261, DMPX and KF17837 were all shown to inhibit motor deficits such as catalepsy and decreased locomotion induced by haloperidol and in models of tardive dyskinesia in rodents (Mandhane et al, 1997; Bishnoi et al, 2006, 2007; Salamone et al, 2008; Trevitt et al, 2009). It has also been shown that oral administration of preladenant and SCH412348 potentiated L-Dopa-induced contralateral rotation behavior in animals lesioned with 6-OHDA.…”

Section: Introductionmentioning

confidence: 99%

Advances in non-dopaminergic treatments for Parkinson's disease

Stayte

2014

Front. Neurosci.

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Since the 1960's treatments for Parkinson's disease (PD) have traditionally been directed to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has resulted in extensive efforts to develop new therapies that work in ways other than restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a detailed account of their success in animal models and their translation to human clinical trials. We then consider how advances in understanding the mechanisms of PD, genetics, the possibility that PD may consist of multiple disease states, understanding of the etiology of PD in non-dopaminergic regions as well as advances in clinical trial design will be essential for ongoing advances. We conclude that despite the challenges ahead, patients have much cause for optimism that novel therapeutics that offer better disease management and/or which slow disease progression are inevitable.

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“…[6061] Combined targeted blockage of A1 and A2A receptors could therefore synergistically provide a potential alternative to conventional PD treatments. Several novel adenosine A1/A2A antagonists that have been effective in treating motor deficits are based on the common structure of the synthesized 2-aminopyrimidine motif, with potent adenosine A1/A2A affinity.…”

Section: Adenosine Optionsmentioning

confidence: 99%

Current Nondopaminergic Therapeutic Options for Motor Symptoms of Parkinson's Disease

Chen

2017

Chinese Medical Journal

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Objective:The aim of this study was to summarize recent studies on nondopaminergic options for the treatment of motor symptoms in Parkinson's disease (PD).Data Sources:Papers in English published in PubMed, Cochrane, and Ovid Nursing databases between January 1988 and November 2016 were searched using the following keywords: PD, nondopaminergic therapy, adenosine, glutamatergic, adrenergic, serotoninergic, histaminic, and iron chelator. We also reviewed the ongoing clinical trials in the website of clinicaltrials.gov.Study Selection:Articles related to the nondopaminergic treatment of motor symptoms in PD were selected for this review.Results:PD is conventionally treated with dopamine replacement strategies, which are effective in the early stages of PD. Long-term use of levodopa could result in motor complications. Recent studies revealed that nondopaminergic systems such as adenosine, glutamatergic, adrenergic, serotoninergic, histaminic, and iron chelator pathways could include potential therapeutic targets for motor symptoms, including motor fluctuations, levodopa-induced dyskinesia, and gait disorders. Some nondopaminergic drugs, such as istradefylline and amantadine, are currently used clinically, while most such drugs are in preclinical testing stages. Transitioning of these agents into clinically beneficial strategies requires reliable evaluation since several agents have failed to show consistent results despite positive findings at the preclinical level.Conclusions:Targeting nondopaminergic transmission could improve some motor symptoms in PD, especially the discomfort of dyskinesia. Although nondopaminergic treatments show great potential in PD treatment as an adjunct therapy to levodopa, further investigation is required to ensure their success.

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Adenosine antagonists reverse the cataleptic effects of haloperidol: Implications for the treatment of Parkinson's disease

Cited by 41 publications

References 65 publications

Adenosine A<sub>2A</sub>-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders

Adenosine A<sub>2A</sub>-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders

Advances in non-dopaminergic treatments for Parkinson's disease

Current Nondopaminergic Therapeutic Options for Motor Symptoms of Parkinson's Disease

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