The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of l-DOPA in MPTP treated common marmosets

Rose, Sarah; Jackson, Michael; Smith, Lance A.; Stockwell, K.; Johnson, Louisa; Carminati, Paolo; Jenner, Peter

doi:10.1016/j.ejphar.2006.07.017

Cited by 59 publications

(46 citation statements)

References 30 publications

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“…41 In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, A 2A antagonists have been shown to reverse the MPTP-induced Parkinsonism in monkeys 37,42 and to potentiate the levodopa-induced restoration of motor activity. 43,44 A 2A antagonists also consistently enhance basal locomotor activity in unlesioned rodents, 45 as well as in animals rendered cataleptic with the dopamine receptor antagonist haloperidol. 46 These observations have led to clinical trials in PD patients with the caffeine-derived A 2A antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002) (2).…”

Section: A 2a Receptors In the Cnsmentioning

confidence: 99%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Section: A 2a Receptors In the Cnsmentioning

confidence: 99%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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“…For example, Kanda and coworkers found that the selective A 2A antagonist KW-6002 (istradefylline) dose-dependently enhanced locomotion and reduced motor disabilities in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets with no development of tolerance or dyskinesia (Kanda et al 1998a, b) and enhanced the therapeutic effect of various dopamine (DA) agonists, including L-DOPA, without enhancing the dyskinesias produced by these drugs (Kanda et al 2000). Similar effects of KW-6002 and other A 2A antagonists were found in MPTP-treated cynomolgus monkeys (Bibbiani et al 2003;Grondin et al 1999) and marmosets (Rose et al 2006).…”

Section: Introductionmentioning

confidence: 63%

The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat

et al. 2008

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“…7.2; Grondin et al 1999;Hodgson et al 2010;Kanda et al 1998Kanda et al , 2000Rose et al 2006). Furthermore, when co-administered with L-DOPA A 2A receptor antagonists enhanced the intensity and duration of the efficacy of L-DOPA in reversing motor disabilities and increasing locomotor activity in parkinsonian monkeys ( Kanda et al 2000).…”

Section: Effect Of a 2a Receptor Antagonists On Akinesia Bradykinesimentioning

confidence: 96%

“…Pinna A 2A receptor antagonists with L-DOPA has been demonstrated to strengthen the anti-cataleptic effect induced by L-DOPA suggesting that there may be a synergism between the adenosine A 2A receptor antagonists and the dopaminergic agents (Table 7.1; Kanda et al 1994;Shiozaki et al 1999;Stasi et al 2006) . Interestingly, Varty and collaborators have also evaluated the efficacy of A 2A receptor antagonists against catalepsy induced by haloperidol in primates ( Rose et al 2006 To better verify the anti-parkinsonian effects of A 2A receptor antagonists, these compounds have been evaluated in the most frequently used PD model of hemiparkinsonian rats, characterized by a unilateral intracerebral infusion of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA), which produces massive degeneration of the nigrostriatal dopaminergic neurons, similar to that occurring in idiopathic PD (Schwarting and Huston 1996;Simola et al 2007;Ungerstedt 1968). In this model, the ability of a specific drug to induce contralateral rotational behaviour, as well as to potentiate the rotational behaviour stimulated by dopamine receptor agonists, can be assumed as a parameter reflecting its anti-parkinsonian activity (Schwarting and Huston 1996;Simola et al 2007).…”

Section: Effect Of a 2a Receptor Antagonists On Akinesia Bradykinesimentioning

confidence: 98%

Adenosine A2A Receptor Antagonists as Drugs for Symptomatic Control of Parkinson’s Disease in Preclinical Studies

Pinna

2015

Current Topics in Neurotoxicity

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Parkinson's disease (PD) is primarily a neurological basal ganglia (BG)-related disorder caused by progressive degeneration of the nigrostriatal dopaminergic neurons, which results in the cardinal motor symptoms of PD, including bradykinesia (slow movement and difficulty in initiation movement), resting tremor, muscle tone rigidity, postural instability, and sensorimotor integration deficits. The gold standard of PD therapy is characterized by the dopamine precursor L-DOPA however, after several years, this therapy leads to neuropsychiatric and motor complications, including fluctuations in motor response and dyskinesias, which develop in the majority of patients. Consequently, one of the main targets of research in PD is to identify alternative therapeutic approaches to ameliorate PD symptoms without inducing motor complications. Among the non-dopaminergic strategies for PD, one of the most promising is represented by adenosine A 2A receptor antagonists, due to the colocalization of these receptors and dopamine D 2 receptors in the striatopallidal neurons of the BG, which provides the anatomical basis for the existence of a functional antagonistic interaction between these receptors. Thus, extensive preclinical studies have been performed to prove the effectiveness of adenosine A 2A receptor blockade in counteracting the cardinal motor symptoms of PD.This chapter describes the effects of A 2A antagonists alone or in combination with L-DOPA against the cardinal motor symptoms of PD, using rodent and primate models of PD, and the main mechanisms responsible for these anti-parkinsonian effects. In addition, findings suggesting the potential utilization of A 2A antagonists, as adjunctive treatments to L-DOPA to reduce the L-DOPA induced wearing-off without modifying dyskinetic movements, have been reviewed. Keywords Parkinson's disease · Rodent models · Non-human primate models · Catalepsy · Rigidity · Tremor · 6-Hydroxydopamine lesion · MPTP lesion · A 2A receptor antagonists · Adenosine

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The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of l-DOPA in MPTP treated common marmosets

Cited by 59 publications

References 30 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat

Adenosine A2A Receptor Antagonists as Drugs for Symptomatic Control of Parkinson’s Disease in Preclinical Studies

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