1,720,973 research outputs found
Adenosine A2A receptor antagonists: potential therapeutic and neuroprotective effects in Parkinson’s disease
No full textThe most effective treatment of Parkinson's disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A(2A) receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A(2A) antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Fos-like-immunoreactivity in neurons of the lesioned striatum. Likewise, other A(2A) receptor antagonists such as (3,7-dimethyl-1-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] (KF 17837) and [E-1,3-diethyl-8(3,4-dimethoxystyryl-7-methyl-3,7-dihydro-1H-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in non-human primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTP-treated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A(2A) receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A(2A) antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the MPTP model of PD. Adenosine A(2A) receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD
Impulse control disorders and dopamine dysregulation syndrome associated with dopamine agonist therapy in Parkinson's disease
No full textOver the last decade, evidence has emerged linking disorders in the impulsive-compulsive spectrum in Parkinson's disease to dopamine receptor agonist treatment. These disorders include hypersexuality, gambling and, to a minor extent, compulsive shopping and eating, as well as dopamine dysregulation syndrome, characterized by an addictive pattern toward dopamine replacement therapy and stereotyped behaviors, such as punding. These syndromes, which have only recently been recognized and are still underdiagnosed, have deleterious social consequences that warrant interventions at the clinical level and promotion of research at the preclinical level. In this review, we first provide a summary of features of Parkinson's disease and current pharmacological therapies associated with the development of dopamine dysregulation syndrome and impulsive-compulsive disorders. We also examine the dopamine receptors and brain areas important in reward and compulsive behaviors. We then critically examine the neuroadaptations in dopaminergic circuitries and the literature concerning gambling, hypersexuality, and other addictive behaviors in parkinsonian patients. Finally, we focus on suggestions pointing to a role for dopamine D(3) receptors and sensitization phenomena as the main factors which may be the origin of these disorders
Adenosine A2 receptors stimulate c-fos expression in striatal neurons of 6-hydroxydopamine-lesioned rats
No full textThe induction of the early-gene c-fos after administration of the adenosine A2a receptor agonist CGS 21680, was studied in the striatum of normal rats or in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal neurons. CGS 21680 (2.25 mg/kg) induces c-fos expression in the 6-hydroxydopamine-lesioned striatum, while up to 40 mg/kg fails to induce c-fos in the intact striatum or in the striatum of normal rats. Blockade of muscarine receptors by scopolamine (5 mg/kg) partially prevents, and stimulation of dopamine D2 receptors by quinpirole (0.5 mg/kg) completely reverses, CGS 21680-induced c-fos expression in the 6-hydroxydopamine-lesioned striatum. In turn, CGS 21680 partially reverses c-fos expression induced by quinpirole in the lesioned globus pallidus. CGS 21680, in addition, dose-dependently reduces the turning behavior induced by quinpirole (0.5 mg/kg) in 6-hydroxydopamine-lesioned rats. The results suggest that CGS 21680 induces c-fos expression in the striatum through direct and indirect mechanisms related to the ability of A2a receptors to stimulate cyclic AMP formation or acetylcholine release which in turn would activate c-fos through muscarinic receptor
Blockade of A(2a) adenosine receptors positively modulates turning behaviour and c-Fos expression induced by D-1 agonists in dopamine-denervated rats
No full textIn rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway, administration of the A(2a) adenosine antagonist SCH 58261 alone did not induce any motor asymmetry but strongly potentiated the contralateral turning behaviour induced by the dopamine D-1 agonist SKF 38393. SCH 58261 also increased the number of Fos-like positive nuclei induced by SKF 38393 in the 6-hydroxydopamine-lesioned striatum. intense potentiation of D-1-dependent turning behaviour and c-Fos expression was also observed after administration of the A(2a)/A(1) antagonist CGS 15943. Administration of the A(1) adenosine receptor antagonist DPCPX induced a small potentiation of D-1-mediated contralateral turning while c-Fos expression induced by SKF 38393 was not modified. The results suggest that endogenous adenosine acting on A(2a) receptors can exert an inhibitory influence on the functional expression of D-1-mediated responses in dopamine-denervated rats, and propose new possible therapeutic approaches in the treatment of Parkinson's disease
Involvement of adenosine receptors in the induction of c-fos expression by clozapine and haloperidol
No full textAcute administration of the atypical antipsychotic clozapine induced a regional pattern of c-fos expression characterized by an increase in Fos-like-immunoreactivity (FLI) in the prefrontal and prelimbic/infralimbic cortices, nucleus accumbens, and lateral septum and a weak activation of FLI in the striatum. Haloperidol, similarly to clozapine, increased FLI in the nucleus accumbens and lateral septum, but it did not induce FLI in prefrontal and prelimbic/infralimbic cortices. Moreover, haloperidol increased FLI in the striatum. To gain insight into the mechanism by which clozapine and haloperidol induced FLI in these brain structures, we evaluated whether blockade of adenosine A2A receptors could influence these effects. The selective and high-affinity A2A receptor antagonist SCH 58261 (5 mg/kg) completely abolished FLI induced by clozapine (20 mg/kg) in all subdivisions of the nucleus accumbens (rostral pole, shell and core) and striatum, but did not affect the number of Fos-like positive neurons in the prefrontal, prelimbic/infralimbic cortices, and lateral septum. SCH 58261 (5 mg/kg) reduced FLI induced by haloperidol (0.1 mg/kg) in the striatum, lateral septum, and all nucleus accumbens subdivisions. In contrast, FLI induced by 0.5 mg/kg of haloperidol in the shell and core of the nucleus accumbens was not affected by SCH 58261. The results show that adenosine A2A receptors participate in the induction of FLI by clozapine and haloperidol and support the concept that A2A receptors are involved in the mediation of antipsychotic effects
New therapies for the treatment of Parkinson's disease: adenosine A2A receptor antagonists
No full textThe development of non-dopaminergic therapies for the treatment of Parkinson's disease (PD) has attracted much interest in recent years. Among new different classes of drugs, adenosine A2A receptor antagonists have emerged as best candidates. The present review will provide an updated summary of the results reported in literature concerning the effects of adenosine A2A antagonists in rodent and primate models of PD. These results show that A2A receptor antagonists improve motor deficits without inducing dyskinesia and counteract parkinsonian tremor. In progress clinical trials have shown that a low dose of L-DOPA plus KW-6002 produced symptomatic relief no different from that produced by an optimal dose of L-DOPA alone, whereas dyskinesias were reduced rendering this class of compounds particularly attractive
Preface [ to The Adenosinergic System. A Non-Dopaminergic Target in Parkinson’s Disease]
No full textAdenosine A2A receptors: localization and function
No full textAdenosine is an endogenous purine nucleoside present in all mammalian tissues, that originates from the breakdown of ATP. By binding to its four receptor subtypes (A1, A2A, A2B, and A3), adenosine regulates several important physiological functions at both the central and peripheral levels. Therefore, ligands for the different adenosine receptors are attracting increasing attention as new potential drugs to be used in the treatment of several diseases. This chapter is aimed at providing an overview of adenosine metabolism, adenosine receptors localization and their signal transduction pathways. Particular attention will be paid to the biochemistry and pharmacology of A2A receptors, since antagonists of these receptors have emerged as promising new drugs for the treatment of Parkinson's disease. The interactions of A2A receptors with other nonadenosinergic receptors, and the effects of the pharmacological manipulation of A2A receptors on different body organs will be discussed, together with the usefulness of A2A receptor antagonists for the treatment of Parkinson's disease and the potential adverse effects of these drugs
Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson's disease model.
No full textThiazolidinedione (TZD) class of peroxisome proliferator receptor gamma (PPAR-γ)
agonists display neuroprotective effects in experimental Parkinson's disease (PD)
models. Neurons and microglia express PPAR-γ, therefore both of them are
potential targets for neuroprotection, although the role of each cell type is not
clear. Moreover, receptor-dependent as well as receptor-independent mechanisms
have been involved. This study further investigated mechanisms of TZD-mediated
neuroprotection in PD. We investigated the rosiglitazone effect in the
progressive MPTP/probenecid (MPTPp) model of PD. C57BL/6J mice received MPTP (25
mg/kg) plus probenecid (100 mg/kg) twice per week for 5 weeks. Rosiglitazone (10
mg/kg) was given daily until sacrifice, starting on the fourth week of MPTPp
treatment, in presence of an ongoing neurodegeneration with microgliosis. Changes
in PPAR-γ levels were measured by immunofluorescence and confocal microscopy in
tyrosine hydroxylase (TH)-positive neurons and CD11b-positive microglia of the
substantia nigra pars compacta (SNc). Chronic MPTPp treatment induced a PPAR-γ
overexpression in both TH-positive neurons and microglia (139.9% and 121.7% over
vehicle, respectively). Rosiglitazone administration to MPTPp-treated mice,
reverted PPAR-γ overexpression in microglia without affecting TH-positive
neurons. Thereafter, changes in CD11b and tumor necrosis factor α (TNF-α)
immunoreactivity in microglia were evaluated in the SNc. MPTPp progressively
increased CD11b immunoreactivity, conferring to microglia a highly activated
morphology. Moreover, TNF-α levels were increased (457.38% over vehicle) after
MPTPp. Rosiglitazone administration counteracted the increase in CD11b
immunoreactivity caused by MPTPp. Moreover, rosiglitazone reverted TNF-α
expression to control levels. Nigrostriatal degeneration was assessed by high
pressure liquid chromatography (HPLC) measurement of striatal dopamine, and
counting of TH-positive neurons in the SNc. MPTPp treatment caused a severe
decline of striatal dopamine and a partial degeneration of the SNc. Rosiglitazone
arrested the degenerative process in both areas. Results suggest that PPAR-γ
expression in microglia and TNF-α production by these cells are crucial changes
by which rosiglitazone exerts neuroprotection in PD
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