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

Kelsey, John E.; Langelier, Nicole; Oriel, Brad S.; Reedy, Catherine

doi:10.1007/s00213-008-1319-0

Cited by 35 publications

(25 citation statements)

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“…Also, the use of Istradefylline (KW-6002), another A2a receptor antagonist, was shown to not only slow the onset of motor deficits related to the disease but also induce neurogeneration and reduce neuroplasticity (changes in neural pathways and synapses) that ensues when treating patients with other standard dopamine replacement strategies, like l-DOPA (Schwarzschild et al, 2006). Additionally, in animal models for Parkinson's disease, which displayed significant akinesia (the loss or impairment of voluntary movements), the application of caffeine and the A2a receptor antagonists 8-(3-chlorostyryl) caffeine (CSC) and SCH-58261 but not an A1 antagonist (8-cyclopentyltheophylline) or an A1 receptor agonist (N(6)-cyclopentyladenosine) was shown to provide a therapeutic effect by reducing the onset of akinesia in these animals (Coccurello et al, 2004; Kelsey et al, 2009). Thus, blockade of adenosine receptors, especially the A2a receptor subtype, can confer a beneficial effect by reducing some of the side effects experienced by other traditional pharmacological treatments for Parkinson's patients (Fig.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review

2014

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Caffeine is the most consumed pychostimulant in the world, and it is known to affect basic and fundamental human processes such as sleep, arousal, cognition and learning and memory. It works as a nonselective blocker of adenosine receptors (A1, A2a, A2b and A3) and has been related to the regulation of heart rate, the contraction/relaxation of cardiac and smooth muscles, and the neural signaling in the central nervous system (CNS). Since the late 1990s, studies using adenosine receptor antagonists, such as Caffeine, to block the A1 and A2a adenosine receptor subtypes have shown to reduce the physical, cellular and molecular damages caused by a spinal cord injury (SCI) or a stroke (cerebral infarction) and by other neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Interestingly, other studies using adenosine receptor agonists have also shown to provide a neuroprotective effect on various models of neurodegenerative diseases through the reduction of excitatory neurotransmitter release, apoptosis and inflammatory responses, among others. The seemingly paradoxical use of both adenosine receptor agonists and antagonists as neuroprotective agents has been attributed to differences in dosage levels, drug delivery method, extracellular concentration of excitatory neurotransmitters and stage of disease progression. We discuss and compare recent findings using both antagonists and agonists of adenosine receptors in animal models and patients that have suffered spinal cord injuries, brain strokes, and Parkinson's and Alzheimer's diseases. Additionally, we propose alternative interpretations on the seemingly paradoxical use of these drugs as potential pharmacological tools to treat these various types of neurodegenerative diseases.

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Section: Parkinson's Diseasementioning

confidence: 99%

Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review

2014

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“…Caffeine has been found to block the MPTP-induced decrease in the numbers of tyrosine hydroxylase-positive dopaminergic neurons in the striatum in mice [37]. The dosage of 2 mg/kg SCH58261 can significantly improve the ability in an animal model of PD and enhance the therapeutic efficacy of L-DOPA [14]. These observations indicated that in addition to mesolimbic dopaminergic pathway, caffeine in this dosage has effects on the nigrostriatal dopaminergic pathway, and is probably mediated by the adenosine A 2A receptor.…”

Section: Discussionmentioning

confidence: 99%

“…There is also evidence to indicate that administration of caffeine and adenosine A 2A antagonists have therapeutic effects in animal models of PD [13,14]. Many studies have demonstrated that A 2A antagonists attenuated the 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration [15] and enhanced the therapeutic effect of various dopamine agonists, including L-DOPA in animals [15-18].…”

Section: Introductionmentioning

confidence: 99%

“…Many studies have demonstrated that A 2A antagonists attenuated the 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration [15] and enhanced the therapeutic effect of various dopamine agonists, including L-DOPA in animals [15-18]. Kelsey et al [14] found that caffeine and a selective adenosine A 2A antagonist SCH58261, but not a selective adenosine A 1 agonist N 6 -cyclopentyladenosine and a selective A 2A antagonist 8-cyclopentyltheophylline, exhibited both monotherapeutic and adjunctive therapeutic effects in an established model of PD. These observations indicate that caffeine has neuroprotective effect on nigrostriatal dopaminergic pathway via antagonism of adenosine A 2A receptors.…”

Section: Introductionmentioning

confidence: 99%

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Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice

2010

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BackgroundCaffeine, a nonselective adenosine A1 and A2A receptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and selective adenosine A2A antagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect in Parkinson's disease (PD). Evidence also indicates that low doses of caffeine and a selective adenosine A2A antagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in the striatum.MethodsIn this study, we evaluated the neuroadaptations in the striatum by using reverse-phase high performance liquid chromatography (HPLC) to quantitate the concentrations of striatal dopamine and its metabolites, dihydroxylphenylacetic acid (DOPAC) and homovanilic acid (HVA), and using immunoblotting to measure the level of phosphorylation of tyrosine hydroxylase (TH) at Ser31, following chronic caffeine and SCH58261 sensitization in mice. Moreover, to validate further that the behavior sensitization of caffeine is through antagonism at the adenosine A2A receptor, we also evaluate whether chronic pretreatment with a selective adenosine A2A antagonist SCH58261 or a selective adenosine A1 antagonist DPCPX can sensitize the locomotor stimulating effects of caffeine.ResultsChronic treatments with low dose caffeine (10 mg/kg) or SCH58261 (2 mg/kg) increased the concentrations of dopamine, DOPAC and HVA, concomitant with increased TH phosphorylation at Ser31 and consequently enhanced TH activity in the striatal tissues in both caffeine- and SCH58261-sensitized mice. In addition, chronic caffeine or SCH58261 administration induced locomotor sensitization, and locomotor cross-sensitization to caffeine was observed following chronic treatment of mice with SCH58261 but not with DPCPX.ConclusionsOur study demonstrated that low dosages of caffeine and a selective adenosine A2A antagonist SCH58261 elicited locomotor sensitization and cross-sensitization, which were associated with elevated dopamine concentration and TH phosphorylation at Ser31 in the striatum. Blockade of adenosine A2A receptor may play an important role in the striatal neuroadaptations observed in the caffeine-sensitized and SCH58261-sensitized mice.

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“…Moreover, caffeine’s metabolites, paraxanthine and theophylline, also provide protection against MPTP neurotoxicity (Xu et al, 2010). Other preclinical studies have shown that caffeine protects against dopaminergic neuron degeneration, dopamine loss and/or associated behavioral changes induced by 6-hydroxydopamine (6-OHDA) in rats (Joghataie et al, 2004; Aguiar et al, 2006; Kelsey et al, 2009) and by the pesticide combination of paraquat and manebin mice (Kachroo et al, 2010). Interestingly, the neuroprotective effect of caffeine could be dissociated from its psychomotor stimulant properties (Xu et al, 2002; Yu et al, 2008); whereas the latter showed tolerance to repeated administration, under the same conditions caffeine’s neuroprotective action persisted unabated (Xu et al, 2002).…”

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confidence: 99%

Neuroprotection by caffeine in the MPTP model of parkinson’s disease and its dependence on adenosine A2A receptors

Luca

Orrù

et al. 2016

Neuroscience

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Considerable epidemiological and laboratory data have suggested that caffeine, a nonselective adenosine receptor antagonist, may protect against the underlying neurodegeneration of Parkinson’s disease (PD). Although both caffeine and more specific antagonists of the A2A subtype of adenosine receptor (A2AR) have been found to confer protection in animal models of PD, the dependence of caffeine’s neuroprotective effects on the A2AR is not known. To definitively determine its A2AR dependence, the effect of caffeine on MPTP neurotoxicity was compared in wild-type (WT) and A2AR gene global knockout (A2A KO) mice, as well as in CNS cell type-specific (conditional) A2AR knockout (cKO) mice that lack the receptor either in postnatal forebrain neurons or in astrocytes. In WT and in heterozygous A2AR KO mice caffeine pretreatment (25 mg/kg ip) significantly attenuated MPTP-induced depletion of striatal dopamine. By contrast in homozygous A2AR global KO mice caffeine had no effect on MPTP toxicity. In forebrain neuron A2AR cKO mice, caffeine lost its locomotor stimulant effect, whereas its neuroprotective effect was mostly preserved. In astrocytic A2AR cKO mice, both caffeine’s locomotor stimulant and protective properties were undiminished. Taken together, these results indicate that neuroprotection by caffeine in the MPTP model of PD relies on the A2AR, although the specific cellular localization of these receptors remains to be determined.

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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

Cited by 35 publications

References 46 publications

Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review

Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review

Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice

Neuroprotection by caffeine in the MPTP model of parkinson’s disease and its dependence on adenosine A2A receptors

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