Adenosine receptor ligands: differences with acute versus chronic treatment

Jacobson, Kenneth A.; Lubitz, Dag K.J.E. Von; Daly, John W.; Fredholm, Bertil B.

doi:10.1016/0165-6147(96)10002-x

Cited by 244 publications

(194 citation statements)

References 41 publications

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“…Caffeine acts as an A 1 and A 2a adenosine receptor antagonist (13,14), and regular consumption of caffeine is associated with an upregulation of the number of these adenosine receptors in the vascular and neural tissues of the brain (14,21,22,26). The resultant cascade of cellular events that follow adenosine receptor blockade, including increased dopamine and noradrenaline release (14), have been proposed as key regulatory mechanisms to explain the ergogenic effect of the drug.…”

Section: Discussionmentioning

confidence: 99%

Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers

Bell

Mclellan

2002

Journal of Applied Physiology

220

191

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Bell, Douglas G., and Tom M. McLellan. Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers. J Appl Physiol 93: 1227-1234, 2002. First published May 17, 2002 10.1152/japplphysiol.00187.2002The purpose of the present study was to examine the duration of caffeine's ergogenic effect and whether it differs between users and nonusers of the drug. Twenty-one subjects (13 caffeine users and 8 nonusers) completed six randomized exercise rides to exhaustion at 80% of maximal oxygen consumption after ingesting either a placebo or 5 mg/kg of caffeine. Exercise to exhaustion was completed once per week at either 1, 3, or 6 h after placebo or drug ingestion. Exercise time to exhaustion differed between users and nonusers with the ergogenic effect being greater and lasting longer in nonusers. For the nonusers, exercise times 1, 3, and 6 h after caffeine ingestion were 32.7 Ϯ 8.4, 32.1 Ϯ 8.6, and 31.7 Ϯ 12.0 min, respectively, and these values were each significantly greater than the corresponding placebo values of 24.2 Ϯ 6.4, 25.8 Ϯ 9.0, and 23.2 Ϯ 7.1 min. For caffeine users, exercise times 1, 3, and 6 h after caffeine ingestion were 27.4 Ϯ 7.2, 28.1 Ϯ 7.8, and 24.5 Ϯ 7.6 min, respectively. Only exercise times 1 and 3 h after drug ingestion were significantly greater than the respective placebo trials of 23.3 Ϯ 6.5, 23.2 Ϯ 7.1, and 23.5 Ϯ 5.7 min. In conclusion, both the duration and magnitude of the ergogenic effect that followed a 5 mg/kg dose of caffeine were greater in the nonusers compared with the users. time to exhaustion; ergogenic aid; drug sensitivity THERE HAVE BEEN NUMEROUS STUDIES and reviews indicating that caffeine ingested before exercise causes rapid and significant improvements in performance, especially in aerobic exercise capacity (6,8,16,20,28,30). The dose of caffeine studied has ranged from 1 to 15 mg/kg of body mass. The optimal dose has not been determined because it may vary according to the sensitivity of the individual to caffeine. However, doses between 3 and 6 mg/kg produce an equivalent ergogenic effect to higher doses (5, 29), and this has led Graham et al. (17) to suggest that the optimal dose thus lies in this lower range.Even though caffeine has a half-life of 4-6 h that implies high levels of caffeine will be in the blood for up to 3-4 h after ingestion, most studies have focused on exercise performance ϳ1 h after ingestion. The assumption is that the ergogenic effect is related to the circulating level of the drug in the blood. Thus maximal effects are assumed to occur ϳ1 h after ingestion, when peak blood concentrations are observed (2, 14). Some studies (27,35) have suggested that waiting 3 h may be more optimal because the caffeine-induced effect on lipolysis is greater than at earlier times after ingestion. However, the hypothesis that the ergogenic effect from caffeine is due to an enhanced free fatty acid mobilization and tissue utilization has not found much support in the recent literature (16,17,29).For sustained operations, as is quite commo...

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Section: Discussionmentioning

confidence: 99%

Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers

Bell

Mclellan

2002

Journal of Applied Physiology

220

191

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“…This is aggravated by the fact that is not conceivable to administer A 1 R agonists chronically (as a preventive strategy) because it causes an effect inversion, i.e. chronic A 1 R stimulation actually exacerbates neuronal loss caused by noxious brain stimulation (reviewed in [183]). Finally, the last major limitation to develop A 1 R agonists as neuroprotective drugs is the observation that the effect of A 1 R activation desensitize in chronic stressful brain conditions, as shall be discussed in more detail in BLong-term desensitization of A 1 receptors and up-regulation of A 2A receptors by chronic noxious conditions.Î n conclusion, it appears that the activation of A 1 Rs is an endogenous neuroprotective system, but its usefulness is limited to acute noxious brain conditions, i.e., to control the onset or enhance the threshold of neuronal damage.…”

Section: Modification Of Adenosine Metabolism On Stressful Conditionsmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

484

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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“…In addition, approaches involving the chronic activation of adenosine receptors by selective ligands may lead to rapid adaptive changes, thus limiting their clinical potential (Jacobson et al, 1996). The low blood brain barrier permeability and pronounced peripheral side effects of adenosine receptor agents (Malhotra and Gupta, 1997) constitute a significant limitation to their therapeutic use.…”

Section: Pharmacological Approaches For Seizure Suppressionmentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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Adenosine receptor ligands: differences with acute versus chronic treatment

Cited by 244 publications

References 41 publications

Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers

Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

The adenosine kinase hypothesis of epileptogenesis

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