Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number

Georgiev, Vasil; Johansson, B.; Fredholm, Bertil B.

doi:10.1016/0006-8993(93)91672-f

Cited by 90 publications

(58 citation statements)

References 27 publications

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“…We used doses which gave plasma concentrations in the 0.2-1 mg/L range. The present data are in complete agreement with results in mice where oral treatment with low doses of caffeine, producing plasma concentrations of 0.2-1 mg/L, had marked adaptive effects that were not associated with any change in receptor binding (44). Thus we conclude that the effects observed in this study are unlikely to be due to an increased transmission through A , receptors.…”

Section: Discussionsupporting

confidence: 92%

“…Because the product of immediate early genes acts as a transcription factor, several consequent changes can be anticipated. Irrespective of what the precise mechanism proves to be, it is likely that the cerebroprotective effect of long term caffeine treatment can be related to changes in susceptibility to seizures, spreading depression, or other forms of hyperexcitation, whereas acute administration of caffeine has the opposite effect (44).…”

Section: Discussionmentioning

confidence: 99%

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The Effect of Long Term Caffeine Treatment on Hypoxic-Ischemic Brain Damage in the Neonate

et al. 1995

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There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion + exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A, and A,, receptors, A, mRNA and A, , mRNA, were examined by receptor autoradiography and in situ hybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 rt 3.2% in controls to 29.8 ? 4.0% (p < 0.05) in low dose and 33.7 2 3.9% (NS) in the high dose group. The A, receptor density measured as [3~]-1,3-dipropyl-8-cyclopentyl xanthine ([?HI-DPCPX) bindCaffeine is widely consumed by women during pregnancy and immediately thereafter (1) and it is used, together with its metabolite theophylline, in the treatment of premature apnea (2). Furthermore, the fetus and the newborn become exposed because caffeine crosses the placenta (3,4) and diffuses into the breast milk (5). Caffeine affects several systems in the body, e.g. the renal, respiratory, cardiovascular (6), gastrointestinal, and the C N S (7,8). Caffeine is metabolized in the liver (9), and the metabolites are then excreted in the urine. The metabolism is much slower in neonates than in adults: tl12 in infants is 50-103 h (7,10, 11) and tIl2 in adults is 2-6 h (7, 12). Several recent reports have raised concern about the safety of caffeine use during and after pregnancy (13). Caffeine is a receptor antagonist for the endogenous nucleoside adenosine. Adenosine influences various transmitter systems in the CNS: noradrenaline, dopamine, serotonin, acetylcholine, y-aminobutyrate, and glutamate (14). Adenosine also has neuroprotective actions during ischemia (15)(16)(17)(18)(19)(20). The extracellular concentration of adenosine increases rapidly during ischemia (21,22), and the number of adenosine receptors decreases promptly (23,24). In the adult brain, chronic caffeine treatment, which leads to up-regulation of adenosine receptors, reduces ischemic damage (25), whereas acute exposure (receptor antagonistic effect) increases ischemic damage (26). The purpose of this study was to extend present knowledge to the neonatal setting, considering the common situation of fetal and neonatal caffeine exposure (1). Adenosine receptors appear and are functional at an early ontogenetic age (27,28). There are four types of adenosine receptors, A,, A,,, A,,, and A,, all of which are expressed in the brain (29). A , and A,, receptors are the most likely targets for caffeine actions. Exposure of neonatal rats to high amounts of caffeine given by gavage during postnatal d 2-6 incre...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The Effect of Long Term Caffeine Treatment on Hypoxic-Ischemic Brain Damage in the Neonate

et al. 1995

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“…Some authors (Abbracchio et al, 1992;Szot et al, 1987;Fastbom and Fredholm, 1990) documented receptor density changes following chronic stimulation of adenosine A 1 receptors both in vitro and in vivo. On the other hand, absence of such alterations has been also reported (Georgiev et al, 1993;Von Lubitz et al, 1994a,b). Since prolonged exposure to adenosine m I receptor agonists causes uncoupling of G-proteins from the receptor (Ramkumar et al, 1988), downregulation of cellular levels of G-proteins, or their redistribution from the membranes to the cytosol (Milligan, 1993), it has been suggested that the regimen-dependent inversion of the therapeutic outcome may result from changes induced in G-proteins (Von Lubitz et al, 1994a,b).…”

Section: Discussionmentioning

confidence: 56%

Adenosine A3 receptor stimulation and cerebral ischemia

Lubitz

Lin

Popik

et al. 1994

European Journal of Pharmacology

271

257

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Chronic treatment with the selective adenosine A 3 receptor agonist N 6 -(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) administered prior to either 10 or 20 min forebrain ischemia in gerbils resulted in improved postischemic cerebral blood circulation, survival, and neuronal preservation. Opposite effects, i.e., impaired postischemic blood flow, enhanced mortality, and extensive neuronal destruction in the hippocampus were seen when IB-MECA was given acutely. Neither adenosine A 1 nor A 2 receptors are involved in these actions. The data indicate that stimulation of adenosine A 3 receptors may play an important role in the development of ischemic damage, and that adenosine A 3 receptors may offer a new target for therapeutic interventions.

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“…Nonetheless, studies in which cerebral adenosine A 1 receptors have been chronically exposed to either agonists (Von Lubitz et al, 1994a) or non-selective antagonists (Georgiev et al, 1993) provided contradictory data indicating that, contrary to the expectations, chronic treatment with drugs acting at adenosine A 1 receptors does not result in the decrease of the receptor density.…”

Section: Discussionmentioning

confidence: 93%

Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

Lubitz¹,

Lin

Bischofberger

et al. 1999

European Journal of Pharmacology

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Although the selectivity and potency of adenosine amine congener (ADAC) at adenosine A 1 receptors are similar to other highly selective agonists at this receptor type, the chemical structure of the N 6 substituent is completely different. We now demonstrate that the characteristics of the therapeutic profile of ADAC are distinct from those observed during our previous studies of adenosine A 1 receptor agonist-mediated neuroprotection. Most significantly, chronic treatment with low microgram doses of ADAC (25-100 µg/kg) protects against both mortality and neuronal damage induced by 10 min bilateral carotid occlusion in gerbils. At higher chronic doses, the statistical significance of the protective effect is lost. Acute preischemic administration of the drug at 75-200 µg/kg also results in a statistically significant reduction of postischemic mortality and morbidity. These data indicate that, contrary to other adenosine A 1 receptor agonists whose chronic administration enhances postocclusive brain damage, ADAC may be a promising agent in treatment of both acute (e.g., cerebral ischemia) and chronic (seizures) disorders of the central nervous system in which adenosine A 1 receptors appear to be involved.

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Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number

Cited by 90 publications

References 27 publications

The Effect of Long Term Caffeine Treatment on Hypoxic-Ischemic Brain Damage in the Neonate

The Effect of Long Term Caffeine Treatment on Hypoxic-Ischemic Brain Damage in the Neonate

Adenosine A3 receptor stimulation and cerebral ischemia

Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

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