Protective effect of adenosine and a novel xanthine derivative propentofylline on the cell damage after bilateral carotid occlusion in the gerbil hippocampus

Dux, E.; Fastbom, Johan; Ungerstedt, Urban; Rudolphi, Karl Asmund; Fredholm, Bertil B.

doi:10.1016/0006-8993(90)90925-2

Cited by 164 publications

(75 citation statements)

References 33 publications

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“…This manifested as a delay in the depression and acceleration in the recovery of excitatory synaptic transmission [59]. Whilst this could reflect an artefact of the slice preparation, similar observations of reduced adenosine release were being made around that time in in vivo preparations [60][61][62]. Furthermore, it was known that such repetitive insults to the brain could provoke greater brain damage [63], a fact that is of great current concern in the context of sport-related concussions [64].…”

Section: Atp Loss and Replenishment In Brain Tissue: Lessons From Thementioning

confidence: 95%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity. Far from this being a disadvantage, the ATP-impoverished slice can serve as a useful and experimentally-tractable surrogate for the injured brain, which experiences similar depletion of cellular ATP. We have shown that the restoration of cellular ATP in brain slices to in vivo values is possible with a simple combination of d-ribose and adenine (RibAde), two substrates for ATP synthesis. Restoration of ATP in slices to physiological levels has implications for synaptic transmission and plasticity, whilst in the injured brain in vivo RibAde shows encouraging positive results. Given that ribose, adenine, and a third compound, allopurinol, are all separately in use in man, their combined application after acute brain injury, in accelerating ATP synthesis and increasing the reservoir of the neuroprotective metabolite, adenosine, may help reduce the morbidity associated with stroke and traumatic brain injury.

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Section: Atp Loss and Replenishment In Brain Tissue: Lessons From Thementioning

confidence: 95%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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“…have led to the conclusion that adenosine may act as a protective agent (15,38,39). Much less is known about the situation in neonatal animals.…”

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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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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“…The ability of PPF to reduce ischemia-induced glutamate release (47) and increase ischemia-induced extracellular adenosine levels secondary to inhibition of adenosine transport has been demonstrated in vitro (23,48) and in vivo (47). Evidence of reduction in hippocampal injury, including the amelioration of calcium influx, neuronal degeneration, and astroglial edema, has been documented in pretreated gerbils (49,50). Our finding of a significant improvement in outcome with postischemic administration is consistent with the reductions in hippocampal injury (51), edema (52,53), and superoxide production (52), and the accelerated energy recovery (53) achieved with similar posttreatment regimens in adult animals.…”

Section: Dcf-treated Animalsmentioning

confidence: 99%

Reduction in Cerebral Ischemic Injury in the Newborn Rat by Potentiation of Endogenous Adenosine

et al. 1995

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Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebroprotection in a well established newborn rat model of hypoxiaischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p = 0.02) and 31% ( p = 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% ( p = 0.03) and 32% ( p = 0.04), Although the brain of the newborn exhibits a higher tolerance to ischemia than that of the adult, morbidity and mortality from hypoxic-ischemic encephalopathy in the perinatal period remain high (1). Although the general pathophysiologic mechanisms underlying cerebral ischemic injury are probably similar between age groups, the unique characteristics of energy and glucose metabolism (2), glutamate receptor physiology (3, 4), and vascular regulation (5, 6) in the newborn brain may dictate separate therapeutic regimens for affected neonates relative to adults.In recent years, experimental evidence has accumulated from adult animal models attesting to the neuroprotective properties of the purine nucleoside adenosine in the setting of Received February 3, 1995; accepted April 6, 1995 7 for review), and the mechanistic basis for such an adenosine-mediated reduction in ischemic brain injury has been outlined (8). Ontogenic studies of the brains of fetal and newborn animals indicate that the requisite metabolic enzymes and transporters for adenosine are fully matured at birth or earlier (9-12). There is also consistent evidence that cerebral adenosine production increases in response to perinatal hypoxia-ischemia (13-16). Although cerebral vessels in fetal and newborn animals exhibit the characteristic vasodilatative response to adenosine (17, 18), significant development of neuronal adenosine receptors, particularly in terms of density and coupling to second messengers, may occur postnatally (12,19,20). Thus, adenosinebased treatments may not provide therapeutic efficacy against cerebral hypoxia-ischemia in the perinatal period. To address this possibility, we used two different drugs to determine whether potentiating endogenous adenosine would confer cerebroprotection in a neonatal model of hypoxia-ischemia.

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Protective effect of adenosine and a novel xanthine derivative propentofylline on the cell damage after bilateral carotid occlusion in the gerbil hippocampus

Cited by 164 publications

References 33 publications

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

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

Reduction in Cerebral Ischemic Injury in the Newborn Rat by Potentiation of Endogenous Adenosine

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