Deoxycoformycin and oxypurinol: protection against focal ischemic brain injury in the rat

Lin, Yu‐Wei; Phillis, John W.

doi:10.1016/0006-8993(92)90665-v

Cited by 71 publications

(19 citation statements)

References 44 publications

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“…29,30 In the previous study, we demonstrated neuroprotective effects of EPC-K1 in focal cerebral ischemia in rats. 31 However, in the present study, EPC-K1 reduced infarct volume but did not significantly improve neurological scores.…”

Section: Discussionmentioning

confidence: 93%

Combination of a Free Radical Scavenger and Heparin Reduces Cerebral Hemorrhage After Heparin Treatment in a Rabbit Middle Cerebral Artery Occlusion Model

Zhao

Suzuki

Kondo

et al. 2001

Stroke

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Background and Purpose-We sought to investigate the effects of EPC-K1, a free radical scavenger, on reducing heparin-produced cerebral hemorrhage in a rabbit model of middle cerebral artery (MCA) photothrombosis and to investigate whether the combination of EPC-K1 and heparin enhances neuroprotection from cerebral ischemic damage. Methods-In the heparin-alone group (nϭ8), heparin was administered intravenously for 24 hours, starting from 3 hours after MCA occlusion. In the EPC-K1-alone group (nϭ8), EPC-K1 was administered as a bolus injection (10 mg/kg) twice at 3 and 6 hours after MCA occlusion. In the combination group (nϭ8), EPC-K1 and heparin both were administered as in the single-drug procedures. In the vehicle group (nϭ10), saline were infused for 24 hours. Results-Heparin prolonged activated partial thromboplastin time by Ϸ3 times that of control animals. In the heparin-treated animals, the hemorrhage size was significantly increased (PϽ0.0001) and neurological symptoms were significantly worse (PϽ0.01) than in control animals at 48 hours. The combination of EPC-K1 and heparin dramatically reduced heparin-produced cerebral hemorrhage (PϽ0.0001), with a significant reduction in infarct volume (reduction by 63.2% and 57.2% of heparin-alone and control animals, respectively, PϽ0.0001) and a significant improvement in neurological symptoms (PϽ0.01 versus heparin-alone and control animals, respectively). Conclusions-These data indicate that free radical formation may play a key role in intracerebral hemorrhage exacerbated by heparin treatment and that the combination of a free radical scavenger and heparin augmented neuroprotection from acute brain ischemia. The results of the present study may suggest a potential clinical approach for the treatment of acute stroke.

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Section: Discussionmentioning

confidence: 93%

Combination of a Free Radical Scavenger and Heparin Reduces Cerebral Hemorrhage After Heparin Treatment in a Rabbit Middle Cerebral Artery Occlusion Model

Zhao

Suzuki

Kondo

et al. 2001

Stroke

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“…Thus, it was shown that the novel putative anticonvulsant drug 1-[2,6-difluorophenyl)-methyl]-1H-1,2,3-triazolo[4,5-c]) pyridine-4-amine monohydrochloride (BW534U87) effectively reduced seizures induced in rodents by threshold maximal and supramaximal electroshock, electrical kindling, pentylenetetrazole (PTZ) infusion and by vestibular stimulation in the genetically seizure-prone epilepsy-like (EL) mouse, likely via inhibition of ADA [243, 244]. Protection against focal ischemic brain damage in rats was evident when deoxycoformycin (500 micrograms/kg), was administered prior to the onset of ischemia, whereas delayed dosage was without any effect [245]. …”

Section: Inhibitors Of Nucleoside Metabolismmentioning

confidence: 99%

Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

Boison¹

2011

CTMC

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Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affect several signal transduction pathways simultaneously and therefore have the unique potential to modify complex neurochemical networks; (ii) by acting on the network level, inhibitors of nucleoside metabolism are highly suited to fine-tune, restore, or amplify physiological functions of nucleosides; (iii) therefore inhibitors of nucleoside metabolism have promise for the "soft and smart" therapy of neurological diseases with the added advantage of reduced systemic side effects. This review will first highlight the role of nucleoside function and dysfunction in physiological and pathophysiological situations with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. The second part of this review will cover pharmacological approaches to use inhibitors of nucleoside metabolism, with a special emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, novel gene-based therapeutic strategies to inhibit nucleoside metabolism and focal treatment approaches will be discussed.

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“…Intraperitoneal administration of 1 mg/kg DCF inhibits brain adenosine deaminase >98% (22), and subsequent increases in ischemia-evoked release of adenosine (43) have been documented. When administered preischemically, DCF (0.5 mg/kg) afforded protection in rat (44) and gerbil (45) cerebral ischemia models. Our study is the first to show a reduction in ischemic injury with DCF when administered after the ischemic insult.…”

Section: Dcf-treated Animalsmentioning

confidence: 99%

“…Our study is the first to show a reduction in ischemic injury with DCF when administered after the ischemic insult. By inhibiting the catabolism of adenosine, DCF may also reduce the production of oxygen free radicals via the xanthine oxidase pathway, and conserve adenosine for direct resynthesis of ATP (44).…”

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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Deoxycoformycin and oxypurinol: protection against focal ischemic brain injury in the rat

Cited by 71 publications

References 44 publications

Combination of a Free Radical Scavenger and Heparin Reduces Cerebral Hemorrhage After Heparin Treatment in a Rabbit Middle Cerebral Artery Occlusion Model

Combination of a Free Radical Scavenger and Heparin Reduces Cerebral Hemorrhage After Heparin Treatment in a Rabbit Middle Cerebral Artery Occlusion Model

Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

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

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