Oxypurinol reduces focal ischemic brain injury in the rat

doi:10.1016/0304-3940(91)90550-D

Neuroscience Letters

Volume 126, Issue 2, 27 May 1991, Pages 187-190

https://doi.org/10.1016/0304-3940(91)90550-D Get rights and content

Abstract

When measured within 2 days of a unilateral occlusion of the middle cerebral artery (MCA) combined with tandem occlusion of the ipsilateral common carotid artery in rats, contralateral neurological deficits were detectable, with brain swelling and a consistent degree of neocortical infarction in the ipsilateral hemisphere. Oxypurinol (40 mg/kg i.p. administered 0.5 h prior to, and 24 h after, the onset of focal ischemia) significantly reduced the development of the ischemic infarct (P < 0.001); attenuated tissue swelling (P < 0.01) and ameliorated the neurological deficits (P < 0.05). These findings suggest that this compound may be useful for the prevention or treatment of ischemic brain injuries, such as those occurring during stroke.

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Cited by (29)

Pathways involved in the generation of reactive oxygen and nitrogen species during glucose deprivation and its role on the death of cultured hippocampal neurons
2010, Neuroscience
Citation Excerpt :
In agreement with these observations, a role of 12-LOX on neuronal death induced by GD and glucose reperfusion has been recently demonstrated (Nagasawa et al., 2007). The present results agree with previous observations supporting the role of cPLA2 and XaO on ROS generation and neuronal death during ischemia/reperfusion (Owada et al., 1994; Saluja et al., 1997; Arai et al., 2001; Lin and Phillis, 1991; Abramov et al., 2007), and suggests that the activation of these enzymes is related to the hypoglycemic component of the ischemic episode. In the present experimental conditions activation of these Ca2+-dependent enzymes would result from the increase in the intracellular concentration of calcium recorded during the GD episode.
Oxidative stress has been suggested as a mechanism contributing to neuronal death induced by hypoglycemia, and an early production of reactive species (RS) during the hypoglycemic episode has been observed. However, the sources of reactive oxygen (ROS) and nitrogen (RNS) species have not been fully identified. In the present study we have examined the contribution of various enzymatic pathways to RS production and neuronal death induced by glucose deprivation (GD) in hippocampal cultures. We have observed a rapid increase in RS during GD, which depends on the activation of NMDA and non-NMDA receptors and on the influx of calcium from the extracellular space. Accordingly, intracellular calcium concentration [Ca²⁺]_i progressively increases more than 30-fold during the GD period. It was observed that superoxide production through the activation of the calcium-dependent enzymes, phospholipase A₂ (cPLA₂) and xanthine oxidase (XaO), contributes to neuronal damage, while nitric oxide synthase (NOS) is apparently not involved. Inhibition of cPLA₂ decreased RS at early times of GD whereas inhibition of XaO diminished RS at more delayed times. The antioxidants trolox and ebselen also showed a protective effect against neuronal death and diminished RS generation. Inhibition of NADPH oxidase also contributed to the early generation of superoxide. Taking together, the present results suggest that the early activation of calcium-dependent ROS producing pathways is involved in neuronal death associated with glucose deprivation.
The effect of infusing hypoxanthine or xanthine on hypoxic-ischemic brain injury in rabbits
2007, Brain Research
Citation Excerpt :
It has been argued that during reperfusion, XO generates free radicals through the metabolism of hypoxanthine and xanthine, causing cerebral injury (Granger et al., 1981). Inhibition of XO with allopurinol or oxypurinol before ischemia does reduce brain damage as evidenced by a reduction in brain infarct volume, decreased cerebral edema and improved neuroelectrophysiologic recovery (Itoh et al., 1986; Palmer et al., 1990; Betz et al., 1991; Mink et al., 1991; Lindsay et al., 1991; Lin and Phillis, 1991, 1992). Inhibition of XO has also been correlated with a decrease in free radical formation (Phillis et al., 1994).
Xanthine oxidase (XO), an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid, is thought to contribute to hypoxic–ischemic brain injury by generating oxygen-free radicals during reperfusion. This is based largely on the observation that inhibition of XO reduces brain damage, but the precise mechanism by which the enzyme contributes to cerebral ischemic injury has not been specifically evaluated. We examined the role of XO in generating oxygen-free radicals that cause brain injury, hypothesizing that if XO generated a significant amount of free radicals during hypoxia–ischemia and reperfusion, providing additional substrate at the time of injury should increase brain damage. Anesthetized rabbits were first subjected to 8 min of cerebral hypoxia by breathing 3% oxygen and then to 8 min of ischemia by raising intracranial pressure equal to mean arterial pressure with an artificial CSF. In order to promote oxygen-free radical generation, hypoxanthine (n = 9) or xanthine (n = 9), XO substrates, or the vehicle (n = 8) was infused intravenously beginning 30 min before and continuing until 30 min after the insult. Animals were sacrificed after 4 h of reperfusion. Neither hypoxanthine nor xanthine infusion increased brain damage. However, administration of hypoxanthine significantly improved somatosensory evoked potential recovery and preserved neurofilament 68 kDa protein, a neuronal structural protein. This study does not support free radical generation by XO as a major cause of damage in cerebral hypoxia–ischemia. Infusion of hypoxanthine reduced cerebral injury suggesting that another mechanism may explain why inhibition of XO reduces brain damage.
Investigation on the electrochemiluminescent behaviors of oxypurinol in alkaline Ru (bpy)<inf>3</inf><sup>2 +</sup> solution using a flow injection analytical system
2007, Electrochemistry Communications
Electrochemiluminescent (ECL) behaviors of oxypurinol in alkaline tris(2,2-bipyridine)ruthenium(II) $(Ru (bpy)_{3}^{2 +})$ solution were studied in a flow injection electrochemiluminescent system (FI-ECL) in this paper. It was found that the ECL response of oxypurinol was significantly pH-dependent. It inhibited the ECL of $Ru (bpy)_{3}^{2 +}$ at ⩽pH 10.0, whereas exhibited enhanced ECL response at pH ⩾ 11.0. Additionally, other experimental conditions such as the applied potential of working electrode, the flow rate of carrier solution, and the concentration of $Ru (bpy)_{3}^{2 +}$ were all observed to affect the ECL response of oxypurinol. Under the optimum conditions, the logarithm of enhanced ECL intensity, ΔI, was found linearly proportional to the logarithm of oxypurinol concentration in the range of 1.0 × 10⁻⁷–1.0 × 10⁻⁴ mol L⁻¹, and the detection limit (S/N = 3) was 3.0 × 10⁻⁹ mol L⁻¹. The mechanism of inhibited and enhanced $Ru (bpy)_{3}^{2 +}$ ECL by oxypurinol was studied, and a new and sensitive flow injection analysis (FIA) method basing on the enhanced ECL was proposed for detection of oxypurinol.
Effect of allopurinol on brain adenosine levels during hypoxia in newborn piglets
2006, Brain Research
Citation Excerpt :
Oxypurinol forms a stable complex with xanthine oxidase and is a strong non-competitive inhibitor of xanthine oxidase. Studies of ischemic brain injury in rats and gerbils have demonstrated that oxypurinol can reduce brain swelling, decrease cerebral infarct volume, attenuate hippocampal injury, and limit neurological deficits (Lin and Phillis, 1991, 1992; Phillis, 1989). In addition, allopurinol and oxypurinol may act as free radical scavengers (Das et al., 1987; Fauré et al., 1990; Moorhouse et al., 1987).
Adenosine, a purine nucleoside, is a potent inhibitory neuromodulator in the brain which may provide an important endogenous neuroprotective role during hypoxia–ischemia. Allopurinol, a xanthine oxidase inhibitor, blocks purine degradation and may result in the accumulation of purine metabolites, including adenosine, during hypoxia. The present study determines the effect of allopurinol administration prior to hypoxia on brain levels of adenosine and purine metabolites in the newborn piglet. Twenty-two newborn piglets (age 3–7 days) were studied: 5 untreated normoxic and 6 allopurinol-treated normoxic controls were compared to 5 untreated hypoxic and 6 allopurinol-treated hypoxic animals. Brain tissue energy metabolism was continuously monitored during hypoxia by ³¹P NMR spectroscopy. Brain tissue levels of purines increased in both hypoxic groups during hypoxia, however, there were significantly higher increases in brain tissue levels of adenosine (66.5 ± 30.5 vs. 19.4 ± 10.7 nmol/gm), P < 0.01 and inosine (265 ± 97.6 vs. 162.8 ± 38.3 nmol/gm), P = 0.05 in the allopurinol-treated hypoxic group. Allopurinol inhibits purine degradation under severe hypoxic conditions and results in a significant increase in brain tissue levels of adenosine and inosine. The increased accumulation of CNS adenosine during hypoxia which is seen in the allopurinol-treated animals may potentiate adenosine's intrinsic neuroprotective mechanisms.
Antioxidant strategies in the treatment of stroke
2005, Free Radical Biology and Medicine
Excessive production of free radicals is known to lead to cell injury in a variety of diseases, such as cerebral ischemia. In this review, we describe some of the numerous studies that have examined this oxidative stress and the efficiency of antioxidant strategies in focal cerebral ischemia. Besides using genetically modified mice, these strategies can be divided into three groups: (1) inhibition of free radical production, (2) scavenging of free radicals, and (3) increase of free radical degradation by using agents mimicking the enzymatic activity of endogenous antioxidants. Finally, the clinical trials that have tested or are currently testing the efficiency of antioxidants in patients suffering from stroke are reviewed. The results presented here lead us to consider that antioxidants are very promising drugs for the treatment of ischemic stroke.
Oxypurinol administration fails to prevent hypoxic-ischemic brain injury in neonatal rats
2003, Brain Research Bulletin
The purpose of the present study was to determine whether oxypurinol, a xanthine oxidase inhibitor, reduces free radicals and brain injury in the rat pup hypoxic–ischemia (HI) model. Seven-day-old rat pups had right carotid arteries ligated followed by 2.5 h of hypoxia (8% oxygen). Oxypurinol or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily for 3 days. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Oxypurinol treatments did not reduce weight loss in the right hemisphere. Brain weight loss in the right hemisphere were −26.2±3.6, −15.2±6.9, −21.7±4.4, −15.8±5.1, and −16.7±3.4% in vehicle (n=33), 10 (n=17), 20 (n=16), 40 (n=15), and 135 mg/kg (n=13) oxypurinol-treated groups (p>0.05), respectively. Brain thiobarbituric acid-reacting substances (TBARS) were assessed 3 and 6 h after reoxygenation. Concentrations of TBARS rose 1.5-fold due to HI. Oxypurinol did not significantly reduce an HI-induced increase in brain TBARS. Thus, xanthine oxidase may not be the primary source of oxy-radicals in pup brain and as such oxypurinol does not prevent free radical-mediated lipid peroxidation or protect against brain injury in the neonatal rat HI model.

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View full text

Oxypurinol reduces focal ischemic brain injury in the rat

Abstract

Brain Res. Bull.

Biochem. Pharmacol.

Threshold in cerebral ischemia — The ischemic penumbra

Stroke

Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats

Stroke

Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination

Stroke

Focal brain ischemia in the rat: methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries

J. Cereb. Blood Flow Metab.

Hypothermia but not the N-methyl-d-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia

J. Neurosci.

Hypothermia but not the $N- methyl- d -aspartate$ antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia