Allopurinol inhibits uric acid accumulation in the rat brain following focal cerebral ischemia

Kanemitsu, Hideaki; Tamura, Akira; Kirino, Takaaki; Oka, Hidemune; Sano, Keiji; Iwamoto, Takeo; Yoshiura, Masahiko; Iriyama, Keiji

doi:10.1016/0006-8993(89)90786-5

Cited by 25 publications

(14 citation statements)

References 13 publications

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“…In the present study, UA 24 h after focal ischaemia was observed to increase approximately 13-fold over nonischaemic hemisphere levels. This increase is consistent with those observed in other studies [11,12,24].…”

Section: Discussionsupporting

confidence: 83%

“…The UA increase in the brain was inhibited by injecting allopurinol, a specific inhibitor of xanthine oxidase [12,24]. Allopurinol enters brain as a result of its affinity to the transporter in the brain capillaries [4,15].…”

Section: Discussionmentioning

confidence: 99%

“…Our data show that the xanthine concentration in the ischaemic hemisphere of rabbit brain increases after MCAO, reaching a maximum 24 h after occlusion. Kanemitsu and coworkers [12] showed that there was no increase in plasma UA values after MCAO. In our study, it was found that allopurinol significantly suppressed the increase in UA levels after ischaemia, which may result from xanthine inhibition; and compensatory accumulation of hypoxanthine was also observed.…”

Section: Discussionmentioning

confidence: 99%

“…McCord [18] suggested that xanthine oxidase is the primary free radical-generating enzyme in cases of ischaemia reperfusion. Allopurinol, one pharmacological agent used for neural tissue damage produced by the free radicals, is an analogue of hypoxanthine and inhibits biosynthesis of uric acid (UA) [12,13,21,24]. It has been reported to be as effective as free radical scavengers in limiting tissue injury [18].…”

Section: Introductionmentioning

confidence: 99%

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The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits

et al. 2001

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In this experimental study, the neuroprotective effect of the xanthine oxidase inhibitor allopurinol on focal cerebral ischaemia created by permanent middle cerebral artery occlusion (MCAO) was investigated. Using high performance liquid chromatography (HPLC), we measured hypoxanthine, xanthine, and uric acid (UA) levels in rabbit brains following focal cerebral ischaemia. Rabbits were randomly and blindly assigned into four groups of eight animals each. The control groups received 2% carboxymethylcellulose solution, while 10% allopurinol 150 mg/kg was given to the treatment group 1 h before ischaemia. Each group was subdivided into two groups which were sacrificed 4 h or 24 h after ischaemia, respectively. UA and xanthine values of the rabbits in the control groups were quite high at both times and highest after 24 h, particularly in the centre of the ischaemia. A significant decrease in UA and xanthine values was observed in rabbits that were given allopurinol (P<0.05). According to our results, it was concluded that allopurinol pretreatment protects neural tissue in the early period after arterial occlusion and prevents cerebral injury in the late period, especially in the perifocal area, possibly by preventing the formation of free radicals with xanthine oxidase inhibition.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits

et al. 2001

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“…It not only activates immune effectors in the innate and adaptive immune systems (Shi et al., 2003), but also enhances antibody immunity (Behrens et al., 2008). Some studies have also suggested that UA is a strong peroxynitrite scavenger and antioxidant (Hooper et al., 2000; Sevanian, Davies, & Hochstein, 1991; Waugh, 2008), while others have shown that UA reflects xanthine oxidase activity with its subsequent production of free radicals (Kanemitsu et al., 1989) and is associated with oxidative stress and glutamate‐mediated excitotoxicity in neurological patients (Stover, Lowitzsch, & Kempski, 1997). …”

Section: Introductionmentioning

confidence: 99%

Elevated cerebrospinal fluid uric acid during relapse of neuromyelitis optica spectrum disorders

Shu

Zhang

et al. 2016

Brain and Behavior

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IntroductionPrevious studies have shown that serum uric acid (UA) modulates outcomes of neurological diseases, although little is known about cerebrospinal fluid (CSF) UA levels in neuromyelitis optica spectrum disorders (NMOSDs).MethodsCerebrospinal fluid and serum UA levels were measured in samples from 68 patients, including NMOSDs during relapse (n = 38) and controls with noninflammatory and non‐neurodegenerative diseases (CTLs, n = 30). Correlation analysis was performed between CSF UA and clinical characteristics, serum UA, and blood–brain barrier integrity in NMOSDs.ResultsCerebrospinal fluid UA levels in NMOSDs were significantly higher than in CTLs (p = .002), while serum UA differences between NMOSDs and CTLs were not statistically significant. In NMOSDs, CSF UA levels were significantly higher in patients with an impaired blood–brain barrier than in patients with an intact one (p < .001), and significantly higher in longer disease duration than in shorter disease duration patients (p = .002). CSF UA levels were also significantly higher in active patients upon MRI than in inactive patients (p < .001), and significantly higher in patients with brain lesions than without brain lesions (p = .024). CSF UA was significantly associated with the serum UA levels (r = .454, p = .002), disease duration (r = .383, p = .018), and blood–brain barrier index (r = .805, p < .001), but did not correlate with age, gender, annualized relapse rate, duration, or severity of NMOSD. Multiple regression analysis demonstrated that CSF UA was independent of the blood–brain barrier index (β = .765, p < .001) and serum UA levels (β = .01, p = .019) in NMOSDs.ConclusionsCerebrospinal fluid UA levels were elevated in NMOSD patients during relapse, and were likely modified by serum UA levels and blood–brain barrier integrity.

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Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo

et al. 1998

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Uric acid is a well-known natural antioxidant present in fluids and tissues throughout the body. Oxyradical production and cellular calcium overload are believed to contribute to the damage and death of neurons that occurs following cerebral ischemia in victims of stroke. We now report that uric acid protects cultured rat hippocampal neurons against cell death induced by insults relevant to the pathogenesis of cerebral ischemia, including exposure to the excitatory amino acid glutamate and the metabolic poison cyanide. Confocal laser scanning microscope analyses showed that uric acid suppresses the accumulation of reactive oxygen species (hydrogen peroxide and peroxynitrite), and lipid peroxidation, associated with each insult. Mitochondrial function was compromised by the excitotoxic and metabolic insults, and was preserved in neurons treated with uric acid. Delayed elevations of intracellular free calcium levels induced by glutamate and cyanide were significantly attenuated in neurons treated with uric acid. These data demonstrate a neuroprotective action of uric acid that involves suppression of oxyradical accumulation, stabilization of calcium homeostasis, and preservation of mitochondrial function. Administration of uric acid to adult rats either 24 hr prior to middle cerebral artery occlusion (62.5 mg uric acid/kg, intraperitoneally) or 1 hr following reperfusion (16 mg uric acid/kg, intravenously) resulted in a highly significant reduction in ischemic damage to cerebral cortex and striatum, and improved behavioral outcome. These findings support a central role for oxyradicals in excitotoxic and ischemic neuronal injury, and suggest a potential therapeutic use for uric acid in ischemic stroke and related neurodegenerative conditions.

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Allopurinol inhibits uric acid accumulation in the rat brain following focal cerebral ischemia

Cited by 25 publications

References 13 publications

The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits

The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits

Elevated cerebrospinal fluid uric acid during relapse of neuromyelitis optica spectrum disorders

Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo

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