allopurinol and Cerebrovascular-Disorders

Topics: Allopurinol; Antihypertensive Agents; Benzbromarone; Cerebrovascular Disorders; Humans; Hypertension; Hyperuricemia; Insulin Resistance; Myocardial Ischemia; Uricosuric Agents

Acute, severe increases in arterial blood pressure cause sustained cerebral arteriolar dilation, abnormal reactivity to carbon dioxide and to changes in blood pressure, abolition of endothelium-dependent dilation from acetylcholine, discrete morphological lesions of the endothelium and vascular smooth muscle, and breakdown of the blood-brain barrier to plasma proteins. The dilation, abnormal reactivity, and morphological abnormalities are inhibited by pretreatment with cyclooxygenase inhibitors or with free radical scavengers. Superoxide dismutase-inhibitable reduction of nitroblue tetrazolium applied to the brain surface was detectable both during hypertension and one hour after hypertension subsided. Nitroblue tetrazolium reduction is also reduced by inhibitors of the anion channel. The abnormalities seen after hypertension are reproduced by topical application of arachidonate. The results are consistent with the view that acute hypertension induces generation of superoxide anion radical in association with accelerated arachidonate metabolism via cyclooxygenase. This radical enters cerebral extracellular space via the anion channel and gives rise to hydrogen peroxide and hydroxyl radical. All three radicals are capable of causing vasodilation by relaxation of cerebral vascular smooth muscle. The hydroxyl radical is the most likely candidate for vascular wall damage. The significance of this mechanism in chronic experimental hypertension or its relevance to human disease is not known.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arterioles; Blood Proteins; Blood-Brain Barrier; Bradykinin; Brain; Brain Injuries; Cardiovascular Agents; Catalase; Cerebrovascular Circulation; Cerebrovascular Disorders; Cyclooxygenase Inhibitors; Endothelium; Free Radicals; Hydrogen Peroxide; Hydroxides; Hydroxyl Radical; Hypertension; Leukocytes; Leukotrienes; Lipid Peroxides; Muscle, Smooth, Vascular; Peroxidases; Prostaglandin-Endoperoxide Synthases; Prostaglandins G; Superoxide Dismutase; Superoxides; Vasodilation; Xanthine Oxidase

Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.

Topics: Animals; Cardiovascular Physiological Phenomena; Cerebrovascular Circulation; Cerebrovascular Disorders; Cognitive Dysfunction; Enzyme Inhibitors; Febuxostat; Free Radicals; Hydrogen Peroxide; Memory, Short-Term; Mice; Mice, Inbred C57BL; Stress, Psychological; Xanthine Oxidase

Few studies focus on the relationship between allopurinol and ischemic cerebrovascular disease. The goal of the study was to investigate the association of long-term therapy of allopurinol with the first-time attack of ischemic cerebrovascular disease in Taiwan. We performed a case-control study using the database of the Taiwan National Health Insurance Program. The case group included 14,937 subjects aged 20-84 years with the first-time attack of ischemic cerebrovascular disease from 2000 to 2013. The control group included 14,937 sex-matched and age-matched subjects aged 20-84 years without any type of cerebrovascular disease. Ever use of allopurinol was defined as subjects who had at least a prescription for allopurinol before the index date. The OR and the 95% CI for ischemic cerebrovascular disease associated with allopurinol use were measured by the multivariable logistic regression model. The adjusted OR of ischemic cerebrovascular disease was 0.992 (95% CI 0.989 to 0.996) for subjects with increasing cumulative duration of allopurinol use for every 1 month, compared with never use. In a further analysis, the adjusted OR of ischemic cerebrovascular disease was 0.74 (95% CI 0.57 to 0.96) for cumulative duration of allopurinol use >3 years, compared with never use. Our findings suggest that lone-term therapy of allopurinol >3 years is associated with decreased risk of the first-time attack of ischemic cerebrovascular disease, compared with no allopurinol therapy.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Case-Control Studies; Cerebrovascular Disorders; Female; Humans; Male; Middle Aged; Time Factors; Young Adult

It is well-known that, in ischemic cerebral injury, a free radical and its byproducts are generated by xanthine-xanthine oxidase system and eliminated by scavengers such as superoxide dismutase (SOD), catalase, uric acid and ascorbic acid. To investigate the possible involvement of the xanthine-xanthine oxidase system in hypertensive cerebral injury, we examined chronological changes in uric acid level in the cerebral cortex and the effects of the inhibition of xanthine oxidase or catalase using stroke-prone spontaneously hypertensive rats (SHRSP). In young SHRSP, uric acid content was lower than age-matched Wistar-Kyoto rats (WKY), but in mature SHRSP strongly exposed to oxidative stress uric acid content had risen dramatically. Administration of allopurinol, an inhibitor of xanthine oxidase, caused a marked decrease in uric acid content. In these SHRSP, cerebral injury was much more intense compared to the control group. On the other hand, administration of aminotriazole, an inhibitor of catalase, did not affect the brain pathology of SHRSP, in spite of a mild reduction in tissue uric acid content. These results suggest that the xanthine-xanthine oxidase system is not the major source of free radical generation in hypertensive cerebral injury. Moreover, the results also suggest that tissue uric acid may have a key role for the incidence of hypertensive cerebral injury in SHRSP.

Topics: Allopurinol; Amitrole; Animals; Brain; Catalase; Cerebral Cortex; Cerebrovascular Disorders; Enzyme Inhibitors; Genetic Predisposition to Disease; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Uric Acid; Xanthine; Xanthine Oxidase; Xanthines

Shichimotsu-koka-to, a Chinese herb, is a medicine prescribed to treat patients with hypertension. We investigated the effects of Shichimotsu-koka-to on the lesions of stroke-prone spontaneously hypertensive rats (SHRSP). The SHRSP were given 1% or 2% Shichimotsu-koka-to solution (1 g/kg/day or 2 g/kg/day) instead of drinking water from 8 to 42 weeks of age. When the 2 g/kg/day Shichimotsu-koka-to was chronically administered to the SHRSP, their life span was significantly prolonged by prevention of stroke, but there was no effect on blood pressure. The Shichimotsu-koka-to treatment decreased superoxide dismutase (SOD) activities in the cytosol of the cerebral cortex and increased SOD activities in the cytosol of the brain stem. The treatment with 2 g/kg/day Shichimotsu-koka-to decreased xanthine oxidase (XOD) activities in the cytosol of the cerebral cortex, and Shichimotsu-koka-to quenched superoxide anion (O2-) as determined by electron spin resonance analysis in vitro. In addition, SOD activities in the cytosol of the cerebral cortex of SHRSP not administered Shichimotsu-koka-to were increased by the drug in vitro. XOD activities in the cytosol of the cerebral cortex of SHRSP not administered Shichimotsu-koka-to were inhibited by this herb in vitro. These results suggest that these preventive effects of Shichimotsu-koka-to on the stroke in SHRSP are due its ability to scavenge O2- and to inhibit O2- production by the hypoxanthine-XOD system in the cytosol of the cerebral cortex.

Topics: Animals; Brain; Cerebrovascular Disorders; Drugs, Chinese Herbal; Free Radical Scavengers; Free Radicals; Rats; Rats, Inbred SHR; Superoxide Dismutase; Superoxides; Xanthine Oxidase

A 45-year-old man developed cerebral vasculitis associated with a systemic hypersensitivity response shortly after commencing treatment with allopurinol. The illness settled on withdrawal of the drug and no other cause was found.

Topics: Allopurinol; Cerebrovascular Disorders; Drug Hypersensitivity; Enzyme Inhibitors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Magnetic Resonance Imaging; Male; Middle Aged; Vasculitis; Xanthine Oxidase

Topics: Allopurinol; Cerebrovascular Disorders; Colchicine; Diagnosis, Differential; Diet Therapy; Female; Gout; Humans; Hypertension; Male; Probenecid; Thrombosis