Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment

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)...

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Published in:Journal of cerebral blood flow and metabolism 2023-06, Vol.43 (6), p.905-920
Main Authors: Burrage, Emily N, Coblentz, Tyler, Prabhu, Saina S, Childers, Ryan, Bryner, Randy W, Lewis, Sarah E, DeVallance, Evan, Kelley, Eric E, Chantler, Paul D
Format: Article
Language:English
Subjects:
Animals
Cardiovascular Physiological Phenomena - drug effects
Cerebrovascular Circulation - drug effects
Cerebrovascular Circulation - physiology
Cerebrovascular Disorders - drug therapy
Cerebrovascular Disorders - etiology
Cerebrovascular Disorders - psychology
Cognitive Dysfunction - enzymology
Cognitive Dysfunction - etiology
Cognitive Dysfunction - metabolism
Enzyme Inhibitors - pharmacology
Febuxostat - pharmacology
Free Radicals - metabolism
Hydrogen Peroxide
Memory, Short-Term - drug effects
Memory, Short-Term - physiology
Mice
Mice, Inbred C57BL
Original
Stress, Psychological - enzymology
Stress, Psychological - metabolism
Xanthine Oxidase - antagonists & inhibitors
Xanthine Oxidase - metabolism
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container_title Journal of cerebral blood flow and metabolism
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creator Burrage, Emily N
Coblentz, Tyler
Prabhu, Saina S
Childers, Ryan
Bryner, Randy W
Lewis, Sarah E
DeVallance, Evan
Kelley, Eric E
Chantler, Paul D
description 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 
doi_str_mv 10.1177/0271678X231152551
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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 &lt; 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 &lt; 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. 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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.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>36655326</pmid><doi>10.1177/0271678X231152551</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-6960-9728</orcidid><oa>free_for_read</oa></addata></record>
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ispartof Journal of cerebral blood flow and metabolism, 2023-06, Vol.43 (6), p.905-920
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1559-7016
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source PubMed Central Free; SAGE Journals
subjects Animals
Cardiovascular Physiological Phenomena - drug effects
Cerebrovascular Circulation - drug effects
Cerebrovascular Circulation - physiology
Cerebrovascular Disorders - drug therapy
Cerebrovascular Disorders - etiology
Cerebrovascular Disorders - psychology
Cognitive Dysfunction - enzymology
Cognitive Dysfunction - etiology
Cognitive Dysfunction - metabolism
Enzyme Inhibitors - pharmacology
Febuxostat - pharmacology
Free Radicals - metabolism
Hydrogen Peroxide
Memory, Short-Term - drug effects
Memory, Short-Term - physiology
Mice
Mice, Inbred C57BL
Original
Stress, Psychological - enzymology
Stress, Psychological - metabolism
Xanthine Oxidase - antagonists & inhibitors
Xanthine Oxidase - metabolism
title Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment
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