Chronic psychosocial stress is a major risk factor for cognitive impairment. Xanthine oxidase (XO) generates reactive oxygen species (ROS), but it is unclear if XO is involved with chronic stress. We tested the hypothesis that chronic stress leads to an upregulation of XO leading to cerebrovascular dysfunction. The unpredictable chronic mild stress (UCMS) protocol was performed on mice at 4 months of age for a period of 8 weeks. In study 1, the mice were treated with regular or Febuxostat treated water (50 mg/L) to pharmacologically inhibit XO production. In study 2, we genetically knockout XO using the novel hepatic liver-XO (HXO) knockout C57BL/6 mouse model. The mice were separated into wild-type and HXO for control and UCMS groups. For both studies, mice were euthanized at 6 months of age and tissues were harvested. The middle cerebral artery (MCA) was isolated to study the vessel function via ex vivo pressure myography. The production of hydrogen peroxide (H2O2) was measured in the liver tissues using the Coumarin Boronic Acid assay. We concluded from study 1 that the UCMS group showed a 50% deficit in MCA dilation to Acetylcholine and a 7-fold increase in H2O2 production compared to the control group. Study 2 concluded that the HXO UCMS group showed an 80-85% restoration of MCA function, and a non-significant 1.5-fold increase in H2O2 production vs. HXO control. Conclusion, we show that XO plays a role in the stress induced cerebrovascular dysfunction and ROS production.

Xanthine oxidase (XO) mediates chronic stress-induced cerebrovascular dysfunction

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