Chronic Febuxostat Treatments Prevents Cerebrovascular Dysfunction Associated with Chronic Stress

Abstract

Chronic stress is a risk factor for many cerebrovascular diseases including stroke and vascular dementia. Our lab has previously shown that chronic stress impairs cerebrovascular function potentially mediated by an increase in oxidative stress driven by the xanthine oxidase pathway. However, the therapeutic avenues of the xanthine oxidase inhibitor, febuxostat have yet to be examined in the context of chronic stress induced cerebrovascular dysfunction. Here, we examined the effect of chronic febuxostat treatment on middle cerebral artery function in a mouse model of chronic stress. At 18 weeks of age, mice underwent the unpredictable chronic mild stress (UCMS; 5 days/weeks for 7hrs/day) paradigm to elicit a chronic stress phenotype; simultaneously, drinking water was treated with febuxostat (50mg/L) and provided to mice ad libitum (n=9-10/group). On week 26 mice were euthanized and the middle cerebral arteries (MCA) were removed and positioned in a pressurized myobath. To test for vessel health, the MCA was exposed to increasing concentrations of acetylcholine (Ach; 10-9M to 10-4M), phenylephrine (PE; 10-9M to 10-4M), and sodium nitroprusside (SNP; 10-9M to 10-4M). Consistent with previous work, mice exposed to chronic stress with no treatment displayed impaired MCA dilation to Ach compared to controls (8.4±0.8um to 19.7±0.8um, respectively; p<0.0001). Interestingly, mice exposed to chronic stress while simultaneously treated with febuxostat displayed comparable MCA dilation to Ach compared to controls (18.6±0.4um to 19.7±0.8um, respectively; n.s.). There were no differences found between groups in response to PE or SNP. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by increased xanthine oxidase activity.