Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia

Dhanesha, Nirav; Vázquez‐Rosa, Edwin; Cintrón-Pérez, Coral J.; Thedens, Daniel; Kort, Alexa; Chuong, Vicky; Rivera-Dompenciel, Adriana M.; Chauhan, Anil K.; Leira, Enrique C.; Pieper, Andrew A.

doi:10.1016/j.jstrokecerebrovasdis.2017.12.043

Cited by 27 publications

(23 citation statements)

References 15 publications

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“…Stroke is a major cause of age-related morbidity and mortality. Treatment with exogenous UA or more soluble UA analogs can be beneficial in animal stroke models (Dhanesha et al, 2018; Haberman et al, 2007; Romanos et al, 2007; Yu et al, 1998). However, in humans, both positive and negative associations between levels of UA and the outcome of ischemic stroke have been reported.…”

Section: Resultsmentioning

confidence: 99%

“…UA is one of the most abundant antioxidant molecules in humans with a potent ability to scavenge peroxynitrite, nitric oxide, and hydroxyl radicals, thereby preventing protein nitration and lipid peroxidation (Hooper et al, 1997, 1998). Studies in animal models have shown that administration of UA or soluble UA analogs that retain the antioxidant properties of UA protects the brain against ischemic injury (Aliena-Valero et al, 2018; Dhanesha et al, 2018; Haberman et al, 2007; Justicia et al, 2017; Yu et al, 1998), and a UA analog accelerates wound healing (Chigurupati et al, 2010), suggesting that UA can protect cells against injury and enhance repair of damaged tissue. The positive correlation between life span and UA levels among mammalian species suggests a potential role for UA in mitigating the aging process (Cutler, 1984).…”

Section: Introductionmentioning

confidence: 99%

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Uric acid enhances longevity and endurance and protects the brain against ischemia

Cutler

Camandola

Feldman

et al. 2019

Neurobiology of Aging

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Among mammals, there is a positive correlation between serum uric acid (UA) levels and life span. Humans have high levels of UA because they lack a functional urate oxidase (UOX) enzyme that is present in shorter lived mammals. Here, we show that male and female mice with UOX haploinsufficiency exhibit an age-related elevation of UA levels, and that the life span of female but not male UOX+/− mice is significantly increased compared to wild-type mice. Serum UA levels are elevated in response to treadmill exercise in UOX+/− mice, but not wild-type mice, and the endurance of the UOX+/− mice is significantly greater than wild-type mice. UOX+/− mice exhibit elevated levels of brain-derived neurotrophic factor, reduced brain damage and improved functional outcome in a model of focal ischemic stroke. Levels of oxidative protein nitration and lipid peroxidation are reduced in muscle and brain tissues of UOX+/− mice under conditions of metabolic and oxidative stress (running in the case of muscle and ischemia in the case of the brain), consistent with prior evidence that UA can scavenge peroxynitrite and hydroxyl radical. Our findings reveal roles for UA in life span determination, endurance and adaptive responses to brain injury, and suggest novel approaches for protecting cells against injury and for optimizing physical performance.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uric acid enhances longevity and endurance and protects the brain against ischemia

Cutler

Camandola

Feldman

et al. 2019

Neurobiology of Aging

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“…[8] In addition, ROS are critical in initiating the post-ischemic inflammatory response which further exacerbates ischemic injury. [10][11][12][13][14][15] However, low molecular weight antioxidants (for instance NXY-059) have historically not translated well in the treatment of stroke patients. [10][11][12][13][14][15] However, low molecular weight antioxidants (for instance NXY-059) have historically not translated well in the treatment of stroke patients.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, ROS are critical in initiating the post‐ischemic inflammatory response which further exacerbates ischemic injury . There is an abundance of experimental and clinical research supporting ROS as a promising therapeutic target for acute ischemic stroke . However, low molecular weight antioxidants (for instance NXY‐059) have historically not translated well in the treatment of stroke patients.…”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species‐Responsive Nanoparticles for the Treatment of Ischemic Stroke

Rajkovic

Gourmel

d’Arcy

et al. 2019

Advanced Therapeutics

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Ischemic stroke is a leading cause of death and long-term disability worldwide, yet availability of current treatments is limited. The downstream events resulting from cerebral ischemia lead to an imbalance in the production of harmful reactive oxygen species (ROS) over endogenous antioxidant mechanisms. Thus, treatments that can reduce this imbalance can limit the extent of injury resulting from ischemic stroke. In this work, the potential of novel ROS-scavenging PEGylated polymeric nanoparticles (NPs) composed of poly(propylene sulfide) (PPS) (PPS-NPs) for ischemic stroke therapy is evaluated in vitro and in a mouse model of stroke. In vitro results show that PPS-NPs display remarkable anti-oxidant and anti-inflammatory properties, whilst exhibiting negligible cytotoxicity. NPs administered intravenously rapidly accumulate in ischemic brain regions as visualized through fluorescence imaging, reduced infarct volume, blood-brain barrier damage, neuronal loss, and neuroinflammation as determined by immunohistochemistry, and improved recovery of neurological function as determined through behavioral analyses. Crucially, the data show that the therapeutic time window for administration of PPS-NPs extends up to 3 h, a clinically relevant time window for stroke. The findings provide new strong evidence that these NPs may be an effective antioxidant therapy for ischemic stroke.

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“…MRI was performed on day-1 post reperfusion as per previously described protocol. 17 Briefly, animals were anesthetized with isoflurane (2.5% induction, 1.2% maintenance) and placed in the bore of the 7.0 Tesla MRI (Agilent Technologies Inc., Santa Clara, CA, USA) with a two-channel receive-only surface coil. Following scout scans to orient the imaging planes; high-resolution images were acquired with a 9-minute T2-weighted 2D fast spinecho pulse sequence oriented coronally.…”

Section: Mri Imaging and Infarct Volume Quantificationmentioning

confidence: 99%

Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation

Dhanesha

Chorawala

Jain

et al. 2019

Stroke

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Background and Purpose-Cellular fibronectin containing extra domain A (Fn-EDA) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. While global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods-We generated novel plasma Fn-EDA −/− (Fn-EDA fl/fl Alb Cre) and endothelial Fn-EDA −/− (Fn-EDA fl/fl Tie2 Cre) strains on hyperlipidemic apolipoprotein E-deficient (Apoe −/−) background. By following the STAIR guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in two different models of stroke: intraluminal monofilament and embolic model, on day 1, 3 and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by MRI), cerebral blood flow (CBF, by laser speckle imaging), neurological and sensory-motor outcome, and post-ischemic thrombo-inflammation (platelet thrombi, fibrin, neutrophil, phospho-NFκB, TNFα, and IL-1β). Results-Stroke outcome was comparable in Apoe −/− Fn-EDA fl/fl Tie2 Cre and control Apoe −/− Fn-EDA fl/fl mice suggesting endothelial Fn-EDA does not contribute to stroke. Apoe −/− Fn-EDA fl/fl Alb Cre mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3 and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased post-ischemic thrombo-inflammatory response (P<0.05 versus Apoe −/− Fn-EDA fl/fl). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional CBF at 1 hour in Apoe −/− Fn-EDA fl/fl Alb Cre mice suggesting plasma Fn-EDA promotes post-ischemic secondary thrombosis. Co-infusion of anti-Fn-EDA antibody with recombinant tissue plasminogen activator (rtPA) in Apoe −/− mice, 1 hour after embolization, improved stroke outcome with enhanced survival and improved neurological outcome (P<0.05 versus rtPA).

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Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia

Cited by 27 publications

References 15 publications

Uric acid enhances longevity and endurance and protects the brain against ischemia

Uric acid enhances longevity and endurance and protects the brain against ischemia

Reactive Oxygen Species‐Responsive Nanoparticles for the Treatment of Ischemic Stroke

Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation

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