Clinical and Basic Evaluation of the Prognostic Value of Uric Acid in Traumatic Brain Injury

Abstract

Background: As a major antioxidant in serum, uric acid (UA) was once considered only as the leading cause of gout; however, recent studies have validated its neuroprotective role in ischemic stroke. Because the potential protective effects of UA in traumatic brain injury (TBI) remain largely unknown, this study investigated the role of UA in TBI in both clinical patients and experimental animals. Methods: In TBI patients, serum UA concentrations were measured within 3 days after injury. Clinical outcomes at discharge were classified according to the Glasgow Outcome Scale: good outcome (4-5) and poor outcome (1-3). Risk factors for good outcome were identified via backward logistic regression analysis. For the animal study, a controlled cortical impact (CCI) injury model was established in mice. These mice were given UA at different doses intraperitoneally, and subsequent UA concentrations in mouse serum and brain tissue were determined. Neurological function, oxidative stress, inflammatory response, neuronal maintenance, cerebral blood flow, and lesion size were also assessed. Results: The serum UA level was significantly lower in TBI patients who had a good outcome (P<0.01), and low serum UA was an independent predictor of good outcome after TBI (P<0.01; odds ratio, 0.023; 95% confidence interval, 0.006-0.082). Consistently, decreased levels of serum UA were observed in both TBI patients and CCI animals (P<0.05), whereas the UA concentration was increased in CCI brain tissue (P<0.05). Administration of UA further increased the UA level in brain tissue as compared to that in control animals (P<0.05). Among the different doses administered, 16 mg/kg UA improved sensorimotor functional recovery, spatial learning, and memory in CCI mice (P<0.05). Moreover, oxidative stress and the inflammatory response were inhibited by UA treatment (P<0.05). UA treatment also improved neuronal maintenance and cortical blood flow (P<0.05) but not lesion size (P>0.05). Conclusions: UA acted to attenuate neuronal loss, cerebral perfusion impairment and neurological deficits in TBI mice through suppression of neuronal and vascular oxidative stress. Following TBI, active antioxidant defense in the brain may result in consumption of UA in the serum, and thus, a decreased serum UA level could be predictive of good clinical recovery.

Keywords: UA (uric acid); inflammation; oxidative stress; traumatic brain injury.

Figure 1

Measurements of UA in human serum, mouse serum and mouse brain tissue after TBI. (A) The measurement of UA in human serum (μmol/L). (B-C) The measurements of UA in mouse serum (μmol/L) and mouse brain tissue (ng/g). Results are presented as mean±SD (n=5 per group), * indicates P<0.05.

Figure 2

Effects of UA treatment on functional outcomes following CCI. (A) The Neurological Severity Score and (B) the wire grip test. (C-F) The assessment of learning and spatial memory ability in Morris water maze. (C) The latency to locate the hidden platform, (D) dwelling time in quadrant 4, (E) path length in quadrant 4 and (F) the times to pass over the platform. ''Saline” stands for the group that received CCI+Saline, ''UA1” stands for the group that received CCI+UA (16 mg/kg), ''UA2” stands for the group that received CCI+UA (80 mg/kg) and ''UA3” stands for the group that received CCI+UA (160 mg/kg) (n=6 per group). Results are presented as mean±SD. * indicates P<0.05.

Figure 3

Effects of UA treatment on oxidative stress and the inflammatory response following CCI. (A-D) Representative bands and quantitative analysis of oxidative markers after CCI. (E-G) Quantitative analysis of inflammatory cytokines after CCI by ELISA. Results are presented as mean±SD (n=5 per group). * indicates P<0.05.

Figure 4

Effects of UA treatment on neuronal maintenance, cerebral blood flow and lesion size following CCI. (A-B) Representative images and quantitative analysis of neuronal maintenance (NeuN-positive number) in the injured hippocampus after CCI (Scale bar, 200 μm), (n=5 per group). (C-D) Representative laser speckle images and statistical analysis of cortical brain blood flow changes (% CBF in the traumatic hemisphere) in different groups. Color bar shows arbitrary linear perfusion units. Results are expressed as percentage change from baseline (saline group), (n=5 per group). (E-F) Representative images and quantitative analysis of lesion volume in the injured hemisphere after CCI (n=5 per group). * indicates P<0.05.