Relationships between Cerebrospinal Fluid Markers of Excitotoxicity,Ischemia,and Oxidative Damage after Severe TBI: The Impact of Gender,Age,and Hypothermia

Abstract

Excitotoxicity and ischemia can result in oxidative stress after TBI. Female sex hormones are hypothesized to be neuroprotective after TBI by affecting multiple mechanisms of secondary injury, including oxidative damage, excitotoxicity and ischemia. Ca²⁺ mediated oxidative stress increases with age, and hypothermia is known to attenuate secondary injury. The purpose of this study was to determine if the relationship between cerebral spinal fluid (CSF) markers of excitotoxicity, ischemia, and oxidative damage are gender and age specific and the role of hypothermia in affecting these relationships. F₂-isoprostane, glutamate, and lactate/pyruvate, were assessed in CSF from adults (n = 68) with severe TBI (Glasgow coma scale [GCS] score ≤ 8) using ventricular CSF samples (n= 207) collected on days 1, 2, and 3 post-injury. F2-isoprostane/glutamate and F₂-isoprostane/lactate/pyruvate ratios were determined for patients at each time point. Six-month Glasgow Outcome Scores (GOS) were also obtained. Repeated measures multivariate analysis showed a significant gender effect (p < 0.002) and gender*time interaction (p = 0.012) on F2-isoprostane/glutamate ratios. A significant gender effect (p = 0.050) and gender*time interaction (p = 0.049) was also seen with F2-isoprostane/lactate/pyruvate. Hypothermia (p = 0.001) and age (p= 0.026) significantly increased F2-isoprostane/glutamate ratios. Females had a significant inverse relationship between day 1 F2-isoprostane/glutamate ratios and GOS scores (r =- 0.43; p= 0.05) as well as day 1 F₂-isoprostane/lactate/pyruvate ratio (r =- 0.46; p = 0.04) and GOS scores. These results indicate that females have smaller oxidative damage loads than males for a given excitotoxic or ischemic insult and female gonadal hormones may play a role in mediating this neuroprotective effect. These results also suggest that susceptibility to glutamate mediated oxidative damage increases with age and that hypothermia differentially attenuates CSF glutamate versus F₂-isoprostane production. Gender and age differences in TBI pathophysiology should be considered when conducting clinical trials in TBI.