Marked Gender Effect on Lipid Peroxidation after Severe Traumatic Brain Injury in Adult Patients

Abstract

Striking gender differences have been reported in the pathophysiology and outcome of acute neurological injury. Greater neuroprotection in females versus males may be due, in part, to direct and indirect sex hormone-mediated antioxidant mechanisms. Progesterone administration decreases brain levels of F(2)-isoprostane, a marker of lipid peroxidation, after experimental traumatic brain injury (TBI) in male rats, and estrogen is neuroprotective in experimental neurological injury. In this study, we evaluated the effect of gender on lipid peroxidation, as assessed by cerebrospinal fluid (CSF) levels of F(2)-isoprostane, after severe TBI in humans. Lipid peroxidation was assessed in CSF from 68 adults enrolled in two randomized controlled trials evaluating the effect of therapeutic hypothermia after severe TBI (Glasgow coma scale [GCS] score </= 8). Patients treated with hypothermia (n = 41, 12 females, 29 males) were cooled to 32-33 degrees C (within approximately 6 h) for either 24 or 48 h and then re-warmed. F(2)-isoprostane levels were assessed by ELISA in ventricular CSF samples (n = 199) on day 1, 2, and 3. The association between age, GCS score, time, gender, treatment, duration of treatment, core temperature at the time of CSF sampling, secondary hypoxemia, and CSF F(2)-isoprostane level was assessed by multivariate and dichotomous analyses. F(2)-isoprostane was approximately 2-fold higher in males than females (145.8 +/- 39.6 versus 75.4 +/- 16.6 pg/mL, day 1 p = 0.018). An effect of time after injury (p = 0.007) was reflected by a marked early peak in F(2)-isoprostane (day 1). CSF F(2)-isoprostane was also associated with hypoxemia (p = 0.04). Hypothermia tended to decrease F(2)-isoprostane levels only in males on d1 after TBI. To our knowledge, this is the first study showing gender differences in lipid peroxidation after clinical TBI. Lipid peroxidation occurs early after severe TBI in adults and is more prominent in males vs females. These results established that gender is an important consideration in clinical trial design, particularly in the case of antioxidant strategies.

A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury

“…12,13,23 Cerebrospinal fluid F2-isoprostanes are a unique series of prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation of arachidonic acid and have been used to assess peroxidation in patients with severe TBI. 3,4,17,35 Glycerol is an end product of phospholipid degradation in neural tissue cell membranes and is a marker of cell damage whether caused by O 2 toxicity via free radical formation and lipid peroxidation or secondarily from ischemia. 16,19,32 Levels of CSF F2-isoprostanes as well as microdialysate glycerol were significantly decreased following combined HBO 2 /NBH treatment.…”

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

“…In adults, a gender bias was found in that males had approximately twice the levels of CSF F2-isoprostane than females, and only males had decreased levels of this lipid metabolite in response to hypothermia. 86 This disparity in lipid peroxidation has been proposed to be a potential reason for the greater neuroprotection seen in females than in males. Although F2-isoprostane levels have been called the "gold standard" of lipid peroxidation, determination of its levels requires specialized equipment, thereby limiting its clinical usefulness.…”

The Effect of Premorbid Demographic Factors on the Recovery of Neurocognitive Function in Traumatic Brain Injury Patients

“…me 13,17) . Other authors have reported that sexual dysmorphism may play an important role in outcome following TBI 1,22) . The mechanism by which gender may influence the outcome following TBI is not yet clear.…”