Peroxiredoxin VI oxidation in cerebrospinal fluid correlates with traumatic brain injury outcome

Abstract

Traumatic brain injury (TBI) patients would benefit from the identification of reliable biomarkers to predict outcomes and treatment strategies. In our study, cerebrospinal fluid (CSF) from patients with severe TBI was evaluated for oxidant stress-mediated damage progression after hospital admission and subsequent ventriculostomy placement. Interestingly, substantial levels of peroxiredoxin VI (Prdx6), a major antioxidant enzyme normally found in astrocytes, were detected in CSF from control and TBI patients, and were not associated with blood contamination. Functionally, Prdx6 and its associated binding partner glutathione S-transferase pi (GSTP1-1, also detected in CSF) act in tandem to detoxify lipid peroxidation damage to membranes. We found Prdx6 was fully active in CSF of control patients but becomes significantly inactivated (oxidized) under TBI. Furthermore, significant and progressive oxidation of “buried” protein thiol in CSF of TBI patients (as compared to that of non-trauma control) were detected over a 24h period following hospital admission, with increased oxidation correlating with severity of trauma. Conversely, recovery of Prdx6 activity after 24h indicated more favorable patient outcome. Not only is this the first report of an extracellular form of Prdx6 but also the first report of its detection at a substantial level in CSF. Taken together, our data suggest a meaningful correlation between TBI-initiated oxidation of Prdx6, its specific phospholipid hydroperoxide peroxidase activity, and severity of trauma outcome. Consequently, we propose that Prdx6 redox status detection has the potential to be a biomarker for TBI outcome and a future indicator of therapeutic efficacy.

Effects of haloperidol and clozapine administration on oxidative stress in rat brain, liver and serum

“…The 1-Cys peroxiredoxin-6 is localised to astrocytes and has been postulated to provide protection against membrane lipid peroxidation [40], whereas the 2-Cys peroxiredoxin-2 is present mainly in neurons [41]. In this study, we observed increased peroxiredoxin-6 levels in frontal grey matter following haloperidol administration, which may reflect an attempt to limit membrane lipid damage, or alternatively, an effect on astrocyte function.…”

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery

“…PRDX-6 is an antioxidant enzyme found primarily in astrocytes that may protect neuronal membranes and mitochondria from damage due to lipid peroxidation (38). PRDX-6 has been targeted in TBI due to the vulnerability of the brain to lipid peroxidation (38), and was recently uncovered as a candidate TBI biomarker in a rodent model using unsupervised autoimmune screening (39).…”

“…PRDX-6 is an antioxidant enzyme found primarily in astrocytes that may protect neuronal membranes and mitochondria from damage due to lipid peroxidation (38). PRDX-6 has been targeted in TBI due to the vulnerability of the brain to lipid peroxidation (38), and was recently uncovered as a candidate TBI biomarker in a rodent model using unsupervised autoimmune screening (39). Elevated PRDX-6 levels have been observed acutely across the spectrum of TBI in humans (40), and the restitution of PRDX-6 levels within 24 h of severe TBI in humans has been associated with improved recovery (38).…”

“…PRDX-6 has been targeted in TBI due to the vulnerability of the brain to lipid peroxidation (38), and was recently uncovered as a candidate TBI biomarker in a rodent model using unsupervised autoimmune screening (39). Elevated PRDX-6 levels have been observed acutely across the spectrum of TBI in humans (40), and the restitution of PRDX-6 levels within 24 h of severe TBI in humans has been associated with improved recovery (38). While the mechanism remains elusive in human injury, these findings generally support the metabolic dysfunction noted in experimental brain injury models (6) and human advanced neuroimaging (9-11,41).…”

Oxidative stress, redox regulation and diseases of cellular differentiation

“…Prx6 and GSTP in cerebrospinal fluid could be potential targets for therapeutic interventions in the TBI patients [94, 95]. …”