Temporal Profile of Cerebrospinal Fluid, Plasma, and Brain Interleukin-6 After Normothermic Fluid-Percussion Brain Injury: Effect of Secondary Hypoxia

Abstract

Interleukin-6 (IL-6) is a proinflammatory cytokine that may play multiple roles in the pathogenesis of traumatic brain injury (TBI). The present study determined time-dependent changes in IL-6 concentrations in vulnerable brain regions, cerebrospinal fluid (CSF) samples, and plasma after normothermic TBI. Because secondary insults are common in head injured patients, we also assessed the consequences of a post-traumatic secondary hypoxic insult on this pleiotropic cytokine. Male Sprague-Dawley rats were intubated, anesthetized, and underwent a moderate parasagittal fluid-percussion brain injury (1.8-2.1 atm, 37°C) followed by either 30 minutes of normoxic or hypoxic (pO 2 = 30-40 mmHg) gas levels. Rats were sacrificed 3, 6, or 24 hours after TBI or shamoperated procedures. Brain samples, including the ipsilateral cerebral cortex and hippocampus were dissected and analyzed. Plasma and CSF samples were collected at similar times and stored at -80°C until analysis. IL-6 levels were significantly increased ( p < 0.05) at 3, 6, and 24 hours in the cerebral cortex and at 6 hours in the hippocampus after TBI. IL-6 levels in the TBI normoxic group for both structures returned to control levels by 24 hours. Plasma levels of IL-6 were elevated at all time points, while CSF levels were high at 3 and 6 hours, but normalized by 24 hours. Post-traumatic hypoxia led to significantly elevated ( p < 0.05) IL-6 protein levels in the cerebral cortex at 24 hours compared to sham-operated controls. These findings demonstrate that moderate TBI leads to an early increase in IL-6 brain, plasma, and CSF protein levels. Secondary post-traumatic hypoxia, a common secondary injury mechanism, led to prolonged elevations in plasma IL-6 levels that may participate in the pathophysiology of this complicated TBI model.

A single dose of PPARγ agonist pioglitazone reduces cortical oxidative damage and microglial reaction following lateral fluid percussion brain injury in rats

“…In our study unchanged levels of IL-1β, IL-6 and TNF-α were detected in the rat parietal cortex 24 h following LFPI of moderate severity. These observations are consistent with previously demonstrated upregulation of cortical IL-1β, IL-6 and TNF-α mRNA or proteins within a few hours after LFPI and their normalization up to 24 h, suggesting the role of the tested cytokines as early biomarkers of neuroinflammation in this brain trauma model (Chatzipanteli et al, 2012;Fan et al, 1995Fan et al, , 1996Kinoshita et al, 2002;Knoblach and Faden, 1998;Knoblach et al, 1999;Mukherjee et al, 2011;Taupin et al, 1993;Teng and Molina, 2014;Vitarbo et al, 2004;Zhu et al, 2004). In contrast, decreased (Mukhheerje et al, 2011) or increased (Su et al, 2014) levels of several mentioned cytokines in the cortex of the injured rats at 24 h following LFPI were also described.…”

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods

“…Less frequently, others have analyzed cytokines from cerebrospinal fluid (118, 127, 167, 168). In addition to many examples of this phenomenon in the rodent literature [e.g., (169–171)], human studies have also demonstrated that cytokine concentration in cerebrospinal fluid vs. blood can differ, with some examples showing a positive correlation, some showing lack of correlation, and some showing anticorrelation [e.g., (172–176)]. Because the presence of cytokines usually reflects local rather than systemic conditions (see Box 1), measuring cytokines from the cerebrospinal fluid is a more direct representation of the central nervous system environment than from peripheral blood.…”

Elucidating Pro-Inflammatory Cytokine Responses after Traumatic Brain Injury in a Human Stem Cell Model

“… 8 Moreover, because of logistical reasons, it is difficult to measure the inflammatory response the first hours after trauma in patients with severe TBI. 8 Based on the animal literature, the initial hours after trauma usually present the highest levels of key cytokines, 47–49 and given that anti-inflammatory treatments in TBI are highly sought after, 50 the current in vitro platform holds promise for future translational work. Further, one of the main benefits of a hESC system is that it may be used to study further applied clinical scenarios, such as cytokine inhibitors, 51 on functional consequences and cytokine expression patterns.…”