Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

Abstract

Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (tBi). However, their relationship with diffuse histopathology remains unclear. Additionally, translatability is a focus of neurotrauma research, however, studies using translational animal models are limited. Here, we evaluated associations between circulating biomarkers and acute thalamic histopathology in a translational micro pig model of mTBI. Serum samples were collected pre-injury, and 1 min-6 h following mTBI. Markers of neuronal injury (Ubiquitin Carboxy-terminal Hydrolase L1 [UCH-L1]), microglial/macrophage activation (Ionized calcium binding adaptor molecule-1 [Iba-1]) and interleukin-6 [IL-6]) and astrogliosis/astrocyte damage (glial fibrillary acidic protein [GFAP]) were measured. Axonal injury and histological features of neurons and glia were also investigated using immunofluorescent labeling and correlated to serum levels of the associated biomarkers. Consistent with prior experimental and human studies, GFAP, was highest at 6 h post-injury, while no substantial changes were observed in UCH-L1, Iba-1 or IL-6 over 6 h. This study also found promising associations between thalamic glial histological signatures and ensuing release of Iba-1 and GFAP into the circulation. Our findings suggest that in diffuse injury, monitoring serum Iba-1 and GFAP levels can provide clinically relevant insight into the underlying acute pathophysiology and biomarker release kinetics following mTBI, providing previously underappreciated diagnostic capability. Traumatic brain injury (TBI) is an increasing challenge and a global health priority 1 , with more than 50 million TBIs occurring worldwide each year with an associated cost of approximately $400 billion 2. The vast majority (~ 95%) of patients suffer a mild TBI (mTBI) with Glasgow Come Scale (GCS) scores of 13-15 3,4 which, contrary to common perception, cause structural sequelae with variable degrees of injury to neurons, glia, and vascular structures, leading to a spectrum of potential clinical outcomes. As translatability is a primary focus of neurotrauma research, there has been a call for use of higher-order gyrencephalic animal models prior to transitioning to the clinic 5-9 , however, knowledge regarding the TBI-induced pathophysiology in higher order animal models is still limited. Operation Brain Trauma Therapy (OBTT) is a drug-and biomarker-screening

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“…Importantly, the GFAP patterns that emerged in this investigation were also consistent with a lower level of severity while confirming the reproducibility of the injury, thereby providing evidence that our model behaves in a reliable and predictable fashion. These results are in line with and extend our previous work ( 13 , 25 ), showing that GFAP enables the reliable, specific, objective, and measurable assessment and characterization of TBI models while providing a robust framework for its use as a tool in different species. The UCH-L1 serum biomarker levels, however, may not be as reliable in this pig models of diffuse TBI as was highlighted in our previous study ( 25 ).…”

“…These results are in line with and extend our previous work ( 13 , 25 ), showing that GFAP enables the reliable, specific, objective, and measurable assessment and characterization of TBI models while providing a robust framework for its use as a tool in different species. The UCH-L1 serum biomarker levels, however, may not be as reliable in this pig models of diffuse TBI as was highlighted in our previous study ( 25 ). The addition of a pathobiologically diverse set of biomarkers, including their exosomal component, may substantially improve the current approach, enabling us to reflect and gauge the response to therapy more effectively ( 38 – 41 ).…”

Effects of Rewarming with Extracorporeal Membrane Oxygenation to Restore Oxygen Transport and Organ Blood Flow After Hypothermic Cardiac Arrest in a Porcine Model.

“…Deliberate hypothermic cardiac arrest is used for repair of complex cardiovascular conditions, and for cerebral protection the safe use of cardiac arrest for up to 60 min at 8-13 °C [40][41][42] has been documented. In the present experiment biomarkers of brain injury disclose no pathological changes as GFAP and UCHL1 (Table 3), both highly selective for CNS injury [24], are within normal control levels in pigs [43].…”

Buprenorphine alters microglia and astrocytes acutely following diffuse traumatic brain injury

“…Activated astrocytes undergo hypertrophy and increased expression of the intermediate filament, GFAP 66 , 67 . Such activation-associated morphological changes of both microglia and astrocytes are seen in various brain regions following diffuse TBI 30 , 40 , 41 , 66 , 68 , 69 , however, the effects of Bup on such changes are not well understood. Both microglia and astrocytes express all three opioid receptors, suggesting that Bup could potentially play a role in modulation of microglial and/or astrocyte morphological changes associated with activation 10 .…”