Serum Glial Fibrillary Acidic Protein Predicts Tissue Glial Fibrillary Acidic Protein Break-Down Products and Therapeutic Efficacy after Penetrating Ballistic-Like Brain Injury

Abstract

Acute traumatic brain injury (TBI) is associated with neurological dysfunction, changes in brain proteins, and increased serum biomarkers. However, the relationship between these brain proteins and serum biomarkers, and the ability of these serum biomarkers to indicate a neuroprotective/therapeutic response, remains elusive. Penetrating ballistic-like brain injury (PBBI) was used to systematically analyze several key TBI biomarkers, glial fibrillary acidic protein (GFAP) and its break-down products (BDPs)-ubiquitin C-terminal hydrolase-L1 (UCH-L1), α-II spectrin, and α-II spectrin BDPs (SBDPs)-in brain tissues and serum during an extended acute-subacute time-frame. In addition, neurological improvement and serum GFAP theranostic value was evaluated after neuroprotective treatment. In brain tissues, total GFAP increased more than three-fold 2 to 7 d after PBBI. However, this change was primarily due to GFAP-BDPs which increased to 2.7-4.8 arbitrary units (AU). Alpha-II spectrin was nearly ablated 3 d after PBBI, but somewhat recovered after 7 d. In conjunction with α-II spectrin loss, SBDP-145/150 increased approximately three-fold 2 to 7 d after PBBI (vs. sham, p<0.05). UCH-L1 protein levels were slightly decreased 7 d after PBBI but otherwise were unaffected. Serum GFAP was elevated by 3.2- to 8.8-fold at 2 to 4 h (vs. sham; p<0.05) and the 4 h increase was strongly correlated to 3 d GFAP-BDP abundance (r=0.66; p<0.05). Serum GFAP showed such a strong injury effect that it also was evaluated after therapeutic intervention with cyclosporin A (CsA). Administration of 2.5 mg/kg CsA significantly reduced serum GFAP elevation by 22.4-fold 2 h after PBBI (vs. PBBI+vehicle; p<0.05) and improved neurological function 1 d post-injury. Serum biomarkers, particularly GFAP, may be correlative tools of brain protein changes and feasible theranostic markers of TBI progression and recovery.

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

“…Nonetheless, GFAP and GFAP-DPs and αII-SDPs are emerging as sensitive serum biomarkers. 8,13,26 Clinically, elevated peripheral levels of GFAP following TBI are associated with unfavorable neurological outcomes. 20,56 Notably, in children with TBI, GFAP outperforms other biomarkers such as S100β in detecting head trauma and predicting intracranial lesions on head CT. 66 Moreover, GFAP levels are typically higher in serum following severe injury than after diffuse injury, and serum GFAP levels may be especially relevant in the pediatric patient population to detect contusion or intracerebral hemorrhage.…”

Brain-related proteins as serum biomarkers of acute, subconcussive blast overpressure exposure: A cohort study of military personnel

“…GFAP and UCH-L1 are, perhaps, the most thoroughly studied as biomarkers for moderatesevere TBI or closed head hemorrhagic injury. Levels dramatically increase in the serum or plasma within 12-24h [13][14][15][16]. GFAP and UCH-L1 are not typically evident in patients with an mTBI unless hemorrhage or intracranial lesions are presented [17,18].…”

New astroglial injury-defined biomarkers for neurotrauma assessment

“…Few animal studies address primary cellular injury events or early biomarker release. [55][56][57][58] After mild TBI, GFAP's passage into the circulation is delayed, limiting its benefit as an urgent care tool. 52 UCHL1 declines on injury day, restricting its later post-injury use.…”