Cerebrospinal Fluid Biomarkers in Human Spinal Cord Injury from a Phase II Minocycline Trial

Abstract

Inflammatory changes after spinal cord injury (SCI) have been reported in animal models, but human studies are relatively limited. We examined cerebrospinal fluid (CSF) collected from subjects enrolled in a phase II placebo-controlled trial of minocycline for evidence of inflammatory and structural changes after acute human SCI. CSF was collected from 29 subjects every 6 h for 7 days and investigated for eight molecules. CSF from 6 normal subjects (lumbar microdiscectomy patients without central nervous system pathology) was also examined for comparison. Cumulative levels of CSF molecules were compared between patients with motor complete and motor incomplete injury, between those receiving minocycline or placebo, and correlated to neurological outcome at 1 year (alpha = 0.05). We found that levels of C-C motif chemokine ligand 2 (monocyte chemoattractant), C-X-C motif chemokine 10 (CXCL10; T-cell chemoattractant), interleukin-1β (IL-1β), matrix metalloproteinase-9 (MMP-9), neurofilament heavy chain (NfH), and heme oxygenase-1 (HO-1) were significantly elevated after SCI. Neural cell adhesion molecule and nitric oxide oxidation products (NOx) were not significantly altered. Levels of IL-1β, MMP-9, and HO-1 were higher in subjects with more severe motor impairment. Higher cumulative levels of IL-1β, MMP-9, and CXCL10 exhibited moderate, but significant, correlation with worse motor recovery at 12 months. Only HO-1 and NfH appeared to vary with minocycline treatment; HO-1 lacked a later peak compared to placebo-treated subjects while NfH did not manifest its early peak with treatment. These analyses of CSF biomarkers imply a pathophysiological role for particular molecules and suggest mechanistic targets for minocycline in human traumatic SCI.