IL-6 induces weakness with axonal degeneration and loss of myelin when infused into the spinal subarachnoid space of adult rats. (A) We infused IL-6 via a subarachnoid spinal catheter into adult rats over a 7-day period. Control animals received saline through the spinal catheter, while another cohort of animals received intrathecal IL-6 and were also given the iNOS inhibitor aminoguanidine (AG) intraperitoneally for the length of the experiment beginning at day 0. *P < 0.05. (B) Pathologic specimens from IL-6–infused rat spinal cords exhibited reduced myelin staining and white matter vacuolation (asterisks). Scale bar: 20 μm. (C) White matter vacuoles (asterisks) were strongly NF positive, confirming the presence of axonal degeneration. Scale bar: 20 μm. (D and E) Plastic sections (1 μM) from IL-6–infused rat spinal cords revealed 2 pathologic features, seen principally in superficial white matter regions: (D) swollen axons with intact myelin (asterisks), consistent with axonal degeneration, and (E) demyelinated axons (arrows). Scale bar: 10 μm (D and E). (F) These pathologic features could also be seen in autopsy material from a patient with severe TM and high CSF IL-6 levels (1,997 pg/ml). Regions of demyelination (arrows) were seen throughout the cervical spinal cord both with H&E staining and with luxol fast blue (LFB), and there were areas of vacuolation within the white matter (asterisks), consistent with axonal degeneration. (G) Immunohistochemical analysis of the autopsy material also revealed axonal dysfunction as defined by disruption of NF staining and accumulation of APP, a marker of disrupted axonal transport.