Anti-Inflammatory Treatments during the Chronic Phase of Spinal Cord Injury Improve Locomotor Function in Adult Mice

Abstract

Our previous data suggested that ongoing inflammation in the spinal cord 6 weeks following spinal cord injury was detrimental to locomotor function. Others have shown in the acute and sub-acute post-injury phase that microglial/macrophage activation and T regulatory cells are detrimental to recovery. Here, C57BL/6 mice with a moderately severe T9 contusion were injected intravenously daily with minocycline, which reduces microglial/ macrophage activation, or with CD25 antibodies, which reduce T regulatory cell function, starting at 6 weeks after injury. Both anti-inflammatory drugs caused an improvement in hindlimb locomotor function over the 2-week treatment, as measured by the Basso Mouse Scale (BMS). The improvement was functionally important, with mice having problems with coordinated stepping (BMS *6) before treatment to walking essentially normally (BMS > 7) at the end of the treatment. The effects diminished within 1 week after termination of the treatments, suggesting an ongoing and dynamic inflammatory process. The area of white matter or the inflammatory markers CD68 for activated microglia/macrophages and CD45 for leukocytes were not different between the groups. These data suggest that inflammation during the chronic phase following spinal cord injury reduces conduction through the epicenter, possibly by release of cytokines, and is amenable to treatment for improved neurological function.

Reciprocal Modulation Between Microglia and Astrocyte in Reactive Gliosis Following the CNS Injury

“…Animal studies have shown that anti-inflammatory treatments significantly ameliorated motor and sensory functional recovery [69–73]. Reducing the infiltration of neutrophils, macrophages or T cells with neutralizing antibodies [69, 70], depletion of macrophages [71], or anti-inflammatory cytokine therapy [72] in the acute phase decreased the secondary tissue damage with functional improvement.…”

“…Reducing the infiltration of neutrophils, macrophages or T cells with neutralizing antibodies [69, 70], depletion of macrophages [71], or anti-inflammatory cytokine therapy [72] in the acute phase decreased the secondary tissue damage with functional improvement. Repression of microglial/macrophage activation by administration of minocycline or CD25 antibodies during either acute or chronic phases increased the neuroperformance after the traumatic SCI [73–75]. Inhibiting the astroglial activation or remodeling the ECM of astrocytic scar enhanced axonal plasticity and regeneration, and promoted the functional improvement in the rodent SCI models [76–80].…”

Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury

“…Therefore, 16 articles were identified that met our inclusion criteria. 4,21,29,31,43,45,47,55,62,67,70,75,77,80,84,85 Study Characteristics. The study characteristics are summarized in Table 13; detailed information is available in Table 14.…”

“…Doses of minocycline ranged from 10 to 180 mg/kg; nearly all studies delivered multiple doses of the drug beginning 0-2 hours postinjury and then again every 12-24 hours for 1-6 days. Two studies began minocycline treatment more than 30 days after SCI: Hains et al 31 gave the first injection at 31 days and continued twice a day for 3 days, and Arnold et al 4 gave the first dose at 6 weeks, followed by daily injections for 2 weeks. Teng et al 75 Effectiveness of Therapy.…”

“…21,29,45,67,75,84 Two studies reported a decrease in inflammatory markers between 6 hours and 4 weeks following SCI in minocycline-treated versus saline/vehicletreated or untreated animals, 21,45 whereas 1 study reported no difference between groups at 1 week. 4 Minocycline produced variable functional outcomes following SCI. Ten studies evaluated motor improvement by using the BBB score; 7 of them reported improved outcomes with minocycline versus control treatment at 2-38 days postinjury.…”