Leukemia Inhibitory Factor as a late-stage treatment for delayed white matter loss in concussive head injury

Abstract

Leukemia Inhibitory Factor (LIF) is an injury-induced cytokine that peaks 48 hours after a traumatic brain injury (TBI). Juvenile LIF haplodeficient mice exhibit desynchronized glial responses, increased neurodegeneration, decreased axonal conductivity and behavioral deficits after a concussive head injury. Given the necessity of LIF during the acute recovery phase after injury, we hypothesized that intranasal LIF (IN-LIF) treatment would prevent neurodegeneration when administered during the chronic recovery period from a mild TBI (mTBI). Young adult male CD1 mice were subjected to a midline, closed-head frontal cortex injury using a flat metal impactor with a 3mm tip to induce a mTBI. In the 6-8 weeks post-mTBI, known to precede axonal atrophy in this mTBI model, two doses of 40 ng and 100 ng of LIF were administered twice daily, 5 days/week for two consecutive weeks. Sensorimotor functions were assessed at 4 and 8 weeks post mTBI, followed by ex-vivo brain magnetic resonance imaging at 9.4T and histopathology. mTBI mice showed sensorimotor deficits at 4 weeks, which worsened by 8 weeks post-injury. IN-LIF treatment prevented the progressive sensorimotor loss seen in the vehicle-treated controls. Increased mean diffusivity and decreased fractional anisotropy were observed in the corpus callosum and prefrontal cortex of mTBI brains. In a dose-dependent manner, IN-LIF prevented the mTBI-induced mean diffusivity increase and fractional anisotropy decrease. Histologically, there was significantly less astrogliosis, microgliosis and axonal injury in the IN-LIF treated mice vs. controls. These results support the therapeutic potential of IN-LIF to reduce delayed neurodegeneration and improve neurological outcomes after mTBIs.