Disease-modifying effects on chronic axon damage and white matter degeneration with 4-aminopyridine after acute traumatic brain injury.

Axonal injury is a hallmark pathology of acute traumatic brain injury (TBI) that drives degeneration of white matter in chronic TBI and in neurodegenerative diseases. No available therapies effectively treat damaged axons. We focused on early, potentially reversible, axonal pathologies of abnormal nodes of Ranvier and demyelination as intervention targets. 4-Aminopyridine (4-AP), which blocks potassium Kv channels, is an FDA-approved drug prescribed for multiple sclerosis to enhance axon signal conduction through nodes with Kv channels exposed by demyelination. We hypothesized that early 4-AP treatment after acute TBI could mitigate secondary axon damage and white matter degeneration. Adult male and female mice received a non-penetrating TBI or sham procedure. A low clinically relevant dose of 4-AP (0.5 mg/kg, b.i.d.) or saline vehicle was initiated at 24 h, administered over 4 weeks, then discontinued for 6-weeks prior to analysis at 10 weeks post-injury. TBI caused atrophy of corpus callosum (CC) white matter and increased serum neurofilament light (NfL) protein, a translational biomarker of axonal injury. 4-AP treatment after injury significantly attenuated CC atrophy and lowered serum NfL levels. 4-AP also significantly lessened CC myelin and oligodendrocyte loss while dampening neuroinflammation, i.e. astrogliosis and microgliosis. In a parallel electron microscopy study, 4-AP reduced intra-axonal structural damage and mitochondrial swelling, normalized axon diameters, and increased myelin thickness. These findings reveal 4-AP disease-modifying effects on the progression of evolving TBI pathology that endure long after discontinuing treatment. More broadly, these results demonstrate proof-of-concept support for developing interventions to treat axon damage and white matter degeneration.