Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

作者：Kryslaine L. Radomski, Xiaomei Zi, Fritz W. Lischka, Mark Noble, Zygmunt Galdzicki, Regina C. Armstrong · 发表于：Acta Neuropathologica Communications · 年份：2022 · DOI：10.1186/s40478-022-01366-z · 被引用次数：20 · 研究领域：Traumatic Brain Injury and Neurovascular Disturbances、Traumatic Brain Injury Research、Immunotoxicology and immune responses

Damage to long axons in white matter tracts is a major pathology in closed head traumatic brain injury (TBI). Acute TBI treatments are needed that protect against axon damage and promote recovery of axon function to prevent long term symptoms and neurodegeneration. Our prior characterization of axon damage and demyelination after TBI led us to examine repurposing of 4-aminopyridine (4-AP), an FDA-approved inhibitor of voltage-gated potassium (Kv) channels. 4-AP is currently indicated to provide symptomatic relief for patients with chronic stage multiple sclerosis, which involves axon damage and demyelination. We tested clinically relevant dosage of 4-AP as an acute treatment for experimental TBI and found multiple benefits in corpus callosum axons. This randomized, controlled pre-clinical study focused on the first week after TBI, when axons are particularly vulnerable. 4-AP treatment initiated one day post-injury dramatically reduced axon damage detected by intra-axonal fluorescence accumulations in Thy1-YFP mice of both sexes. Detailed electron microscopy in C57BL/6 mice showed that 4-AP reduced pathological features of mitochondrial swelling, cytoskeletal disruption, and demyelination at 7 days post-injury. Furthermore, 4-AP improved the molecular organization of axon nodal regions by restoring disrupted paranode domains and reducing Kv1.2 channel dispersion. 4-AP treatment did not resolve deficits in action potential conduction across the corpus callosum, based on ex vivo...