title: Acrolein-mediated conduction loss is partially restored by K⁺ channel blockers.
abstract: Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K(+) channels due to myelin damage leads to conduction block, and K(+) channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 μM K(+) channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 μM. We have also shown that while both compounds at 100 μM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K(+) channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases.
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana; and.
authors.forename: Rui
authors.initials: R
authors.lastname: Yan
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana; and.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Page
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana; and Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana riyi@purdue.edu.
authors.forename: Riyi
authors.initials: R
authors.lastname: Shi
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000171:Acrolein / Q000633:toxicity*; D000200:Action Potentials / Q000187:drug effects; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology
chemical_list: C548134:4-aminopyridine-3-methanol; D000631:Aminopyridines; D026902:Potassium Channel Blockers; D000171:Acrolein; D015761:4-Aminopyridine
keywords: 4-aminopyridine; demyelination; hydralazine; potassium ion; spinal cord injury