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Title: Central axons preparing to myelinate are highly sensitivity to ischemic injury
Authors: Alix, James J. P.
Zammit, Christian
Riddle, Art
Meshul, Charles K.
Back, Stephen A.
Valentino, Mario
Fern, Robert
Keywords: Myelin sheath
Myelinated neurofibrils -- Diseases
Cerebral ischemia -- Diagnosis
Axons -- Physiology
Issue Date: 2012
Publisher: John Wiley & Sons, Inc.
Citation: Alix, J. J., Zammit, C., Riddle, A., Meshul, C. K., Back, S. A., Valentino, M., & Fern, R. (2012). Central axons preparing to myelinate are highly sensitivity to ischemic injury. Annals of Neurology, 72(6), 936-951.
Abstract: Objective: Developing central white matter is subject to ischemic-type injury during the period that precedes myelination. At this stage in maturation, central axons initiate a program of radial expansion and ion channel redistribution. Here we test the hypothesis that during radial expansion axons display heightened ischemic sensitivity, when clusters of Ca2þ channels decorate future node of Ranvier sites. Methods: Functionality and morphology of central axons and glia were examined during and after a period of modeled ischemia. Pathological changes in axons undergoing radial expansion were probed using electrophysiological, quantitative ultrastructural, and morphometric analysis in neonatal rodent optic nerve and periventricular white matter axons studied under modeled ischemia in vitro or after hypoxia–ischemia in vivo. Results: Acute ischemic injury of central axons undergoing initial radial expansion was mediated by Ca2þ influx through Ca2þ channels expressed in axolemma clusters. This form of injury operated only in this axon population, which was more sensitive to injury than neighboring myelinated axons, smaller axons yet to initiate radial expansion, astrocytes, or oligodendroglia. A pharmacological strategy designed to protect both small and large diameter premyelinated axons proved 100% protective against acute ischemia studied under modeled ischemia in vitro or after hypoxia–ischemia in vivo. Interpretation: Recent clinical data highlight the importance of axon pathology in developing white matter injury. The elevated susceptibility of early maturing axons to ischemic injury described here may significantly contribute to selective white matter pathology and places these axons alongside preoligodendrocytes as a potential primary target of both injury and therapeutics.
Appears in Collections:Scholarly Works - FacM&SAna
Scholarly Works - FacM&SPB

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