title: Central axons preparing to myelinate are highly sensitive [corrected] to ischemic injury.
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 Ca(2+) 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 Ca(2+) influx through Ca(2+) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom.
authors.forename: James J P
authors.initials: JJ
authors.lastname: Alix
authors.forename: Christian
authors.initials: C
authors.lastname: Zammit
authors.forename: Art
authors.initials: A
authors.lastname: Riddle
authors.forename: Charles K
authors.initials: CK
authors.lastname: Meshul
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Back
authors.forename: Mario
authors.initials: M
authors.lastname: Valentino
authors.forename: Robert
authors.initials: R
authors.lastname: Fern
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D005947:Glucose / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics; D000860:Hypoxia / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism*; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009900:Optic Nerve / Q000254:growth & development / Q000473:pathology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D018800:Thy-1 Antigens / Q000235:genetics; D020867:omega-Agatoxin IVA / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D018800:Thy-1 Antigens; D020867:omega-Agatoxin IVA; D049452:Green Fluorescent Proteins; D016291:Dizocilpine Maleate; D005947:Glucose