Central axons preparing to myelinate are highly sensitivity 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 programme of radial expansion and ion channel re-distribution. Here we test the hypothesis that during radial expansion axons display heightened ischemic sensitivity, when clusters of Ca2+ 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 peri-ventricular 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 Ca2+ influx through Ca2+ 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 pre-myelinated 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 pre-oligodendrocytes as a potential primary target of both injury and therapeutics.

Cerebral White Matter Injuries Following a Hypoxic/Ischemic Insult During the Perinatal Period: Pathophysiology, Prognostic Factors, and Future Strategy of Treatment Approach. A Minireview

“…As we previously reported [23], large (> 0.4 m in diameter) pre-myelinating axons are more sensitive to OGD than smaller premyelinated and myelinating axons. Blockade of NMDA and non-NMDA GluRs alone provides only partial protection from ischemic injury whereas addition of L-type and P/Q-type voltage-gated calcium channel (VGCC) blockers to these GluRs antagonists results in complete recovery of the compound action potential [23,37].…”

“…Comparison of OGD-induced damage to small (< 0.4 m) and to large (>0.4 m) premyelinating axons shows that the former are protected by GluR blockers alone, whilst the latter needs addition of VGCC-blockers to confer protection [23]. This study shed light on the importance of VGCC in this age group, and on the pathophysiological mechanism of injury during ischemia in these very sensitive axons.…”

“…Although the vulnerability of the late OPC is one of the hallmarks of the increased susceptibility of white matter injury to ischemia during development, as we previously reported, the immature myelinating oligodendrocytes also contribute to the continuum of white matter vulnerability following ischemia [22,23]. Thirty minutes of oxygen-glucose deprivation (OGD) is sufficient to kill almost 70% of oligodendrocytes, and the percentage of dead oligodendrocytes in neonatal mice (P10 -post-natal day 10) is significantly higher than that in older age groups (Fig.…”

“…Blockade of NMDA and non-NMDA GluRs alone provides only partial protection from ischemic injury whereas addition of L-type and P/Q-type voltage-gated calcium channel (VGCC) blockers to these GluRs antagonists results in complete recovery of the compound action potential [23,37].…”

Pathophysiology of glia in perinatal white matter injury

“…Glutamate-mediated axonal injury appears related to a mechanism of excessive glutamate depletion from OLs and axons (Fern et al 1998; Fern and Moller 2000; Salter and Fern 2005; Wilke et al 2004), which appear to be the major sources of extracellular glutamate during energy failure from hypoxia-ischemia (Back et al 2007). Recently, it was shown that axons also display maturation-dependent vulnerability to oxidative stress and hypoxia-ischemia (Alix et al 2012). Larger caliber axons, which are preparing to myelinate, are particularly susceptible to injury via axolemma-associated voltage-gated calcium channels, in contrast to smaller caliber unmyelinated axons, which are more resistant.…”