Abstract
Axonal injury in white matter is an important consequence of many acute neurological diseases including ischemia. A role for glutamate-mediated excitotoxicity is suggested by observations from in vitro and in situ models that AMPA/kainate blockers can reduce axonal injury. We assessed axonal vulnerability in primary murine neuronal cultures, with axons isolated from their cell bodies using a compartmented chamber design. Transient removal of oxygen and glucose in the axon compartment resulted in irreversible loss of axon length and neurofilament labeling. This injury was not prevented by addition of ionotropic glutamate receptor blockers and could not be reproduced by glutamate receptor agonists. However, hypoxic injury was prevented by blockade of voltage-gated sodium channels, inhibition of calpain and removal of extracellular calcium. These results suggest that isolated, unmyelinated axons are vulnerable to hypoxic injury which is mediated by influx of sodium and calcium but is independent of glutamate receptor activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axons / metabolism*
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Axons / pathology
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Calcium / metabolism
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Calcium Signaling / physiology
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Calpain / metabolism
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Cell Culture Techniques
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Glucose / deficiency
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Glutamic Acid / metabolism*
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Glutamic Acid / toxicity
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Hypoxia / metabolism
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Hypoxia / physiopathology
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Hypoxia-Ischemia, Brain / metabolism*
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Hypoxia-Ischemia, Brain / physiopathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neurotoxins / metabolism
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Neurotoxins / toxicity
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Receptors, Glutamate / drug effects
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Receptors, Glutamate / metabolism*
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Sodium / metabolism
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Sodium Channel Blockers / pharmacology
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Sodium Channels / metabolism
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Wallerian Degeneration / metabolism*
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Wallerian Degeneration / pathology
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Wallerian Degeneration / physiopathology
Substances
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Neurotoxins
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Receptors, Glutamate
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Sodium Channel Blockers
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Sodium Channels
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Glutamic Acid
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Sodium
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Calpain
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Glucose
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Calcium