Mechanisms of calcium and sodium fluxes in anoxic myelinated central nervous system axons
Section snippets
In vitro incubation of rat optic nerve in modified artificial cerebrospinal fluid solutions
All aspects of this study were in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the local animal care committee. In the present studies, experimental procedures that modify transaxolemmal movements of Na+ and Ca2+ (e.g., perfusion with zero Na+ solutions or bepridil) were used to evaluate routes of Ca2+ entry during in vitro anoxia and subsequent reoxygenation. Long–Evans rats (Charles River, Montreal) aged 50–70 days were anaesthetized with 80% CO
Zero Na+/Li+-substituted perfusion
If influx of extraaxonal Na+ along its inwardly directed electrochemical gradient is functionally linked to entry of extra-axonal Ca2+ during anoxia, then removing external Na+ should prevent axonal accumulation of both Na and Ca. Therefore, isolated optic nerves were perfused with zero Na+/Li+-substituted medium during an anoxic challenge. Elemental composition was determined in axons exposed to zero Na+ solutions at the end of a 60 min anoxic period, and in reoxygenated fibres incubated for an
Discussion
In a previous study using electron probe X-ray microanalysis, we demonstrated that in vitro anoxic challenge of rat optic nerve caused an early derangement of elemental composition characterized by significant accumulation of Ca in axoplasm and mitochondria of myelinated axons.[29]Although substantial evidence strongly implicates a pivotal role for Ca2+ in the pathophysiology of anoxia-induced axon injury, the corresponding route of entry has not been conclusively identified. Pharmacological
Conclusions
The present study provides direct support for the following scenario of anoxia-induced CNS white matter injury:29, 43, 46during periods of oxygen deprivation and reduced aerobic energy production, myelinated axons lose K+ while intra-axonal Na+ concentrations increase following Na+ entry primarily through voltage-gated, TTX-sensitive channels. Elevated axoplasmic Na+ and axolemmal depolarization promote Ca2+ entry mediated primarily by reverse operation of the Na+–Ca2+ exchanger. Ca2+ influx
Acknowledgements
This research was made possible by an NIEHS grant RO1-ES03830 (R.M.L.) and by a grant from the Heart and Stroke Foundation of Ontario No. NA3201 (P.K.S.). The authors thank Dr Ellen Lehning for her insightful comments during the preparation of this manuscript.
References (57)
- et al.
Oxygen free radical involvement in ischemia and reperfusion injury to brain
Neurosci. Lett.
(1988) - et al.
Dimethyl sulfoxide inhibits renal Na+/K+–ATPase at a site different from ouabain and atrial peptides
Life Sci.
(1995) - et al.
Reverse Na+–Ca2+ exchange requires internal Ca2+ and/or ATP in squid axons
Biochim. biophys. Acta
(1986) - et al.
In squid axon, ATP modulates Na+–Ca2+ exchange by a Ca2+-dependent phosphorylation
Biochim. biophys. Acta
(1987) Mitochondrial damage during cerebral ischemia
Ann. emerg. Med.
(1985)- et al.
Characterization and photoaffinity labeling of receptor sites for the Ca2+ channel inhibitors d-cis-diltiazem, (±)-bepridil, desmethoxyverapamil and (+)-PN200-110 in skeletal muscle transverse tubule membrane
J. biol. Chem.
(1986) - et al.
Inhibitors of sodium–calcium exchange: identification and development of probes of transport activity
Biochim. biophys. Acta
(1989) - et al.
Mechanisms of injury-induced calcium entry into peripheral nerve myelinated axons: in vitro anoxia and ouabain exposure
Brain Res.
(1995) - et al.
Reoxygenation of anoxic peripheral nerve myelinated axons promotes re-establishment of normal elemental composition
Brain Res.
(1996) - et al.
Disruption of cellular elements and water in neurotoxicity: Studies using electron probe x-ray microanalysis
Toxic. appl. Pharmac.
(1990)
Acrylamide disrupts elemental composition and water content of rat tibial nerve: I. Myelinated axons
Toxic. appl. Pharmac.
Acrylamide disrupts elemental composition and water content of rat tibial nerve: II. Schwann cells and myelin
Toxic. appl. Pharmac.
Mechanism of calcium entry during axon injury and degeneration
Toxic. appl. Pharmac.
Effects of polyvalent cations and dihydropyridine calcium channel blockers on recovery of CNS white matter from anoxia
Neurosci. Lett.
Elemental composition and water content of rat optic nerve myelinated axons during in vitro post-anoxia reoxygenation
Neuroscience
Correlation between electrophysiological effects of mexiletine and ischemic protection in central nervous system white matter
Neuroscience
Na+ currents that fail to inactivate
Trends Neurosci.
Differential sensitivity to hypoxia of the peripheral versus central trajectory of primary afferent axons
Brain Res.
Non-synaptic mechanisms of Ca2+-mediated injury in CNS white matter
Trends Neurosci.
Ultrastructural concomitants of anoxic injury and early post-anoxic recovery in rat optic nerve
Brain Res.
Protection of the axonal cytoskeleton in anoxic optic nerve by decreased extracellular calcium
Brain Res.
Anoxic injury of rat optic nerve: ultrastructural evidence for coupling between Na+ influx and Ca2+-mediated injury in myelinated CNS axons
Brain Res.
Potassium and calcium changes injured spinal cords
Brain Res.
Application of scanning electron microscopy to x-ray analysis of frozen-hydrated sections. III. Elemental content of cells in the rat renal papillary tip
J. Cell Biol.
Cerebral hypoxia: Some new approaches and unanswered questions
J. Neurosci.
Mitochondria, oxygen and reperfusion damage
Ann. Med.
Voltage-gated calcium channels in CNS white matter: role in anoxic injury
J. Neurophysiol.
Personal computer-based system for electron beam X-ray microanalysis of biological samples
J. Microsc.
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