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Anoxic injury of mammalian central white matter Decreased susceptibility in myelin-deficient optic nerve.

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Anoxic Injury of MammAan Central
m t e Matter: Decreased Susceptibility in
Myelin-deficient Optic Nerve
Stephen G. Waxman, MD, PhD, Peter K. Davis, BS, Joel A. Black, PhD, and Bruce R. Ransom, &ID, PhD
The rat optic nerve, a typical central nervous system white matter tract, rapidly loses excitability when it is exposed to
anoxia and is irreversibly damaged by prolonged anoxia. Neonatal optic nerve is extremely resistant to anoxia-induced
dysfunction and injury; the adult pattern of response to anoxia appears between 10 and 20 days postnatal, that is,
during the period of oligodendroglial proliferation and myelination. To test the hypothesis that myelination, or
associated events, confer anoxic susceptibility on developing white matter, we analyzed the effects of anoxia on the
myelin-deficient (md) strain of rat. Acutely isolated optic nerves from 19- to 21-day-old md rats and control optic
nerves from unaffected male littermates were maintained in vitro at 3 7 T , and exposed to a standard 60-minute period
of anoxia. The supramaximal compound action potential was recorded and amplitude of the compound action potential, expressed as % of amplitude before anoxic exposure, was determined. The compound action potential was nearly
abolished within 3 to 6 minutes after onset of anoxia in control optic nerves, while optic nerves from md rats displayed
a slower decrease in compound action potential amplitude during anoxia, with a distinct action potential present even
after 60 minutes of anoxia. Optic nerves from md rats showed significantly greater recovery of compound action
potential (71 ? 25%) than did control optic nerves (33 -C 21%; p < 0.02) after 60 minutes of anoxia. These findings
support the hypothesis that myelination, or changes associated with it, may be important in the development of anoxic
susceptibility in central white matter.
Waxman SG, Davis PK, Black JA, Ransom BR. Anoxic injury of mammalian central white matter:
decreased susceptibility in myelin-deficient optic nerve. Ann Neurol 1990;28:335-340
The exquisite sensitivity of the central nervous system
(CNS) to anoxia is not fully understood. Within gray
matter, a possible role of increases in intracellular calcium levels, mediated by activation of N-methyl-Daspartate (NMDA) receptors by excitatory neurotransmitters such as glutamate, has been suggested [l, 21.
CNS white matter is also damaged by anoxia, although
it is less sensitive to such injury than gray matter {3,41.
In some types of stroke (ie., lacunar infarcts) white
matter is predominantly involved [ 5 , 61. Anoxic injury
of CNS white matter is dependent on the presence of
extracellular calcium; the rat optic nerve, a typical
white matter tract, can be protected from anoxic injury
by removal of calcium from the perfusate 141. However, since neuronal cell bodies and synapses are not
present in white matter, it is likely that mechanisms of
cellular injury in white matter are different than in gray
matter. One characteristic of white matter that may
contribute to its susceptibility to anoxic injury is the
presence of myelin.
Sensitivity to anoxia in white matter increases as de-
velopment proceeds. Neonatal white matter is extremely resistant to anoxia-induced dyshnction. The
adult pattern of response to anoxia appears between
postnatal day 10 and 20 in the rat optic nerve 131.
During this period oligodendrocytes proliferate and
myelination occurs 17-91. Immature rats subjected to
hypoxic-ischemic insults exhibit white matter necrosis
that originates in myelinogenic foci [l0}.
To test the hypothesis that myelination, or associated events, confer susceptibility to anoxia, we analyzed the effects of anoxia on isolated optic nerves
from the myelin-deficient (md) rat. The md rat is a
mutant of the Wistar strain in which myelin is essentially absent in the CNS of affected males as a result of
a primary oligodendrocyte abnormality [11- 131 involving the genetic regulation of proteolipid protein
(PLP) synthesis 1143. Since md is an X chromosomelinked mutant Ell], amyelinated optic nerves in affected md rats can be compared with unaffected male
littermate controls that show essentially normal myelination El 51.
From the Department of Neurology, Yale University School of
Medicine, New Haven, and the Neuroscience Research Center,
Veterans Administration Hospital, West Haven, CT.
Address correspondence to Dr Waxman, Department of Neurology, LCI 707, Yale University School of Medicine, 333 Cedar
Street, New Haven, CT 06510.
Received Jan 24, 1990, and in revised form Mar 23. Accepted for
publication Mar 29, 1990.
Copyright 0 1990 by the American Neurological Association
Fig I. Electron micrographs showing 2 I-dzji-old md (A) and
male littermate control (B) optic nerves. Note the absence ofmyelin in md optic nerve. { x 25,000.) Scale bar = 1 pm.
In the present study, the effects of anoxia on excitability and the degree of irreversible injury induced by
anoxia were examined in the optic nerves of md rats
and compared to unaffected littermate controls. Our
results demonstrate that amyelinated md optic nerves
exhibit reduced sensitivity to anoxia.
Breeding pairs of md rats I111 were generously provided by
Dr Charles Csiza. As a result of sustained seizure activity,
affected md rats rarely survive for more than 28 days [ll,
121. By 19 to 21 days of age, md rats are easily discriminated
from their unaffected male littermates on the basis of characteristic tremors, seizures, and ataxia. Optic nerves from 19to 21-day-old md rats and unaffected littermate controls of
the same age were selected for analysis. For comparison,
optic nerves from normal rats at 2 days of age (prior to
myelination) and at 19 to 21 days of age were also studied.
The optic nerves of the md mutant at 19 to 21 days of age
were gray and translucent on gross inspection; control nerves
from animals of the same age were white and completely
opaque. The affected nerves contained no myelin while the
controls contained abundant myelin (Fig 1).
For elecrrophysiological study, rats were deeply anesthetized by carbon dioxide (C02) narcosis and decapitated,
and the optic nerves were carefully dissected free. The
isolated optic nerves were placed in an interface recording
chamber and bathed in a physiological saline solution containing in (mM): Na 153; K 3.0, Mg 2.0, Ca 2.0, CI 133,
HC03 26.0, HzP04 1.25, dextrose 10, p H 7.45 to 7.50.
Suction electrodes back-filled with an identical solution were
attached to both ends of the nerve for stimulating and recording the compound action potential (CAP). The CAP was
elicited by a supramaximal stimulus pulse (SO-microsecond
duration) delivered through an isolation unit at 0.5- to 2.0minute intervals. Stimulus strength was set to 25% above
that required to elicit a maximal CAP. Tissue was maintained
at 37°C and oxygenated in a 95% oxygen (02)/5% CO2
atmosphere for control measurements. A standard 60minute period of anoxia was achieved by switching to a 95%
nitrogen (N2)/5% CO2 atmosphere. To ensure that anoxia
was complete and rapid, partial pressure of O2in the recording chamber was monitored with an oxygen pressure (PO*)
meter, with the sensor placed at the point in the chamber
where the nerve was usually positioned. When the gas was
switched from 0 2 to N2, oxygen tension fell to 0% within
2% minutes. After the 60-minute period of anoxia, optic
nerves were reoxygenated in 95% 02159% COZ, and were
allowed a further 60-minute recovery period before postanoxic CAP was measured, since the CAP in all nerves attains maximal recovery so that the CAP is stable by the end
of this 60-minute period [4]. Data were stored on magnetic
disc for subsequent analysis.
336 Annals of Neurology Vol 28 No 3 September 1990
1 msec
Fig 2. Rat optic newe compound action potentials (CAP}before
(control, left columnj, during (anoxia, middle), and after (recovery, right column) exposure to 60 minutes ofanoxia. Data
are shown for an optic nerve obtained from a 2 - h y - o l d normal
animal in which the axons have not yet acquired myelin (top
traces) and from a 19-day-old animal in which myelination is
well under way (bottom traces). The earliest peak of the CAP
in the 2-duy-old animal has a much greater kztency than the
earliest peak in the 19-hy-old animal, indicating a greater conduction velocity in the older animal. Note that even after 60
minutes ofanoxia, the CAP is retained in the 2-day-old
animal, whereas it is totally abolished in the I9-da.y-old animal.
CAP recovery was measured 60 minutes~llowingthe period of
anoxia, at which time maximum recovery has taken place; note
that while CAP amplitude is about 100% of the control amplitude following anoxia in the 2-day-old optic nerve, CAP recovers
to approximately 30% of the controlamplitudein the 19-dayold optic nerve.
Since the md optic nerve is characterized by the absence of myelin, it would be expected that the conduction properties of md optic nerve should be similar to
those in premyelinated optic nerves of normal
neonatal rats, which also lack myelin. Figure 2 (top)
shows, for comparison with md optic nerve, CAPS
from a normal 2-day optic nerve in which the axons
have not acquired myelin. Figure 2 (bottom) shows the
CAP from an optic nerve from a normal rat at the
same age (i.e., 19 to 21 days) as the md rats to be
described; at this age in the normal rat, myelination is
well underway and most axons exhibit at least one
complete layer of compact myelin [77. The prolonged
conduction latency in the 2-day optic nerve reflects the
fact that at this age, the optic nerve axons have not yet
acquired myelin. The CAP of the premyelinated 2-day
optic nerve exhibits striking insensitivity to anoxia
compared to the CAP from a 19- to 21-day normal
optic nerve (see Fig 2, bottom). The CAP of the premyelinated 2-day optic nerve displays essentially full
amplitude even after 60 minutes of anoxia (see Fig 2,
top, middle column). The CAP amplitude after 60
minutes of reoxygenation following a 60-minute period of anoxia (expressed as a percent of control CAP
amplitude) is close to 100% in the 2-day optic nerve
(see Fig 2, top, right column). In contrast, in 19- to 21day normal optic nerves, the amplitude of the CAP
Fig 3. The latencies of the compound action potential {CAP)
peaks are prolongedfollowing anoxia. The CAP from a nomal
rat optic nerve is shown before (control)and after 60 minutes of
anoxia (postanoxia}.The postanoxia recording was made after
60 minutes of reoxygenation. The latency of thejrst peak is
slightly greater after anoxia, whereas the latency of the second
peak is quite markedly prolonged.
falls to zero during anoxia (see Fig 2, bottom, middle
trace) and is substantially reduced (33 k 21%) after a
60-minute period of anoxia (see Fig 2, bottom, right
column). Interestingly, after recovery from anoxia the
latencies of the CAP peaks are prolonged (Fig 3).
Examination of conduction in md optic nerves
showed that the md optic nerve CAP is less rapidly
attenuated by anoxia than normally myelinated optic
nerves. Figure 4 shows the CAP from a 19- to 21-day
unaffected littermate optic nerve (see Fig 4A) and an
age-matched md optic nerve (see Fig 4B). The CAP
latency in the 19- to 21-day unaffected littermate control (see Fig 4A) is similar to the normal 19-day optic
nerve CAP (see Fig 2B), while the CAP from 19- to
21-day md optic nerve (see Fig 4B) shows a prolonged
latency similar to that of the premyelinated (2-day normal) optic nerve. With the onset of anoxia, amplitude
of the CAP in the unaffected littermate control falls
rapidly to zero (see Fig 4A). In contrast, the CAP of
the md optic nerve is attenuated much more slowly by
anoxia. The CAP in the md optic nerve shows an increased latency but is clearly detectable even after 60
minutes of anoxia (see Fig 4B).
The detailed time courses of changes in CAP amplitude, induced by 60 minutes of anoxia in two representative affected md optic nerves and two unaffected
littermate controls, were studied as shown graphically
in Figure 5. The CAP amplitude is shown as a percent
of control CAP amplitude (i.e., percent of CAP amplitude prior to the onset of anoxia) for two representative optic nerves from affected md and unaffected
male littermate 20-day-old animals. At the onset of
anoxia the CAP of littermate controls is rapidly attenuated, and is nearly abolished within 10 minutes
after onset of anoxia. In contrast, amplitude of the
Waxman et al: Anoxic Injury in Myelin-deficient White Matter
2.5 rns
Fig 4. Effect of anoxia on the compound action potential (CAPj
d r a t optic nerves from md rats and from unaffected male littermates ( n o m l ) . (A) The amplitude of the CAP in the unaffected littermate (21 days old) falh quickly t o zero during
anoxia. The time ufter the onset of anoxia in minutes is shown
next to each trace. (B) The CAP of the md rat ( I 9 days old)
falh less rupidly during anoxia but does not disappear. even after
60 minutes of anoxia.
CAP falls only to about 20% when md optic nerve is
exposed to anoxia, and does not fall below 205% even
in later parts of a 60-minute period of anoxia. Decreased susceptibility of md optic nerves to anoxia is
also observed in terms of the extent of recovery of
CAP amplitude after the 60-minute anoxic insult; recovery of CAP amplitude, 60 minutes following cessation of anoxia, is larger in amyelinated md optic nerves
than in control nerves.
As a quantitative measure of recovery from anoxia,
we examined the mean ( + standard deviation) maximum recovery of CAP amplitude after 60 minutes of
anoxia for md (n = 6) and normal optic nerves (19 to
21 days old; n = 6). Optic nerves from rnd rats exhibited a significantly greater degree of recovery of CAP
amplitude (to 7 1 k 25% of preanoxic amplitude)
compared to normal 20-day optic nerves (33 & 21%;
p < 0.02).
Despite the absence of neuronal cell bodies and
synapses in white matter, CNS myelinated tracts display disturbed function after anoxia. To test the hypothesis that sensitivity to anoxia in white matter is
related to myelination, or changes associated with it,
we studied the effects of anoxia on s o n s in the optic
nerve of the md rat. In this mutant model, CNS axons
are devoid of myelin, presumably on the basis of an
oligodendroglial abnormality 112- 141. Axons in the
md CNS are apparently normal, exhibiting a membrane structure and conduction properties similar to
338 Annals of Neurology Vol 28 No 3
A n o x i a d
Tirna (min)
Fig 5. Time course of djcts of 60 minutes of anoxia on rat optic
nervefunction; comparison of compound action potential (GAP)
umplitude in two representuti.te affpcted md optic nerves and two
unaffected mule littemtes. CAP amplitude (shown as % o f
control GAP amplitude) is shown for two dqfirent nerves from
unaffected (filled squares) and affected rml (open squares) 20day-old animalj. The CAP of the unaffected litternates is more
severely affected by unoxia; it shows a more rapid and severe
decline during anoxia and a smuller Agree of recovery following
those of nonmyelinated CNS axons 1151, and are capable of triggering myelination when exposed to competent oligodendrocytes 1161.
While the CAP was abolished within 10 minutes
after onset of anoxia in unaffected littermate optic
nerves, it was never entirely lost in amyelinated axons
in md optic nerve even after 60 minutes of anoxia Moreover, md optic nerves showed significantly less irreversible injury after the GO-minute anoxic exposure,
compared to unaffected littermate optic nerves, as
judged by the extent of CAP recovery. These results
support the suggestion that myelination, or changes
associated with it, are important in the development of
anoxic susceptibility in white matter. Other observa-
September 1990
tions support this hypothesis. In normal rats the development of susceptibility to anoxic injury in white matter coincides with the period of myelination [31, and
following hypoxia-ischemia in immature rats, necrosis
originates in and spreads from foci of myelinogenesis
[lo]. Human infants who suffer perinatal anoxia show
preferential pathological involvement of sites of myelination in the developing white matter [l?}.
In considering why an amyelinated tract of CNS
axons (md optic nerve) should exhibit greater resistance to anoxia than a normally myelinated optic
nerve, several possibilities deserve discussion:
(i) It is possible that this reflects susceptibility of
oligodendrocytes or myelin to anoxia. It has been suggested that oligodendrocytes are relatively sensitive to
anoxia and that as a result of exposure to anoxia, myelin can be damaged [18, 191. While loss of the optic
nerve CAP during anoxia could be due to conduction
block as a result of damage to the myelin 1201, partial
recovery of the CAP, within minutes after returning to
normal oxygenation, argues against this possibility. On
the other hand, the latencies of the optic nerve CAP
peaks remained prolonged after anoxia and this could
represent evidence of persistent oligodendrocyte and
myelin injury resulting in slowed axonal conduction.
Observations of disruption of myelin by treatments
that raise intracellular calcium levels 121-23], together
with results showing that anoxic injury of white matter
depends on accumulation of calcium in a cytoplasmic
compartment [4},are consistent with anoxia-triggered
damage to myelin as a cause of impaired conduction.
(ii) Anoxia may cause disruption of paranodal axodial junctions between oligodendrocytes and axons
[241. The paranodal junctions, which normally form a
seal between myelin and the axon, can be disrupted by
even minor degrees of pathology, producing confluency between the periaxonal (submyelin) and extracellular space so as to shunt an otherwise intact
myelin sheath [25]. Scattered foci of damage to the
axoglial junctions may cause conduction block on the
basis of impedance mismatch [26,27). White matter
glial cells and myelin swell following anoxia [28] and
this might mechanically disrupt paranodal junctions.
Activity-induced cell swelling in the optic nerve develops postnatally with a similar time course to the formation of myelin [29].
(iii) It is possible that perinodal astrocytes, which
comprise an important component of the node of Ranvier 130, 311, may be altered by anoxia. Astrocytes
swell in response to a variety of insults including
anoxia [28). We have shown that ketamine protects
the rat optic nerve from anoxia [32). Since ketamine
has been shown to protect astrocytes from glutamateinduced swelhng [3 31 and hypoxia-induced calcium accumulation {34}, it is possible that its effects on the
optic nerve are mediated, at least in part, by an effect
on astrocytes. In this regard, it should be noted that
astrocytes in md white matter exhibit antigenic abnormalities, possibly due to an astrocyte reaction to degeneration of oligodendrocytes [35}. It is possible that
astrocytes in the md CNS exhibit altered sensitivity to
anoxia, compared to normal astrocytes.
(iv) Differences in membrane properties, or resting potential, of myelinated versus amyelinated axons
could lead to differences in resistance to anoxia. In
particular, a lower ion-channel density may have a protective effect in md optic nerve axons. A low density
(approximately 2/pm') of Na channels supports conduction of the CAP (as a result of a small diameter
and correspondingly high input impedance) in premyelinated axons in the neonatal rat optic nerve 1361.
Freeze-fracture analysis suggests that a low sodiumchannel density may support conduction in amyelinated axons in md optic nerve [l5J If conduction in
amyelinated md axons is supported by low densities of
N a channels, it might be expected that conduction in
md optic nerve is accompanied by relatively small inward ion fluxes, with a consequently reduced energetic
requirement for maintaining the ionic gradients necessary for conduction. htchie [371 argued that under
such circumstances (e.g., in diabetic nerve), axons
should exhibit increased resistance to anoxia. Calcium
influx appears critical for the development of irreversible anoxic injury in normally myelinated white matter
[41.The mechanism(s) underlying anoxia-induced calcium influx is not known, but this property may be
attenuated in amyelinated axons, which would confer
protection from anoxia.
(v) Resting potential may be lower in amyelinated
md axons than in normal myelinated fibers. This would
lead to an increase in resting inactivation of sodium
channels with a consequent reduction in sodium current and, therefore, in the energetic requirements for
conduction. Activity in premyelinated [383 and amyelinated {39] white matter results in large and rapid
elevations in extracellular Kt that might enhance axonal depolarization and produce sodium-channel inactivation.
These results may have several clinical implications.
White matter is affected in most strokes, and 20% of
strokes (i.e., lacunar infarcts) affect predominantly
white matter [5, 61.In addition, both white matter
anoxia [43 and other disorders of white matter such as
brain and spinal cord injury involve abnormal calcium
fluxes 140-421.This suggests the possibility of a final
common pathway involving calcium in cellular injury
in a variety of disorders involving CNS white matter
tracts. On the basis of the present results, we suggest
that myelination, or changes associated with it, may be
important in the development of nonsynaptic mechanisms of cellular injury that contribute to anoxic susceptibility in the CNS.
Waxman et al: Anoxic Injury in Myelin-deficient White Matter
This work was supported in part by grants from the National Institutes of Health and the National Multiple Sclerosis Society, and by
the Medical Research Service, Veterans Administration. Dr Davis
was supported in part by a fellowship from the Blinded Veterans
We thank Dr Charles Csiza who provided helpful advice in working
with the md animals.
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