(Investigative Ophthalmology and Visual Science. 2001;42:476-480.)
© 2001
by The Association for Research in Vision and Ophthalmology, Inc.
Protective Effect of Halothane Anesthesia on Retinal Light Damage: Inhibition of Metabolic Rhodopsin Regeneration
Charlotte Keller1,3,
Christian Grimm2,3,
Andreas Wenzel2,
Farhad Hafezi2 and
Charlotte E. Remé2
1 From the Department of Clinical Studies, University of Guelph, Guelph, Ontario, Canada; and
2 Laboratory of Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland.
 |
Abstract
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PURPOSE. To determine whether the volatile anesthetic halothane protects against
light-induced photoreceptor degeneration in the rodent retina.
METHODS. Albino mice and rats were anesthetized with halothane and exposed to
high levels of white or blue light. Nonanesthetized animals served as
controls. Retinal morphology was assessed by light microscopy, and
apoptosis of photoreceptor cells was verified by detection of
fragmented genomic DNA and in situ staining of apoptotic nuclei (TUNEL
assay). Rhodopsin regeneration after bleaching was determined by
measuring rhodopsin levels in retinas of mice or rats at different time
points in darkness.
RESULTS. Halothane anesthesia reversibly inhibited metabolic rhodopsin
regeneration and thus prevented rhodopsin from absorbing high numbers
of photons during light exposure. Consequently, photoreceptors of mice
and rats anesthetized with halothane were completely protected against
degeneration induced by white light. In remarkable contrast, however,
halothane anesthesia did not protect against blue-light–induced
photoreceptor cell death.
CONCLUSIONS. After the initial bleach, halothane impeded photon absorption by
rhodopsin by inhibiting metabolic rhodopsin regeneration. Apparently,
the rhodopsin-mediated uptake of the critical number of photons to
initiate white light–induced retinal degeneration was prevented. In
contrast, halothane did not protect the retina against blue light. Blue
light can efficiently restore functional rhodopsin from bleaching
intermediates through a process termed photoreversal of bleaching. This
process does not depend on the visual cycle via the pigment epithelium
but nevertheless enables rhodopsin molecules to absorb the critical
number of photons required to induce retinal
degeneration.
|
Introduction
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Visible light can induce photochemical lesions in the
retina of vertebrates1
(for reviews, see refs.
2
3
4
). Furthermore, light exposure may also accelerate
some forms of retinitis pigmentosa (RP) and possibly age-related
macular degeneration (AMD)5
6
7
8
in humans. Similarly to the
human diseases, progression and severity of the degenerative process is
enhanced by light in several animal models, some of which carry gene
mutations identical with those found in human
patients.9
10
11
After exposure to high levels of visible
light, photoreceptors die by apoptosis, the mode of cell death
recognized as the final common death pathway in many human retinal
diseases (for review, see ref. 2
). Therefore, light
exposure of mice and rats represents an experimental system to study
apoptotic signaling and execution pathways that may also be involved in
human diseases.
Light-induced retinal degeneration depends on the presence of
bleachable rhodopsin, which is the primary chromophore mediating light
damage.1
12
13
Susceptibility to light damage is at least
partially determined by the genetic background.14
A
genetic locus associated with light-damage susceptibility has been
mapped recently to Rpe65,15
a gene expressed in
the pigment epithelium (PE) and required for the (re)generation of
rhodopsin in the visual cycle.16
A critical determinant of
light-damage susceptibility appears to be the rate at which rhodopsin
is metabolically regenerated after bleaching: BALB/c mice have a
regeneration rate constant of 0.036/min, whereas C57/Bl6 mice have a
constant of 0.009/min.17
Correspondingly, BALB/c mice have
a high susceptibility to light damage, C57/Bl6 have a low
susceptibility.14
F1 mice of a BALB/c x C57/Bl6 cross have
an intermediate rate constant of 0.017/min17
and show an
intermediate susceptibility to light damage.14
Furthermore, mice completely devoid of rhodopsin regeneration are
completely protected against light damage.12
Anesthesia with halothane slows cone dark adaptation,18
19
and recent in vitro work suggests that halothane may also affect
restoration of the visual pigment in rods by competing with retinal for
binding to opsin (Ishizawa Y, Liebman PA, Eckenhoff RG, personal
communication, June 2000). We therefore tested the effect of
halothane anesthesia on rhodopsin regeneration in vivo during
white-light and blue-light exposure and analyzed its consequences for
the retinal sensitivity to light damage.
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Methods
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Anesthesia and Light Exposure
All experiments conformed to the ARVO statement for care and use
of animals in research and to the guidelines of the Veterinary
Authority of Zurich. Albino mice (BALB/c; 6 to 10 weeks of age) were
reared in a light–dark cycle (12:12 hours) with 60 lux at cage level.
Mice were dark-adapted overnight (16 hours) and were anesthetized with
halothane (1.5% in O2) during exposure to
diffuse, white fluorescent light (TLD36 W/965 tubes, Philips Light
GmbH, Hamburg, Germany; ultraviolet-impermeable diffuser) in
cages with reflective interior. Nonanesthetized mice served as
controls. Mice were exposed to white light for 20 minutes using 5,000
lux (5 klux) or for 60 minutes using 13,000 lux (13 klux).
Immediately after light exposure, anesthesia was discontinued and mice
were either kept in darkness for additional 24 hours or were put back
into the normal light–dark cycle for 10 days before retinal morphology
was analyzed. Albino rats (Sprague–Dawley) were reared in a 12:12 hour
light–dark cycle with 5 lux at cage level. Dark adaptation was as for
mice, and anesthesia was maintained at 1.8% halothane in oxygen. Rats
were exposed to 3,000 lux of white fluorescent light for 60 minutes.
For exposure to blue light, dark-adapted rats were anesthetized with
halothane (1.8% in O2) and exposed for 30
minutes to 3.5 mW/cm2 of blue light (403 ±
10 nm) as described.20
In control experiments, rats were
anesthetized with ketamine (75 mg/kg), xylazine (23 mg/kg), or a
mixture of both.
Microscopy, TUNEL Staining, and DNA Fragmentation Analysis
For morphologic analysis of retinal tissue, enucleated eyes were
fixed in 2.5% glutaraldehyde and embedded in Epon 812. Terminal
transferase-mediated dUTP nick end labeling was performed 24 hours
after light exposure essentially as described.21
Briefly,
retinal tissue was fixed in 2% paraformaldehyde for 2 hours at 4°C
and embedded in paraffin. The in situ cell death detection kit (Roche
Diagnostics, Rotkreuz, Switzerland) was used with minor modifications
to perform staining on 0.5 µm sections. Genomic DNA was prepared 24
hours after light exposure from isolated retinas by
phenol-chloroform-isoamylalcohol extraction.20
Total DNA
(20 µg) was separated on 1.5% agarose gels and stained with ethidium
bromide.
Rhodopsin Regeneration
Dark-adapted mice (16 hours) were exposed to 5 klux of white
light for 10 minutes, either killed immediately thereafter or allowed
to regenerate rhodopsin for different time intervals in darkness. Three
groups of mice were analyzed: mice nonanesthetized with halothane, mice
anesthetized with halothane during bleaching, and mice anesthetized
with halothane during bleaching and the subsequent regeneration period
in darkness. Rhodopsin was extracted from isolated retinas and
quantified as described.22
Both retinas from one mouse
were combined for determination of rhodopsin contents,22
and values were divided by 2 to give pmol rhodopsin per eye.
Significance of the results was tested using an unpaired
t-test.
Rhodopsin regeneration in Sprague–Dawley rats was determined in
dark-adapted (16 hours, overnight) animals after bleaching by an
exposure to 3,000 lux of white light for 10 minutes. Photoreversal was
analyzed after exposure to 700 µW of green light (550 ± 10 nm)
for 5 minutes followed by a 1-minute exposure to 300 µW of blue light
(403 ± 10 nm).
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Results
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Light Damage in Mice
Albino mice exposed to white light without halothane anesthesia
(control mice; Fig. 1A
) showed severe photoreceptor cell death at 24 hours after light
exposure (Fig. 1B
1D)
. Ten days after illumination, the outer nuclear
layer (ONL) was almost completely destroyed (Fig. 1F)
. In contrast,
mice anesthetized with halothane did not show any signs of light damage
(Fig. 1C)
even 10 days after exposure (Fig. 1E)
. Protection by
halothane was significant: the threshold for light damage in
nonanesthetized BALB/c mice was below 20 minutes of exposure to 5 klux
(Fig. 1B)
, at least 8 times lower than the light dose (exposure
time x intensity) used in the experiments shown in Figure 1C
1D
1E
1F
.
Biochemical markers for apoptosis such as positive TUNEL staining and
the presence of internucleosomally fragmented genomic DNA confirmed
that white light exposure induced photoreceptor apoptosis exclusively
in nonanesthetized control mice (Fig. 2A
2C)
. Both markers were negative in mice that were anesthetized with
halothane during light exposure (Fig. 2A
2B)
.
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Figure 1. Halothane anesthesia protects against retinal damage by white light.
Dark-adapted BALB/c mice were either kept in darkness (A) or
exposed to white, fluorescent light for the times and intensities
indicated (B through F). After exposure, mice
recovered in darkness for 24 hours (A through D)
or were kept in a 12:12 hour light–dark cycle for 10 days
(E, F). (C, E) Mice
anesthetized with 1.5% halothane in oxygen for 60 minutes during
exposure. (B, D, F) Mice
nonanesthetized with halothane. (A) Retina of a halothane
anesthetized mouse kept in darkness. Pigment epithelium (PE), rod outer
segments (ROS), rod inner segments (RIS), and outer nuclear layer (ONL)
appear intact and well organized. (B) 20 minutes of exposure
with 5,000 lux (5 klux) induced photoreceptor apoptosis as indicated by
the condensed nuclear chromatin in the majority of the nuclei in the
ONL (arrows). RIS and ROS are disorganized and not clearly
distinguishable. (C) Retinal morphology appears intact in
halothane anesthetized mice even after exposure to 13,000 lux (13 klux)
for 60 minutes, a light dose (exposure time x intensity)
approximately 8 times higher than used in (B).
(D) The same light exposure as in (C) but without
halothane anesthesia caused severe photoreceptor degeneration
(arrows). (E) Mice anesthetized with halothane
show normal retinal morphology 10 days after light exposure.
(F) In contrast, photoreceptor cells of mice nonanesthetized
with halothane were almost completely removed from the retina 10 days
after exposure (arrowheads). Cells of the PE had recovered
and were morphologically indistinguishable to dark controls.
Representative sections (lower central retina) of three independent
experiments are shown. Scale bar, 25 µm.
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Figure 2. Absence of light-induced retinal apoptosis in mice anesthetized with
halothane. Dark-adapted BALB/c mice were or were not anesthetized with
halothane and exposed to 13 klux of white light for 60 minutes. After a
recovery period of 24 hours in darkness, retinas were isolated and
genomic DNA was analyzed by agarose gel electrophoresis. (A,
lane 1) Genomic retinal DNA of halothane anesthetized mice
did not show internucleosomal DNA fragmentation after light exposure.
(A, lane 2) DNA of a control mouse
nonanesthetized with halothane displayed a DNA ladder characteristic
for apoptotic cells. The marker lane 3 shows a 100 bp DNA
ladder. (B) TUNEL staining of a retina from a mouse
anesthetized with halothane. No positive signals were detectable
demonstrating that light exposure did not induce retinal apoptosis.
(C) TUNEL staining of a retina from a mouse nonanesthetized
with halothane. Positive staining of photoreceptor nuclei indicates
ongoing apoptosis. Scale bar, 50 µm.
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Rhodopsin Regeneration in Mice
Rhodopsin regeneration was analyzed after a complete bleach in
nonanesthetized mice and mice anesthetized with halothane (Fig. 3)
. Both anesthetized and nonanesthetized mice had comparable levels of
rhodopsin after dark adaptation (ca. 430 pmol/eye). Exposure to 5 klux
for 10 minutes resulted in an almost complete bleach of rhodopsin in
both groups of mice. Strikingly, metabolic regeneration was
significantly (P < 0.05; unpaired t-test)
and almost completely inhibited in mice anesthetized with halothane
(Fig. 3) . Whereas nonanesthetized mice regenerated rhodopsin to
completion within 1 hour (Fig. 3
, white bars), mice under halothane
anesthesia had regenerated the visual pigment only to 15% to 20% of
the dark value, even after 240 minutes in darkness (Fig. 3
, black
bars). This inhibition of regeneration was reversible. When halothane
anesthesia was terminated immediately after bleaching, rhodopsin
started to regenerate as soon as 15 minutes thereafter (Fig. 3
, gray
bars). Although only approximately 15% of the dark value was
regenerated after 15 minutes, compared to 50% in controls,
regeneration was almost complete after 60 minutes. The delay at 15
minutes might reflect the time needed to sufficiently clear the
halothane from the mouse retina.
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Figure 3. Rhodopsin regeneration is inhibited in mice anesthetized with
halothane. Rhodopsin was bleached by exposing mice to 5 klux of white
light for 10 minutes (arrow). Regeneration was
determined by measuring rhodopsin after different time intervals in
darkness. Black bars: Mice anesthetized with halothane
during bleaching and recovery in darkness. Grey bars:
Mice anesthetized with halothane during bleaching only but not during
regeneration in darkness. Open bars: control mice
nonanesthetized with halothane. All statistically significant (unpaired
t-test; P < 0.05) differences
between rhodopsin values within a particular time point are marked (*).
Error bars: Standard deviations. Numbers of eyes per
condition and time interval, n = 4 to 8.
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Light Damage and Rhodopsin Regeneration in Rats
Exposure of albino rats (Sprague–Dawley) to 3 klux of white light
for 1 hour resulted in many pycnotic photoreceptor nuclei indicating
apoptosis (Fig. 4B
). Furthermore, the PE appeared swollen, irregular, and with many
inclusions, demonstrating that cells of the PE were severely affected
by the light exposure with subsequent death of the PE.23
However, when rats were anesthetized with halothane, exposure to white
light of the same intensity did not induce photoreceptor cell death
(Fig. 4C) showing that the protective effect of halothane against
white-light damage was not species specific. Notably, cells of the PE
were not affected, suggesting that the changes observed in
nonanesthetized rats after light exposure might either be related to
rhodopsin regeneration or might be effects secondary to the changes in
photoreceptor cells. This is in marked contrast to mice where light
exposure did not induce cell death in the PE (Fig. 1D
1F)
. The reason
for this species difference is not clear at this time and is the
subject of ongoing studies in our laboratory. Measurements of rhodopsin
revealed that halothane efficiently prevented metabolic rhodopsin
regeneration also in rats. In animals nonanesthetized with halothane,
37 ± 4.4% rhodopsin (n = 5 retinas) was
regenerated after 30 minutes and 83.3 ± 6.1% after 120 minutes
(n = 5 retinas) in darkness (dark value: 100% =
2.3 ± 0.086 nmol; n = 4 retinas). Rats
anesthetized with halothane, however, regenerated rhodopsin to only
7.6 ± 1.8% (n = 4 retinas) after 30 minutes and
to 8.35 ± 2.3% (n = 4 retinas) after 120 minutes
in darkness.
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Figure 4. Halothane protects against white light damage but not
against blue light damage in albino rats. Retinal morphology of rats
exposed to white light (B, C) or blue light
(D) was analyzed 24 hours after light exposure.
(A) Dark control. Retina of a rat not exposed to light.
(B) Many photoreceptor nuclei with condensed
chromatin (white arrows) were detected in the ONL of
nonanesthetized rats exposed to 3 klux of white light for 60 minutes.
ROS are disorganized, PE cells appear swollen. (C) No signs
of light damage in the retina of a rat anesthetized with halothane
during exposure to 3 klux for 60 minutes. (D) Rat
anesthetized with halothane and exposed to blue light (403 nm, 3.5
mW/cm2) for 30 minutes. Retinal damage was
evidenced by the detection of numerous pycnotic nuclei containing
condensed chromatin (white arrows). Representative sections
from the lower central retina of 2 to 3 independent experiments are
shown. Abbreviations as in Figure 1
. Scale bar, 25 µm.
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Blue-Light Effects in Rats
Blue-light exposure induces the photochemical reversal of
rhodopsin bleaching intermediates in vitro24
and in
vivo,20
which is independent of the metabolic regeneration
via the PE. Therefore, in blue-light conditions, rhodopsin and its
bleaching intermediates can absorb large numbers of photons in a short
period.20
When anesthetized rats were exposed to blue
light, photoreceptor apoptosis was efficiently induced as shown by the
formation of pycnotic nuclei 24 hours after light exposure (Fig. 4D)
.
As for white light in nonanesthetized animals, exposure to blue light
induced severe changes in the PE. Cells appeared irregularly swollen
and contained many inclusions suggesting that these cells would
eventually die. Rhodopsin measurements revealed that halothane did not
prevent photoreversal of bleaching by blue light; when anesthetized
rats were illuminated for 5 minutes with green light (550 ± 10 nm; 700 µW), rhodopsin was bleached to 5.9% of the dark value.
However, when blue light (403 ± 10 nm; 300 µW) was given for 1
minute immediately after the bleach with green light, rhodopsin was
photoreversed to 13.7% ± 1.2% (n = 3) of the dark
value. We used green light for the bleaching process because at this
wavelength no photoreversal of bleaching is occurring.20
In contrast, the blue-light component of white light could interfere
with the analysis of photoregeneration by photoreversing some of
the rhodopsin molecules.
|
Discussion
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Halothane anesthesia suppressed metabolic rhodopsin
regeneration in mice and rats and completely protected against
photoreceptor apoptosis induced by white light. Inhibition of metabolic
rhodopsin regeneration rendered retinas virtually devoid of rhodopsin
during light exposure after the initial bleach. As a result, the
absorption of photons per time—an essential element in the chain of
events leading from light exposure to photoreceptor apoptosis—was
strongly reduced. In contrast, blue light causes photoreversal of
bleaching and enables absorption of photons by rhodopsin independent of
metabolic rhodopsin regeneration.20
Consequently,
halothane anesthesia did not prevent blue-light damage to the retina.
Recent in vitro work by Ishizawa and coworkers suggests that halothane
directly interacts with rhodopsin25
and competes with
retinal for the opsin binding site (Ishizawa Y, Liebman PA, Eckenhoff
RG, personal communication, June 2000). Such a competition
would explain the almost complete inhibition of metabolic rhodopsin
regeneration after light exposure. Previously it was proposed that
halothane reduces the light-induced uptake of protons by rhodopsin in
rod disc membranes26
thereby inhibiting the transition
from metarhodopsin I to metarhodopsin II during the process of
bleaching. Although our present data do not fully exclude this
possibility, they suggest that such an effect might be minor in vivo.
Bleaching of rhodopsin in mice anesthetized with halothane is at least
as efficient as in control mice (Fig. 3) , and no accumulation of
metarhodopsin I could be detected spectrophotometrically immediately
after exposure to 10 minutes of white light in both anesthetized and
control mice (data not shown). Furthermore, rhodopsin could be
regenerated by blue light, indicating that photoreversal was occurring
under halothane anesthesia. As metarhodopsin II is the most probable
intermediate that is photoreversed by blue light (for discussion, see
ref. 20
), it is unlikely that halothane blocked the
metarhodopsin I to metarhodopsin II transition in the living eye.
However, photoreversal was less efficient in rats anesthetized with
halothane than in rats anesthetized with ketamin/xylazine (reversal to
13.7% in halothane compared to 28% in
ketamine/xylazine20
). Therefore, halothane might influence
rhodopsin metabolism by several mechanisms that may act both upstream
and downstream of MII. Halothane did not affect unactivated rhodopsin
as dark values were similar in anesthetized and nonanesthetized
animals.
Because halothane almost completely blocked metabolic rhodopsin
regeneration, but did not or only marginally impair photoreversal,
halothane anesthesia strongly inhibited further photon absorptions by
rhodopsin after the initial bleaching by white light but not by blue
light. Because rhodopsin is the photon receptor needed for the
induction of light damage,12
halothane anesthesia
protected against photoreceptor degeneration induced by white but not
by blue light. The photoreceptor cell death induced by blue light
also indicates that halothane did not interfere with the execution of
the apoptotic program in general. This conclusion is further supported
by the induction of the DNA-binding activity of the transcription
factor AP-1 by blue light in rats anesthetized with halothane (data not
shown). Induction of c-Fos containing AP-1 is essential for
the induction/execution of light-induced photoreceptor
apoptosis.21
27
The protective effect of halothane was not a general effect of
anesthesia: BALB/c mice anesthetized with ketamine or xylazine, for
example, showed severe photoreceptor degeneration after exposure to
white light (data not shown). Furthermore, anesthesia with a mixture of
ketamine/xylazine slowed but did not block metabolic rhodopsin
regeneration in rats: 120 minutes after a complete bleach, anesthetized
rats regenerated rhodopsin to 54% ± 6% (n = 4
retinas) of the dark value. In comparison, rats that were
nonanesthetized regenerated rhodopsin in the same time to 84% ± 6%
(n = 5) and halothane anesthesia allowed regeneration
only to 8.35 ± 2.3% (n = 4 retinas). We
therefore suggest that the observed protective effect is specific for
halothane due to the block of rhodopsin regeneration. However, we
cannot exclude that other volatile anesthetics such as isoflurane might
have effects similar to halothane.
|
Conclusions
|
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Halothane anesthesia prevented metabolic regeneration of rhodopsin
after bleaching. This led to a retina with very little bleachable
rhodopsin after the initial bleaching, and, therefore, to an almost
complete prevention of photon absorption in white light. Because the
rate of photon absorption by rhodopsin is a critical parameter for
light damage, halothane anesthesia led to protection against
photoreceptor apoptosis. In contrast, when rhodopsin molecules could
repeatedly absorb photons under blue-light exposure, halothane did not
protect against light damage.
|
Acknowledgements
|
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The authors would like to thank Cornelia Imsand, Dora
Greuter, and Gaby Hoegger for skilled technical assistance, Joseph
Beatrice for sharing some data on rhodopsin measurements in rats, and
Theo Seiler for continuous support.
|
Footnotes
|
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3 CK and CG contributed equally to the work presented here and should therefore be regarded as equivalent senior authors. 
Supported by the Swiss National Science Foundation; Bruppacher Foundation and EMDO Foundation, Zürich, Switzerland; and Ernst & Berta Grimmke Foundation, Düsseldorf, Germany.
Submitted for publication August 15, 2000; revised October 10, 2000; accepted November 10, 2000.
Commercial relationships policy: N.
Corresponding author: Charlotte E. Remé, Laboratory of Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, Frauenklinikstrasse 24, 8091 Zurich, Switzerland. chreme{at}opht.unizh.ch
|
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H. Song, M. Belcastro, E. J. Young, and M. Sokolov
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D. A. White, W. W. Hauswirth, S. Kaushal, and A. S. Lewin
Increased Sensitivity to Light-Induced Damage in a Mouse Model of Autosomal Dominant Retinal Disease
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A. Laabich, G. P. Vissvesvaran, K. L. Lieu, K. Murata, T. E. McGinn, C. C. Manmoto, J. R. Sinclair, I. Karliga, D. W. Leung, A. Fawzi, et al.
Protective Effect of Crocin against Blue Light- and White Light-Mediated Photoreceptor Cell Death in Bovine and Primate Retinal Primary Cell Culture.
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[Abstract]
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C. E. Reme
The Dark Side of Light: Rhodopsin and the Silent Death of Vision The Proctor Lecture
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A. Wenzel, C. Grimm, M. Samardzija, and C. E. Reme
The Genetic Modifier Rpe65Leu450: Effect on Light Damage Susceptibility in c-Fos-Deficient Mice
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W. C. Gordon, D. M. Casey, W. J. Lukiw, and N. G. Bazan
DNA Damage and Repair in Light-Induced Photoreceptor Degeneration
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Y. Ishizawa, R. Pidikiti, P. A. Liebman, and R. G. Eckenhoff
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Top
Abstract
Introduction
