 |
 Previous Article | Next Article 
The Journal of Neuroscience, February 15, 1998, 18(4):1337-1344
Preconditioning with Bright Light Evokes a Protective Response
against Light Damage in the Rat Retina
Changdong
Liu1,
Min
Peng1,
Alan M.
Laties1, and
Rong
Wen1, 2
Departments of 1 Ophthalmology and 2 Cell
and Developmental Biology, University of Pennsylvania, School of
Medicine, Philadelphia, Pennsylvania 19104
 |
ABSTRACT |
Constant exposure to bright light induces photoreceptor
degeneration and at the same time upregulates the expression of several neurotrophic factors in the retina. At issue is whether the induced neurotrophic factors protect photoreceptors. We used a preconditioning paradigm to show that animals preconditioned with bright light became
resistant to subsequent light damage. The preconditioning consisted of
a 12-48 hr preexposure, followed by a 48 hr "rest phase" of normal
cyclic lighting. The greatest protection was achieved by a 12 hr
preexposure. Preconditioning induces a prolonged increase in two
endogenous neurotrophic factors: basic fibroblast growth factor (bFGF)
and ciliary neurotrophic factor (CNTF). It also stimulates the
phosphorylation of extracellular signal-regulated protein kinases
(Erks) in both photoreceptors and Müller cells. These findings
indicate that exposure to bright light initiates two opposing
processes: a fast degenerative process that kills photoreceptors and a
relatively slower process that leads to the protection of
photoreceptors. The extent of light damage, therefore, depends on the
interaction of the two processes. These results also suggest a role of
endogenous bFGF and CNTF in photoreceptor protection and the importance
of Erk activation in photoreceptor survival.
Key words:
photoreceptor; Müller cell; light damage; degeneration; bFGF; CNTF; Erk; retina; rat
| |
INTRODUCTION |
Noell and coworkers reported in 1966 that unremitting exposure to visible light, even at low irradiance
levels, induced photoreceptor degeneration in albino rats. Although the
exact mechanism is still not fully understood, this model of induced
photoreceptor degeneration has been used widely to study the capability
of photoreceptor protection by antioxidants (Organisciak and Winkler,
1994 ), neurotrophic factors (Faktorovich et al., 1992; LaVail et al.,
1992), and agents that induce endogenous neurotrophic factors (Wen et
al., 1996).
Recent studies provide evidence that endogenous neurotrophic factors
protect photoreceptors from degeneration. For example, photoreceptors
near a wound site are protected from light damage (Faktorovich et al.,
1992; Wen et al., 1995). The injury-induced photoreceptor protection is
accompanied by a dramatic increase in the expression of basic
fibroblast growth factor (bFGF) and ciliary neurotrophic factor (CNTF)
surrounding the wound (Wen et al., 1995). These findings lead to a
hypothesis that the retina responds to injury by upregulating
neurotrophic factors to protect retinal cells and to accelerate repair
and wound healing (Wen et al., 1995). Consistent with the hypothesis
are the observations that retinal bFGF and CNTF are elevated in animals
undergoing inherited retinal degenerations (Gao and Hollyfield, 1995)
or light damage (Steinberg et al., 1995; Gao and Hollyfield, 1996).
Despite the upregulation of neurotrophic factors, severe loss of
photoreceptors occurs in inherited or light-induced retinal degeneration. This raises a question as to whether these endogenous factors really protect photoreceptors. One possible explanation is that
these factors do protect photoreceptors to some extent. In their
absence photoreceptor loss would be more severe, yet in the presence of
progressive photoreceptor degeneration, such putative protection is
hard to demonstrate.
In the present work we used a preconditioning paradigm to detect the
putative protection. The preconditioning consisted of exposure to
bright light, followed by a "rest phase" in normal cyclic light.
Animals so preconditioned displayed a remarkable resistance to light
damage. The preconditioning resulted in a prolonged expression of bFGF
and CNTF in the retina. It also activated extracellular
signal-regulated protein kinases (Erks) in both photoreceptors and
Müller cells. These findings provide evidence that exposure to
bright light evokes a response that protects photoreceptors and suggest
that neurotrophic factors likely mediate the protection.
| |
MATERIALS AND METHODS |
Animals and light exposure. Male Sprague Dawley rats
(2-3 months old) were used in all experiments. Animals were kept in a 12:12 hr light/dark cycle at an in-cage illuminance of <10 candelas (1 cd = 10.76 lux) for at least 7 d before the experiments.
Preexposure to bright light was performed in a constant-light room of
white fluorescent light in which the in-cage illuminance was 115-130 cd. Photoreceptor degeneration (light damage) was induced by exposing animals to the same intensity continuously for 7 d. The in-cage temperature was kept at 20-22°C.
Histological evaluation of photoreceptor preservation.
Animals were killed by CO2 overdose, immediately
followed by vascular perfusion with mixed aldehydes (LaVail and
Battelle, 1975). Eyes were embedded in an Epon/Araldite mixture and
sectioned at 1 µm thickness to display the entire retina along the
vertical meridian of the eye (LaVail and Battelle, 1975). Photoreceptor
preservation was assessed by light microscopy, using a scoring system
to account for the well known nonuniform distribution of light damage
across the retina and, in each retinal region, the number of surviving photoreceptor nuclei as well as the condition of the inner and outer
segments of photoreceptors. The system used a five point scale, with
the score for normal retina being five and the most severe loss of
photoreceptors being one (Wen et al., 1996). Each tissue section was
assessed independently by three scientists equally familiar with the
scoring criteria.
RNA preparation and Northern blot analysis. Retinas were
dissected, snap-frozen in liquid nitrogen, and stored at  80°C.
Total RNA was obtained from pooled retinas with an RNeasy Total RNA Kit
(Qiagen, Chatsworth, CA) according to the manufacturer's instructions. Northern blot analyses were performed as previously described (Wen et
al., 1995). Briefly, total RNA (20 µg of each sample) was
electrophoresed on 1% agarose formaldehyde gels and transferred to a
nylon membrane (Hybond-N, Amersham, Arlington Heights, IL). Blots were
prehybridized for 4 hr at 50°C. Random primed 32P-labeled
cDNA probes for rat bFGF [gift of Dr. A. D. Baird, Whittier Institute for Diabetes and Endocrinology, La Jolla, CA; (Shimasaki et
al., 1988)], rat CNTF [gift of Dr. N. Y. Ip, Regeneron
Pharmaceuticals, Tarrytown, NY (Stöckli et al., 1989)], or rat
18s rRNA [gift of Dr. D. Schlessinger, Washington University, St.
Louis, MO; (Bowman et al., 1981)] were added to the hybridization
buffer (106 cpm/ml) and hybridized at 50°C
overnight. Blots were exposed to a Storage Phosphor Screen (Molecular
Dynamics, Sunnyvale, CA), and data were digitized by scanning the
phosphor screen with a PhosphorImager System (Molecular Dynamics).
Protein preparation and immunoblotting analysis. Retinas
were dissected, snap-frozen in liquid nitrogen, and stored at 80°C. Pooled retinas were homogenized, and total protein (100 µg/lane) was
electrophoresed on polyacrylamide gels and transferred to nitrocellular
membranes (Bio-Rad Labs, Hercules, CA). Blots were examined by
immunoblotting analysis, using the following antibodies: rabbit
anti-bFGF polyclonal antibodies (Santa Cruz Biotechnology, Santa Cruz,
CA), chicken anti-CNTF polyclonal antibodies (Promega, Madison, WI),
rabbit anti-p44/42 phospho-Erk polyclonal antibodies (Promega), and
rabbit anti-p44/42 Erk polyclonal antibodies (New England Biolabs,
Beverly, MA). Signals were visualized with an ECL kit (Amersham,
Arlington Heights, IL) and recorded on Hyperfilm (Amersham).
Immunocytochemistry. Eyes, removed from 4%
paraformaldehyde-perfused animals, were cryoprotected with 20%
sucrose, frozen in Tissue-Tek OCT compound (Miles, Elkhart, IN) in
powdered dry ice, and stored at 80°C. Cryosections of 10 µm were
cut through the entire retina along the vertical meridian and
thaw-mounted onto Super Frost Plus glass slides (Fisher Scientific,
Pittsburgh, PA). For immunostaining, sections were rinsed in PBS and
permeabilized with 0.1% Triton X-100 for 30 min. The sections were
incubated with blocking solution (10% goat serum in PBS) for 1 hr,
followed by a 2 hr incubation with anti-phospho-Erk (1:800 dilution)
antibodies at room temperature. Immunoreactivity was visualized with an
ABC kit (Vector Laboratories, Burlingame, CA) and a TSA-Direct kit (NEN-Life Science Products, Boston, MA), according to the
manufacturers' instructions.
| |
RESULTS |
Preconditioning protects photoreceptors from light damage
The preconditioning paradigm is illustrated schematically in
Figure 1. For preconditioning, animals
were preexposed for 12, 24, or 48 hr to an intensity of 115-130 cd. On
termination of the preexposure, animals were returned to normal cyclic
light conditions for a "rest phase" of 48 hr. To induce light
damage, we placed preconditioned animals to constant light of 115-130 cd for 7 d immediately after the rest phase. Controls received constant light of 115-130 cd for 7 d without any
preconditioning.
View larger version (14K):
[in this window]
[in a new window]
|
Figure 1.
Schematic illustration of the preconditioning
paradigm. Animals were preexposed to 115-130 cd of light continuously
for 12, 24, or 48 hr and then returned to normal cyclic light of 12 hr light (<10 cd)/12 hr dark cycle for 48 hr. Light damage was induced by
a 7 d constant light exposure at 115-130 cd.
|
|
Figure 2 shows representative sections of
superior retinas from a normal animal (Fig. 2A) and
animals that received constant light exposure (115-130 cd) for 7 d without (Fig. 2B) or with (Fig. 2C) a 12 hr preconditioning. Severe photoreceptor degeneration was observed in
animals without preconditioning (Fig. 2B). In these
retinas the outer nuclear layer (ONL), where photoreceptor nuclei
reside, was reduced from 10-11 rows of nuclei in normal animals (Fig.
2A) to one to two rows (Fig. 2B).
There was almost a complete absence of photoreceptor inner segments,
and the remaining outer segments formed large rounded or oblong
profiles (Fig. 2B). In the preconditioned animals,
however, the photoreceptor degeneration was much less severe (Fig.
2C). There were, on average, five to seven rows of
photoreceptor nuclei in the ONL. The inner segments were present,
although shorter than normal. The outer segments were better preserved;
many also showed rounded and oblong profiles (Fig. 2C).
View larger version (189K):
[in this window]
[in a new window]
|
Figure 2.
Protection of photoreceptors by 12 hr
preconditioning. A, Normal retina (superior region) of a
rat kept in cyclic light. The photoreceptor outer segments
(OS) are opposed to the retinal pigment epithelium
(RPE), distinct photoreceptor inner segments
(IS) are present, and the outer nuclear layer
(ONL) consists of 10-11 rows of photoreceptor cell
nuclei. B, Retina of a rat exposed to 7 d of
constant light without preconditioning (superior region). The
ONL is reduced to one to two rows of nuclei; the inner
segments are missing or are reduced to short stumps; the few remaining outer segments are in the form of large rounded or oblong profiles. C, Superior retina of a rat that received a 12 hr
preconditioning and then was exposed to 7 d of constant light. The
ONL shows six to seven rows of nuclei; the inner
segments are shorter than normal, and the outer segments, although
better preserved than in B, are disorganized, many
showing rounded and oblong profiles. Toluidine blue stain was used.
OPL, Outer plexiform layer; INL, inner
nuclear layer. Scale bar, 20 µm.
|
|
The degree of photoreceptor preservation was scored. In animals without
preconditioning the degree of photoreceptor preservation after 7 d
of constant light exposure is 1.10 ± 0.17 (mean ± SD, n = 12). In animals given a 12 hr preconditioning, the
score is 3.17 ± 0.22 (n = 12) and 2.96 ± 0.21 (n = 12) for those that received a 24 hr
conditioning. The score for animals of 48 hr preconditioning is
1.91 ± 0.52 (n = 12) (Fig.
3).
View larger version (36K):
[in this window]
[in a new window]
|
Figure 3.
Degree of photoreceptor preservation in retinas
with or without preconditioning. Preservation of photoreceptors was
determined by weighting the overall thickness of the ONL and the
integrity and organization of the inner and outer segments in a retina. In animals without preconditioning, the degree of photoreceptor preservation after 7 d of constant light exposure was 1.10 ± 0.17 (mean ± SD; n = 12). In animals that had
received a 12 hr preexposure, the score was 3.17 ± 0.22 (n = 12); for 24 hr preexposure the score was
2.96 ± 0.21 (n = 12) and 1.91 ± 0.52 (n = 12) for the 48 hr preexposure.
***p < 0.001; Student's t
test.
|
|
The lesser protection in animals that received longer
preconditioning suggests that some light damage resulted from the
preexposure. To assess the possible light damage induced by
preconditioning itself, we exposed animals to 115-130 cd for 12, 24, or 48 hr and returned them to normal cyclic light for 9 d (to
match the 2 d of the rest phase and the 7 d of constant light
exposure). Figure 4 shows representative
superior retinas from these animals. For those receiving a 12 hr
exposure, there was no obvious morphological change in their
photoreceptors (Fig. 4A). The outer and inner segments of photoreceptors appeared similar to those of normal animals
(see Fig. 2A). No measurable loss of photoreceptor
nuclei was found in the ONL (Fig. 4A). In contrast,
24 hr of exposure led to disorganization of the outer segments and
enlargement of their tips. There was measurable shortening of the inner
segments, and the ONL was reduced by one to two rows of cell nuclei
(Fig. 4B). Significant light damage was evident in
retinas after 48 hr of exposure (Fig. 4C). The outer
segments of photoreceptors exhibited rounded and oblong profiles. There
was a significant shortening of the inner segments. Moreover, the ONL
was reduced to six to seven rows of nuclei. In 24 and 48 hr exposed
animals, the damage to the inferior retinas was slightly greater than
that superiorly (data not shown).
View larger version (154K):
[in this window]
[in a new window]
|
Figure 4.
Light damage by preexposure. A,
Superior retina of a rat received a 12 hr exposure. Outer and inner
segments of photoreceptors appear similar to normal control (see Fig.
2A). There is no apparent loss of photoreceptor
nuclei in the ONL. B, Superior retina
from a rat of 24 hr exposure. Outer segments of photoreceptors are disorganized, and their tips are enlarged. Inner segments are shortened. The ONL is reduced by one to two rows of cell
nuclei. C, Retina of a rat exposed to constant light for
48 hr. Outer segments of photoreceptors clearly are damaged, showing
rounded and oblong profiles. The inner segments are shortened
significantly. The ONL is reduced to six to seven rows
of nuclei. Abbreviations, staining, and scale bar are the same as in
Figure 1.
|
|
Preconditioning induces prolonged expression of bFGF and CNTF
Previous work showed that, among several neurotrophic
factors, only the expression of bFGF and CNTF was induced by exposure to constant light (Steinberg et al., 1995). We therefore examined the
mRNA and protein expression of these two neurotrophic factors. Northern
blotting analysis was used to determine the mRNA expression of bFGF and
CNTF. Retinas from animals exposed to bright light for 12 hr were
collected at 0, 0.5, 1, 2, 4, 7, or 10 d after exposure. A major
7.0 kb transcript was detected by using probes complementary to mRNA
encoding for bFGF (Fig. 5,
top). A significant increase in bFGF mRNA was present by the
end of the exposure (day 0); the maximum was reached within 1 d
after exposure. Although the expression then slowly declined, it was
still at a relatively high level 10 d after exposure. CNTF mRNA
was detected as a single band of 1.2 kb (Fig. 5, middle). An
increase in CNTF mRNA was first detectable 0.5 d after exposure,
reaching its peak in 4 d. The level of 18s rRNA was assessed as a
control for RNA loading (Fig. 5, bottom).
View larger version (104K):
[in this window]
[in a new window]
|
Figure 5.
Expression of bFGF and CNTF mRNAs after 12 hr
exposure. A Northern blot was hybridized with probes for bFGF and
rehybridized with probes for CNTF. A major 7.0 kb transcript was
detected in all lanes (top). The same blot was
rehybridized with probes for CNTF mRNA. CNTF transcript was detected as
a 1.2 kb band (middle). The time after the 12 hr
preexposure is indicated at the top of each lane. The
blot finally was rehybridized with probes for 18s rRNA
(bottom).
|
|
The protein expression of bFGF and CNTF was determined by
immunoblotting analyses. bFGF protein was detected as three bands at
24, 22.5, and 18 kDa. Its expression showed a progressive increase from
day 1 onward (Fig. 6, top).
Increase in CNTF protein (26 kDa) was first observed at 2 d, and
it reached a maximum in 4 d, slowly declining thereafter (Fig. 6,
bottom).
View larger version (25K):
[in this window]
[in a new window]
|
Figure 6.
Expression of bFGF and CNTF protein after 12 hr
exposure. Immunoblotting analyses were performed to assess bFGF and
CNTF proteins after a 12 hr preexposure. Three isoforms of bFGF protein
of 24, 22.5, and 18 kDa were detected. CNTF protein was found as a
single band at 26 kDa. The time after the 12 hr preexposure is
indicated at the top of each lane.
|
|
Preconditioning induces phosphorylation/activation of Erk in
photoreceptors and Müller cells
We next investigated the activation state of Erks by
immunoblotting, using anti-phospho-Erk antibodies to recognize
specifically the dually phosphorylated form of Erk1 (p44) and Erk2
(p42). As shown in Figure 7
(top), a dramatic increase in Erk phosphorylation was
observed immediately after a 12 hr exposure to 115-130 cd, which
lasted at least 12 hr. The protein levels of the two Erks were not
altered by the exposure (see Fig. 6, bottom).
View larger version (25K):
[in this window]
[in a new window]
|
Figure 7.
Phosphorylation of Erks after 12 hr exposure.
Immunoblotting analyses were performed to detect Erk phosphorylation in
the retina. Dually phosphorylated Erks (pp-Erk)
or Erk proteins (Erk) were detected as two bands at 44 and 42 kDa. The time after the 12 hr preexposure is indicated at the
top of each lane.
|
|
The induced phospho-Erks in the retina were localized by
immunocytochemistry. As shown in Figure
8, in the normal retina only a few cells
in the inner nuclear layer were phospho-Erk-positive; at least one
could be identified as a Müller cell, its typical radial
processes positively stained (Fig. 8A). After a 12 hr
exposure to 115-130 cd, some inner segments of photoreceptors stained
positively (Fig. 8B, arrowheads). In addition, there
was a dramatic increase in phospho-Erk-positive cell bodies in the
inner nuclear layer (Fig. 8B). In most of these
cells, positive immunoreactivity also was detected in processes that
extended to the inner and the outer limiting membranes, identifying
them as Müller cells (Fig. 8B).
View larger version (130K):
[in this window]
[in a new window]
|
Figure 8.
Localization of induced Erk phosphorylation.
Phospho-Erk was visualized by immunostaining, using
phospho-Erk-specific antibodies in normal retina
(A) and in a retina from an animal after 12 hr light exposure (B). A few phospho-Erk-positive
cells were labeled in the normal retina. At least one with a typical
radial process can be identified as a Müller cell. After bright
light exposure, a number of photoreceptor inner segments became
phospho-Erk-positive (arrowheads). Many cells in the
inner nuclear layer were labeled also. Processes extending to the inner
and outer limiting membranes identified them as Müller cells.
RPE, Retinal pigment epithelium; ONL,
outer nuclear layer; INL, inner nuclear layer;
GC, ganglion cell layer. Scale bar, 50 µm.
|
|
| |
DISCUSSION |
We have used a preconditioning paradigm to reveal a remarkable
ability of the retina to mount a protective response for
photoreceptors. The preconditioning paradigm is composed of two parts:
a short preexposure to bright light that initiates the protective
response and a 48 hr "rest phase" under normal cyclic light that
allows the protective response to develop. Retinas so preconditioned exhibit a substantial resistance to light damage. These results indicate that exposure to bright light initiates two opposing processes
in the retina: a degenerative process that kills photoreceptors and a
protective response that protects them. The time courses of the two
processes are quite different. The degenerative one is faster, causing
accelerated death of photoreceptors in the first 2 d of exposure,
especially during the second day of exposure. The protective response
is slower and requires 2 d to develop fully. Thus, during the
first 2 d of continuous exposure to bright light (115-130 cd in
the present work), massive photoreceptor death occurs before the
protective response is fully developed.
Since its discovery in 1966, continued research efforts have provided a
wealth of information on light damage (for review, see Organisciak and
Winkler, 1994; Rapp, 1995). It already is known that susceptibility to
light damage relates to light intensity of the rearing environment of
animals (Penn and Anderson, 1994). The relatively low light damage
susceptibility of animals raised in bright lighting environment has
been explained in part by increased antioxidant levels found in retinas
of these animals (Penn et al., 1987). Recently, the photoreceptor
protection properties of several neurotrophic factors, including bFGF
and CNTF, have been clearly demonstrated against light damage in rats,
as well as in the RCS (Royal College of Surgeons) rats bearing an
inherited photoreceptor degeneration (Faktorovich et al., 1990, 1992;
LaVail et al., 1992). In addition, an upregulation of endogenous bFGF and CNTF observed in mechanically injured retina is believed to be
responsible for injury-induced photoreceptor protection (Wen et al.,
1995). Increased bFGF or CNTF expression also is found in inherited and
induced retinal degenerative animal models (Gao and Hollyfield, 1995,
1996; Steinberg et al., 1995). In the present work we show that a 12 hr
exposure to bright light induces a large and prolonged increase in bFGF
and CNTF expression. Moreover, significant elevation of the two
proteins coincides with the 2 d "rest phase" of the
preconditioning paradigm. Together, these findings strongly suggest
that endogenous neurotrophic factors take part in the
preconditioning-induced photoreceptor protection.
Protection of photoreceptors by preconditioning exposure resembles
"conditioning lesion" effects previously recognized in the brain
and the peripheral nervous system. An initial (conditioning) lesion
facilitates tissue recovery from a subsequent (test) lesion (McQuarrie
et al., 1977; Nieto-Sampedro et al., 1984; Perez-Polo et al., 1990).
The accelerated recovery from the second lesion has been attributed to
an increase in synthesis and the secretion of neurotrophic factors
stimulated by the conditioning lesion (Nieto-Sampedro and Cotman,
1985), such as bFGF (Finklestein et al., 1988; Frautschy et al., 1991;
Logan et al., 1992) or CNTF (Ip et al., 1993).
Many neurotrophic factors, including NGF, BDNF, and bFGF, exert their
effects by interacting with receptor tyrosine kinases and by activating
the Ras/Raf/MAPK (mitogen-activated protein kinase) pathway. Activation
of Erks is well recognized as an essential step in the Ras/MAPK cascade
(Davis, 1993; Nishida and Gotoh, 1993; Leevers and Marshall, 1995).
Some stress signals also use this signaling pathway for Erk activation.
For example, ultraviolet irradiation induces phosphorylation of Erks in
HeLa cells via growth factor receptors and a Ras-dependent pathway
(Sachsenmaier et al., 1994). H2O2 rapidly
induces Erk phosphorylation in National Institutes of Health 3T3 and PC
12 cells also via a Ras-dependent pathway (Guyton et al., 1996). In
addition, inhibition of H2O2-induced Erk
activation greatly increases the susceptibility of cells to H2O2 toxicity (Guyton et al., 1996), indicating
that Erk activation is critical for cell survival. Because a 12 hr
exposure to 115-130 cd of light induces a significant and prolonged
increase in Erk phosphorylation in both photoreceptors and Müller
cells, Erk activation likely is involved in mediating photoreceptor
protection. Of special pertinence, two recent reports describe an
increase in Erk phosphorylation in ischemic injury in rat and cat
retinas (Hayashi et al., 1996, 1997), again indicating that Erk
activation represents an important step in retinal response to
injury.
Müller cells are believed to act as housekeepers, maintaining the
integrity and the normal function of the retina. They are also
important for photoreceptor survival (Wen et al., 1995). The present
demonstration of increased Erk phosphorylation suggests that
Müller cells play a role in preconditioning-induced photoreceptor protection.
The present report highlights an endogenous protective system in the
retina. Aspects of this system previously have been glimpsed under
several conditions (Faktorovich et al., 1990, 1992; Wen et al., 1995).
A common underlying mechanism is indicated by the similarity of induced
expression of neurotrophic factors by exposure to bright light
(Steinberg et al., 1995) and by mechanical injury (Wen et al., 1995).
Further investigation of such a mechanism could well have therapeutic
potential for degenerative disorders of photoreceptors.
| |
FOOTNOTES |
Received Oct. 27, 1997; revised Dec. 4, 1997; accepted Dec. 5, 1997.
This work was supported by the Foundation Fighting Blindness and by a
grant from the Paul and Evanina Mackall Foundation Trust. R.W. is a
recipient of a Research to Prevent Blindness Career Development
Award.
Correspondence should be addressed to Dr. Rong Wen, Department of
Ophthalmology, D-603 Richards Building, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104.
| |
REFERENCES |
-
Bowman LH,
Rabin B,
Schlessinger D
(1981)
Multiple ribosomal RNA cleavage pathways in mammalian cells.
Nucleic Acids Res
9:4951-4966[Abstract/Free Full Text].
-
Davis RJ
(1993)
The mitogen-activated protein kinase signal transduction pathway.
J Biol Chem
268:14553-14556[Free Full Text].
-
Faktorovich EG,
Steinberg RH,
Yasumura D,
Matthes MT,
LaVail MM
(1990)
Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor.
Nature
347:83-86[Medline].
-
Faktorovich EG,
Steinberg RH,
Yasumura D,
Matthes MT,
LaVail MM
(1992)
Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat.
J Neurosci
12:3554-3567[Abstract].
-
Finklestein SP,
Apostolides PJ,
Caday CG,
Prosser J,
Philips MF,
Klagsbrun M
(1988)
Increased basic fibroblast growth factor (bFGF) immunoreactivity at the site of focal brain wounds.
Brain Res
460:253-259[ISI][Medline].
-
Frautschy SA,
Walicke PA,
Baird A
(1991)
Localization of basic fibroblast growth factor and its mRNA after CNS injury.
Brain Res
553:291-299[ISI][Medline].
-
Gao H,
Hollyfield JG
(1995)
Basic fibroblast growth factor in retinal development: differential levels of bFGF expression and content in normal and retinal degeneration (rd) mutant mice.
Dev Biol
169:168-184[ISI][Medline].
-
Gao H,
Hollyfield JG
(1996)
Basic fibroblast growth factor: increased gene expression in inherited and light-induced photoreceptor degeneration.
Exp Eye Res
62:181-189[ISI][Medline].
-
Guyton KZ,
Liu Y,
Gorospe M,
Xu Q,
Holbrook NJ
(1996)
Activation of mitogen-activated protein kinase by H2O2.
J Biol Chem
271:4138-4142[Abstract/Free Full Text].
-
Hayashi A,
Koroma BM,
Imai K,
de Juan EJ
(1996)
Increase of protein tyrosine phosphorylation in rat retina after ischemia-reperfusion injury.
Invest Ophthalmol Vis Sci
37:2146-2156[Abstract/Free Full Text].
-
Hayashi A,
Imai K,
Kim HC,
de Juan EJ
(1997)
Activation of protein tyrosine phosphorylation after retinal branch vein occlusion in cats.
Invest Ophthalmol Vis Sci
38:372-380[Abstract/Free Full Text].
-
Ip NY,
Wiegand SJ,
Morse J,
Rudge JS
(1993)
Injury-induced regulation of ciliary neurotrophic factor mRNA in the adult rat brain.
Eur J Neurosci
5:25-33[ISI][Medline].
-
LaVail MM,
Battelle B-A
(1975)
Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat.
Exp Eye Res
21:167-192[ISI][Medline].
-
LaVail MM,
Unoki K,
Yasumura D,
Matthes MT,
Yancopoulos GD,
Steinberg RH
(1992)
Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light.
Proc Natl Acad Sci USA
89:11249-11253[Abstract/Free Full Text].
-
Leevers S,
Marshall C
(1995)
Extracellular signal-regulated kinases (Erks).
In: Guidebook to the small GTPases (Zerial M,
Huber LA,
eds), pp 160-164. New York: Oxford UP.
-
Logan A,
Frautschy SA,
Gonzalez A-M,
Baird A
(1992)
A time course for the focal elevation of synthesis of basic fibroblast growth factor and one of its high-affinity receptors (flg) following a localized cortical brain injury.
J Neurosci
12:3828-3837[Abstract].
-
McQuarrie IG,
Grafstein B,
Gershon MD
(1977)
Axonal regeneration in the rat sciatic nerve: effect of a conditioning lesion and of dbcAMP.
Brain Res
132:443-453[ISI][Medline].
-
Nieto-Sampedro M,
Cotman CW
(1985)
Growth factor induction and temporal order in central nervous system repair.
In: Synaptic plasticity (Cotman CW,
ed), pp 407-455. New York: Guilford.
-
Nieto-Sampedro M,
Whittemore SR,
Needels DL,
Larson J,
Cotman CW
(1984)
Survival of brain transplants is enhanced by extracts from injured brain.
Proc Natl Acad Sci USA
81:6250-6254[Abstract/Free Full Text].
-
Nishida E,
Gotoh Y
(1993)
The MAP kinase cascade is essential for diverse signal transduction pathways.
Trends Biochem Sci
18:128-130[ISI][Medline].
-
Noell WK,
Walker VS,
Kang BS,
Berman S
(1966)
Retinal damage by light in rats.
Invest Ophthalmol Vis Sci
5:450-473[Abstract/Free Full Text].
-
Organisciak DT,
Winkler BS
(1994)
Retinal light damage: practical and theoretical considerations.
In: Progress in retinal and eye research, Vol 13 (Osborne N,
Chader GS,
eds), pp 1-29. Tarrytown, NY: Pergamon.
-
Penn JS,
Anderson RE
(1994)
Effects of light history on the rat retina.
In: Progress in retinal and eye research, Vol 13 (Osborne N,
Chader GS,
eds), pp 75-98. Tarrytown, NY: Pergamon.
-
Penn JS,
Naash MI,
Anderson RE
(1987)
Effect of light history on retinal antioxidants and light damage susceptibility in the rat.
Exp Eye Res
44:915-928.
-
Perez-Polo JR,
Foreman PJ,
Jackson GR,
Shan D,
Taglialatela G,
Thorpe LW,
Werrbach-Perez K
(1990)
Nerve growth factor and neuronal cell death.
In: Molecular neurobiology (Bazan NG,
ed), pp 57-90. Clifton, NJ: Humana.
-
Rapp LM
(1995)
Retinal phototoxicity.
In: Handbook of neurotoxicology (Chang LW,
Dyer RS,
eds), pp 963-1003. New York: Dekker.
-
Sachsenmaier C,
Radler-Pohl A,
Zinck R,
Nordheim A,
Herrlich P,
Rahmsdorf HJ
(1994)
Involvement of growth factor receptors in the mammalian UVC response.
Cell
78:963-972[ISI][Medline].
-
Shimasaki S,
Emoto N,
Koba A,
Mercado M,
Shibata F,
Cooksey K,
Baird A,
Ling N
(1988)
Complementary DNA cloning and sequencing of rat ovarian basic fibroblast growth factor and tissue distribution study of its mRNA.
Biochem Biophys Res Commun
157:256-263[ISI][Medline].
-
Steinberg RH,
Song Y,
Cheng T,
Matthes MT,
Yasumura D,
LaVail MM,
Wen R
(1995)
Exposure to constant light upregulates the expression of bFGF, CNTF, FGFR-1, and GFAP mRNAs in the rat retina.
Invest Ophthalmol Vis Sci
36:S637.
-
Stöckli KA,
Lottspeich F,
Sendtner M,
Masiakowski P,
Carroll P,
Götz R,
Lindholm D,
Thoenen H
(1989)
Molecular cloning, expression, and regional distribution of rat ciliary neurotrophic factor.
Nature
342:920-923[Medline].
-
Wen R,
Song Y,
Cheng T,
Matthes MT,
Yasumura D,
LaVail MM,
Steinberg RH
(1995)
Injury-induced upregulation of bFGF and CNTF mRNAs in the rat retina.
J Neurosci
15:7377-7385[Abstract].
-
Wen R,
Cheng T,
Li Y,
Cao W,
Steinberg RH
(1996)
 2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage.
J Neurosci
16:5986-5992[Abstract/Free Full Text].
Copyright © 1998 Society for Neuroscience 0270-6474/98/1841337-08$05.00/0
This article has been cited by other articles:
|
|
|
|
 
M. Lahne and J. E. Gale
Damage-Induced Activation of ERK1/2 in Cochlear Supporting Cells Is a Hair Cell Death-Promoting Signal That Depends on Extracellular ATP and Calcium
J. Neurosci.,
May 7, 2008;
28(19):
4918 - 4928.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Chrysostomou, J. Stone, S. Stowe, N. L. Barnett, and K. Valter
The Status of Cones in the Rhodopsin Mutant P23H-3 Retina: Light-Regulated Damage and Repair in Parallel with Rods
Invest. Ophthalmol. Vis. Sci.,
March 1, 2008;
49(3):
1116 - 1125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Yi, R. E. I. Nakamura, O. Mohamed, D. Dufort, and A. S. Hackam
Characterization of Wnt Signaling during Photoreceptor Degeneration
Invest. Ophthalmol. Vis. Sci.,
December 1, 2007;
48(12):
5733 - 5741.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Morimoto, T. Fujikado, J.-S. Choi, H. Kanda, T. Miyoshi, Y. Fukuda, and Y. Tano
Transcorneal Electrical Stimulation Promotes the Survival of Photoreceptors and Preserves Retinal Function in Royal College of Surgeons Rats
Invest. Ophthalmol. Vis. Sci.,
October 1, 2007;
48(10):
4725 - 4732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. Wilson, K. Kunchithapautham, and B. Rohrer
Paradoxical Role of BDNF: BDNF+/- Retinas Are Protected against Light Damage-Mediated Stress
Invest. Ophthalmol. Vis. Sci.,
June 1, 2007;
48(6):
2877 - 2886.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. A. Beltran, P. Hammond, G. M. Acland, and G. D. Aguirre
A Frameshift Mutation in RPGR Exon ORF15 Causes Photoreceptor Degeneration and Inner Retina Remodeling in a Model of X-Linked Retinitis Pigmentosa.
Invest. Ophthalmol. Vis. Sci.,
April 1, 2006;
47(4):
1669 - 1681.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Rattner and J. Nathans
The Genomic Response to Retinal Disease and Injury: Evidence for Endothelin Signaling from Photoreceptors to Glia
J. Neurosci.,
May 4, 2005;
25(18):
4540 - 4549.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Valter, S. Bisti, C. Gargini, S. Di Loreto, R. Maccarone, L. Cervetto, and J. Stone
Time Course of Neurotrophic Factor Upregulation and Retinal Protection against Light-Induced Damage after Optic Nerve Section
Invest. Ophthalmol. Vis. Sci.,
May 1, 2005;
46(5):
1748 - 1754.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Huang, F. Li, R. A. Alvarez, J. D. Ash, and R. E. Anderson
Downregulation of ATP Synthase Subunit-6, Cytochrome c Oxidase-III, and NADH Dehydrogenase-3 by Bright Cyclic Light in the Rat Retina
Invest. Ophthalmol. Vis. Sci.,
August 1, 2004;
45(8):
2489 - 2496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Casson, G. Chidlow, J. P. M. Wood, M. Vidal-Sanz, and N. N. Osborne
The Effect of Retinal Ganglion Cell Injury on Light-Induced Photoreceptor Degeneration
Invest. Ophthalmol. Vis. Sci.,
February 1, 2004;
45(2):
685 - 693.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Roth, A. R. Shaikh, M. M. Hennelly, Q. Li, V. Bindokas, and C. E. Graham
Mitogen-Activated Protein Kinases and Retinal Ischemia
Invest. Ophthalmol. Vis. Sci.,
December 1, 2003;
44(12):
5383 - 5395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Li, W. Cao, and R. E. Anderson
Alleviation of Constant-Light-Induced Photoreceptor Degeneration by Adaptation of Adult Albino Rat to Bright Cyclic Light
Invest. Ophthalmol. Vis. Sci.,
November 1, 2003;
44(11):
4968 - 4975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Casson, J. P. M. Wood, J. Melena, G. Chidlow, and N. N. Osborne
The Effect of Ischemic Preconditioning on Light-Induced Photoreceptor Injury
Invest. Ophthalmol. Vis. Sci.,
March 1, 2003;
44(3):
1348 - 1354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Nakazawa, M. Tamai, and N. Mori
Brain-Derived Neurotrophic Factor Prevents Axotomized Retinal Ganglion Cell Death through MAPK and PI3K Signaling Pathways
Invest. Ophthalmol. Vis. Sci.,
October 1, 2002;
43(10):
3319 - 3326.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Zhang, D. M. Rosenbaum, A. R. Shaikh, Q. Li, P. S. Rosenbaum, D. J. Pelham, and S. Roth
Ischemic Preconditioning Attenuates Apoptotic Cell Death in the Rat Retina
Invest. Ophthalmol. Vis. Sci.,
September 1, 2002;
43(9):
3059 - 3066.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Takeda, A. Takamiya, A. Yoshida, and H. Kiyama
Extracellular Signal-Regulated Kinase Activation Predominantly in Muller Cells of Retina with Endotoxin-Induced Uveitis
Invest. Ophthalmol. Vis. Sci.,
April 1, 2002;
43(4):
907 - 911.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bowers, K. Valter, S. Chan, N. Walsh, J. Maslim, and J. Stone
Effects of Oxygen and bFGF on the Vulnerability of Photoreceptors to Light Damage
Invest. Ophthalmol. Vis. Sci.,
March 1, 2001;
42(3):
804 - 815.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
I. Nir, J. M. Harrison, C. Liu, and R. Wen
Extended Photoreceptor Viability by Light Stress in the RCS Rats but not in the Opsin P23H Mutant Rats
Invest. Ophthalmol. Vis. Sci.,
March 1, 2001;
42(3):
842 - 849.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
W. M. Peterson, Q. Wang, R. Tzekova, and S. J. Wiegand
Ciliary Neurotrophic Factor and Stress Stimuli Activate the Jak-STAT Pathway in Retinal Neurons and Glia
J. Neurosci.,
June 1, 2000;
20(11):
4081 - 4090.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. J. Wahlin, P. A. Campochiaro, D. J. Zack, and R. Adler
Neurotrophic Factors Cause Activation of Intracellular Signaling Pathways in Muller Cells and Other Cells of the Inner Retina, but Not Photoreceptors
Invest. Ophthalmol. Vis. Sci.,
March 1, 2000;
41(3):
927 - 936.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Honjo, H. Tanihara, N. Kido, M. Inatani, K. Okazaki, and Y. Honda
Expression of Ciliary Neurotrophic Factor Activated by Retinal Muller Cells in Eyes with NMDA- and Kainic Acid-Induced Neuronal Death
Invest. Ophthalmol. Vis. Sci.,
February 1, 2000;
41(2):
552 - 560.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. Rohrer, J. I. Korenbrot, M. M. LaVail, L. F. Reichardt, and B. Xu
Role of Neurotrophin Receptor TrkB in the Maturation of Rod Photoreceptors and Establishment of Synaptic Transmission to the Inner Retina
J. Neurosci.,
October 15, 1999;
19(20):
8919 - 8930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Nir, C. Liu, and R. Wen
Light Treatment Enhances Photoreceptor Survival in Dystrophic Retinas of Royal College of Surgeons Rats
Invest. Ophthalmol. Vis. Sci.,
September 1, 1999;
40(10):
2383 - 2390.
[Abstract]
[Full Text]
[PDF]
| |
Top
Abstract
Introduction
