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1 From the Istituto di Neurofisiologia, Consiglio Nazionale delle Ricerche, Pisa; 2 Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Universitá di Pisa; 3 Dipartimento STB, Universitá di L’Aquila, Italy; and the 4 New South Wales Retinal Dystrophy Research Centre, Department of Anatomy and Histology, University of Sydney, Australia.
Abstract
PURPOSE. To assess the impact of basic fibroblast growth factor (bFGF) on photoreceptor function and morphology.
METHODS. Impact was assessed in two models. In one, the endogenous expression of bFGF in photoreceptors was raised by sectioning one optic nerve of rats 3 to 4 weeks before study. In the other, bFGF was injected into the vitreous chamber in rats and cats. Retinal function was assessed from the electroretinogram (ERG), and retinal morphology was studied using DNA dyes, immunolabeling, and in situ hybridization.
RESULTS. In both models of bFGF upregulation, the ERG b-wave was suppressed over a wide stimulus range and in light- and dark-adapted conditions. The a-wave was not suppressed by either procedure and at the brightest intensities was enhanced by both procedures. In nerve-sectioned eyes, outer retina appeared normal histologically, but levels of bFGF protein in the inner and outer nuclear layers were raised, whereas bFGF mRNA levels remained unchanged. In both models, levels of synaptophysin in the outer plexiform layer and of cytochrome oxidase in inner segments were raised in association with increases in bFGF protein levels.
CONCLUSIONS. bFGF increased the ability of photoreceptors to respond to light but attenuated the transmission of this response to inner retinal cells, presumably by blocking the photoreceptor–bipolar synapse. If the expression of bFGF protein is upregulated in human photoreceptor dystrophies, it may contribute a reversible component to the loss of vision. The relationship between these actions of bFGF and its ability to protect photoreceptors from stress remains to be established.
Evidence that the retina reacts to the stresses of its normal function by upregulating protective mechanisms came from the studies of Penn and Anderson,1 who showed that moderate levels of light experienced in a normal daily cycle both damage the genetically normal retina (reducing the photoreceptor population) and increase its resistance to further damage. Such evidence indicates a process of basic biologic interest and makes self-protection an important issue in understanding the causes of photoreceptor dystrophies.
Early evidence that bFGF is protective to photoreceptors came from the demonstration that bFGF applied exogenously to photoreceptors of the rat eye promotes their survival in the face of genetic mutation2 and light damage.3 Evidence that photoreceptors protect themselves from damage by expressing bFGF endogenously can be traced to the observation of Bush and Williams4 that optic nerve section makes the photoreceptors of the affected eye resistant to light damage. Kostyk et al.5 related this protective effect of nerve section to bFGF, showing that nerve section induces an increase in bFGF protein in the outer nuclear layer (ONL). Subsequent studies have shown with increasing specificity that stress upregulates the expression of bFGF protein in the retina, and that this upregulation is protective. Small laser lesions that slow the degeneration of surrounding photoreceptors in the retina of the Royal College of Surgeons rat6 also upregulate bFGF protein levels in the rescued cells.7 8 Photoreceptors upregulate their expression of bFGF protein during genetic and light-induced dystrophy of the mouse retina.9 10 The retina upregulates its expression of bFGF protein in response to light damage, and that upregulation is protective.11 bFGF is among the factors upregulated by the retina in response to mechanical damage, and their upregulation is also protective.12
bFGF may also contribute to the protective effect of bright but physiological levels of daily light experience.1 Recent evidence13 suggests that photoreceptors react to normal levels of daily light by expressing bFGF protein in amounts directly related to the intensity of the daily light. Further, this expression of bFGF in photoreceptors appears to determine the severity of damage caused to them when they are stressed by prolonged bright light. The mechanisms by which factors such as bFGF protect photoreceptors are, however, still unknown. The present experiments were designed to assess the impact of bFGF on the structure and function of photoreceptors, as a step toward identifying the mechanisms of protection by bFGF.
Methods
All procedures conformed to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Optic Nerve Section
Nerve section was performed on 11 adult rats under surgical
anesthesia (tribromoethanol, 1.5 mg/100g, by intraperitoneal injection
as a 2% solution in buffered saline). The optic nerve was sectioned in
the orbit several millimeters behind the eyeball. To ensure that the
section spared the vascular supply to the eye, the following steps were
taken: The nerve was approached from its superior aspect, through an
incision in the upper eyelid. It was visualized in the orbit by blunt
dissection. The nerve was raised dorsally and laterally to separate it
from the short ciliary vessels, which approach from its medioventral
aspect. The nerve was cut behind the entry of the short ciliary
arteries into the nerve. Subsequent histology confirmed that the inner
retina and its vessels (which degenerate if the retinal circulation is
blocked14
) remained intact (described later).
Eyeball Injection
The eyeball was injected in 16 adult rats and 2 adult cats, under
surgical anesthesia (as for nerve section). In each case bFGF (human
recombinant, 1 µg/µl; Sigma, St. Louis, MO) in PBS was injected
into the vitreous humor of the right eye, using a fine needle and
following protocols of earlier studies.23
In some animals
the left eye was injected with the same volume of PBS.
Electroretinography
Recordings were made 3 to 4 weeks after optic nerve section and 1
to 10 days after intravitreal injection. Rats were anesthetized with
urethane (1200 mg/kg), kept warm by a feedback-controlled electric
blanket and placed in a conventional head holder. In cats, anesthesia
was induced by an intramuscular injection of ketamine (30 mg/kg;
Ketalar, Parke–Davis, Morris Plains, NJ). An endotracheal tube and a
venous cannula were then inserted. The animal was paralyzed with an
intravenous infusion of a 0.2% solution of pancuronium bromide
(Pavulon; Organon Teknika, Durham, NC) at a rate of 0.1 to 0.2 ml/kg
per hour and artificially ventilated. Anesthesia was maintained
throughout the recording session by intravenous infusion of sodium
thiopental (3.5 mg/kg per hour). Silver wire electrodes were introduced
into the vitreous humor through a minimal incision on the lateral side
of the eyeball. Recordings were made from left and right eyes
separately, with the other eye fully covered. Recordings were made
between the two vitreous electrodes or between the electrode in the
vitreous and an electrode placed on the tongue. The band-pass of the
amplifier was 0.1 Hz to 500 Hz.
Rats were dark-adapted for 40 minutes before recording commenced, and darkness was maintained throughout except for the light stimulus. Three modes of light stimulation were used. In one, dark-adapted responses were evoked with an 8-msec flash of a monitor screen subtending approximately 30° at the eye and of intensity up to 28 cd/m2. Interstimulus intervals were 2 minutes or longer, and during this time the screen was dark. In the second mode, light-adapted responses were obtained using the same screen stimulator. The stimulus was a square-wave variation of intensity of mean brightness 18 cd/m2 (maximum range, 0–36 cd/m2. The frequency of stimulation was 0.5 Hz, and the screen brightness remained high for 1 second, then low for 1 second. In the third series of experiments dark-adapted responses were obtained using a flash unit that produced flashes of 1.5-msec duration and 15, 000 cd/m2 intensity, equivalent to 105,000 scotopic troland/sec. Neutral density filters were used to attenuate the flash for intensity–response relationships. The background was kept dark, and the interstimulus interval was at least 2 minutes. The a-wave was measured from the baseline to the first negative peak, and the b-wave was measured from negative to positive peaks. In a few experiments we recorded ERG responses to bright flashes with an amplifier bandwidth extended up to 3 kHz. In these instances oscillatory potentials could be observed in the normal ERG, but they were almost absent in the optic nerve sectioned eye.
Histology and Immunohistochemistry
Retinas were fixed by immersion of the globe in 4%
paraformaldehyde in PBS at pH 7.4 for 1 to 6 hours. Some eyes were then
embedded in celloidin, sectioned at 30 µm, and stained with cresyl
violet. Other eyes were placed in 20% sucrose until they sank, frozen
embedded in TissueTek (Miles, Elkhart, IN), and cryosectioned at 20
µm for use in immunocytochemistry. Retinas were labeled for bFGF in
steps, according to protocols published previously.15
Sections were labeled with antibodies to cytochrome oxidase (CO;
Molecular Probes, Eugene, OR) at 1 µg/ml, to rod opsin (Rho4D2, gift
from Robert S. Molday, University of British Columbia,
Vancouver, Canada) at 1:100, or to synaptophysin (Dako, Carpinteria,
CA) at 1:100. Some sections were second labeled with a DNA- specific
dye (SYTO-12 or TOTO-3, diluted 1:1000 and applied for 20 seconds;
Molecular Probes) or a biotinylated peanut agglutinin (PNA) lectin
(Vector Laboratories, Burlingame, CA). PNA labels cone sheaths
specifically.16
It was applied at a final dilution of 400
µg/ml in PBS, followed by streptavidin Cy2 or Cy3.
In Situ Hybridization
cRNA probes were prepared from a 477-bp cDNA strand corresponding
to nucleotides 533 to 1009 of a rat ovarian bFGF cDNA. This cDNA
incorporates the complete bFGF coding sequence and a 75 nucleotide 3'
flanking sequence. The strand was cloned into a vector (pBluescript
SK+; Stratagene; La Jolla, CA). The detailed
procedures used have been published.15
Quantitation of Signals
Molecule-specific signals from immunolabeled proteins were
quantified using NIH Image software (the Analysis tool; Bethesda, MD)
applied to digitized images obtained by confocal microscopy. The
quantitative comparisons in Figures 7
8
and 9
were made in the
following conditions. The sections from the two eyes to be compared
were fixed and labeled by identical protocols in the same run and
imaged by the confocal microscope with the photomultiplier tube
settings constant. Any subsequent optimization of the image was
identical in the two images, and identical analytical tools were used
on the digitized images. A similar approach was taken to the
quantification of probes hybridized to bFGF mRNA, except that the label
used was not fluorescent, but the nitroblue tetrazolium chloride
chromogen, and the images were digitized on a conventional microscope.
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Effect of Nerve Section on the ERG Evoked by Dim Stimuli
Dark-Adapted Responses.
Figure 1
shows dark-adapted responses to an 8-msec flash of intensity 0.11 to 28
cd/m2 recorded from the left (Fig. 1
A)
and right (Fig. 1
B) eyes of a rat in which the right nerve
had been sectioned 3 to 4 weeks previously. Responses from the two eyes
are shown to the same five intensities of the flash. The general shape
of the response did not vary markedly between eyes over the intensity
range used, but response amplitude was consistently smaller in the
nerve-sectioned eye. In each of four experiments, responses were
averaged over four stimulus cycles; Figure 1C
shows normalized mean
amplitudes and SEMs. Extrapolation of the data points in Figure 1C
1D
1E
1F
1G
1H
1I
1J
1K
1L
1M
1N
1O
1P
1Q
1R
1S
1T
he abscissa suggests a difference in threshold of approximately 1.2
log units between nerve-intact and nerve-sectioned eyes. Over the
stimulus intensity range used, the data series from the two eyes are
also separated along the abscissa by approximately 1.2 log units.
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Effect of Nerve Section on the ERG Evoked by Bright
Flashes
Figures 3
A and 3B show dark-adapted responses from the nerve-intact (A) and
nerve-sectioned (B) eyes of a rat to 1.5-msec flashes of intensities
3.5, 7, and 28 cd/m2. As in Figure 1
, responses
to these dim flashes were dominated by the b-wave and were of lower
amplitude in the nerve-sectioned eye. When flashes of intensity 112 to
7500 cd/m2 were used, the a-wave of the response
became identifiable and then prominent (Figs. 3C
3D)
. Over the range
of intensities for which it could be identified (>100
cd/m2) the a-wave was detected at lower
intensities in the nerve-sectioned eye, was never less in the
nerve-sectioned eye, and at the highest intensities (7500
cd/m2) was clearly larger in the nerve-sectioned
eye. These features are all apparent when comparing Figures 3C
and 3D .
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Effect of bFGF Injection on the ERG Evoked by Bright Flashes
ERGs elicited by 1.5-msec flashes of 0.3 to 28
cd/m2 are shown in Figures 5
A, and 5B for vehicle- and bFGF-injected eyes. At these low intensities
the ERG was dominated by the b-wave and, as in Figure 4
, was markedly
suppressed by bFGF injection. When flashes of intensity 112 to 7500
cd/m2 were used, the a-wave of the response
became identifiable and at higher intensities became prominent (Fig. 5C
5D)
. Over the range of intensities for which it could be identified
(>100 cd/m2) the a-wave appeared at lower
intensities in the bFGF-injected eye, was never less in the
bFGF-injected eye, and at the highest intensities (7500
cd/m2) was clearly larger in the bFGF-injected
eye. The b-wave evoked by stimuli brighter than 100
cd/m2 appeared to be slightly reduced in
amplitude in the bFGF-injected eye in some animals and slightly
enhanced in others. Again, when the larger size of the a-wave evoked by
bright stimuli is taken into account, these results suggest that the
b-wave elicited by very bright stimuli is suppressed to some degree by
bFGF injection.
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Eye-Injection Data.
Figure 6C
summarizes present results for low-intensity stimuli. The
effect of bFGF injection was more variable than that of nerve section,
but a reduction of amplitude was apparent in the bFGF-injected eye in
13 of the 16 rats studied 3 to 10 days after injection and in both cat
experiments. The reduction was apparent in both light-adapted (open
symbol) and dark-adapted (closed symbol) conditions. In some cases the
reduction was as marked as that after nerve section. Injections of
vehicle were made into the left eye (as well as of bFGF into the right
eye) of 4 of the 18 rats studied and in both the cat experiments. In
all six cases the b-wave amplitude of the bFGF-injected eye was less
than 50% of its value in the vehicle-injected eye. Using the same
convention (Fig. 6D)
for four experiments with bright flashes
(duration, 1.5 msec; intensity 7500 cd/m2), the
a-wave was larger in the bFGF-injected eye in all four experiments,
whereas the b-wave was not consistently suppressed or enhanced.
Effect of Nerve Section on Retinal Structure
With a Nissl stain (Figs. 7
A, 7B) the middle and outer layers of the retina appeared unaffected by
nerve section. At higher power, a DNA label (Figs. 7C
7D)
showed large
somas in the ganglion cell layer (g) of the nerve-intact retina but was
absent from the nerve-sectioned retina, suggesting the retrograde
degeneration of ganglion cells. In Figures 7E
and 7F
a DNA dye (blue)
confirmed that the ONL was normal in general morphology after nerve
section. The labeling of outer segments by the anti-opsin antibody
(green) suggests no abnormality in the outer segments. The labeling of
the inner segments and the outer plexiform layer (OPL) by the antibody
to CO (red) appeared normal in location in the nerve-sectioned eye
(compare Figs. 7E
and 7F
). The CO labeling appeared enhanced in
intensity in the nerve-sectioned retina but showed no evidence of
morphologic abnormality.
Effects of Nerve Section on bFGF Expression
bFGF Protein.
Figures 8
A and 8B show the result obtained in three of the six animals examined.
In the nerve-intact retina (Fig. 8B)
, bFGF distribution resembled that
seen in the normal rat retina.13
bFGF was prominent in
somas in the inner nuclear layer (INL) shown by previous
workers7
to be the somas of Müller cells. bFGF was
evident also in the inner segments of photoreceptors but not in their
somas in the ONL. In the nerve-sectioned retina (Fig. 8A)
, bFGF
appeared more strongly expressed in Müller cell somas, in inner
segments, and in the ONL. These trends, shown quantitatively in Figure 8C
, suggest that the expression of bFGF protein was upregulated by
nerve section in Müller cell somas, in the ONL, and in the inner
segments.
In the other three animals, bFGF protein levels in the nerve-sectioned retina appeared to be elevated in the ONL, as in Figure 8A . However, bFGF protein levels in the nerve-intact eye appeared abnormal. The concentration of bFGF in Müller cell somas had dispersed along Müller cell processes, so that their inner feet and the INL appear strongly labeled (not illustrated).
bFGF mRNA.
Comparison of bFGF mRNA levels in nerve-intact and nerve-sectioned
retinas is shown in Figures 8D
8E
and 8F
. In neither of two animals
examined was there evidence that the expression of bFGF mRNA was
upregulated in the nerve-sectioned retina. In particular, the level of
bFGF mRNA in the somas or inner segments of photoreceptors was no
higher in the nerve-sectioned retina, despite the concentration there
of bFGF protein.
Upregulation of bFGF Protein Expression Cones and Rods.
Granules labeled (green) for bFGF protein appeared to be present in
every soma of the ONL (o in Figs. 8G
8H
8I
; left panels). Sheaths of
cone inner and outer segments, labeled (Figs. 8G
8H 8I
; red) with the
PNA lectin, could occasionally be traced to their somas (8G, 8H; arrows
in right panels). These somas also contained bFGF granules in their
cytoplasm (8G, 8H; lower right panels). The outer segments of both rods
(Fig. 8I
; small arrows) and cones (larger arrow) were also
bFGF+.
Effects of Nerve Section and bFGF Injection on Activity-Related
Molecules
Nerve section induced upregulation of the expression of both CO
and synaptophysin. Comparing Figures 9
A and 9B, CO levels in the inner segments and OPL were higher in the
nerve-sectioned than in the nerve-intact retina. Figure 9C
shows this
comparison quantitatively. Nerve section also induced an upregulation
of the expression of synaptophysin in the OPL (Figs. 9D
9E
9F)
. Both
results were consistent in the four animals examined. bFGF injection
mimicked optic nerve section in upregulating CO expression in the OPL
and inner segments (Fig. 9G)
and synaptophysin expression in the OPL
(Fig. 9H)
. This result was consistent in the three bFGF-injected
animals examined.
Discussion
The two models of upregulation of bFGF protein levels studied were chosen because, in both, photoreceptors are protected from damage.2 3 4 We hoped that identifying the impact of bFGF on photoreceptors in such models might help identify actions of bFGF that mediate protection. The nerve-section model is attractive because the upregulation of the expression of bFGF protein is endogenous, but the retinal expression of other factors may also be changed, so that the effects observed may not be specific to bFGF. The eye-injection model is more specific to bFGF but involves structural damage to the eye. Taken together, present results suggest that bFGF induces specific functional changes in the retina, suppressing the b-wave while maintaining or enhancing the a-wave and upregulating the expression of proteins (CO, synaptophysin) closely related to the signaling function of photoreceptors. The contrast between the actions of bFGF in suppressing the b-wave while increasing the photoreceptors’ signaling capacity is striking, but the significance of the contrast and the link between these several effects and the protective action of bFGF remain enigmatic.
Present results confirm those in a previous report5 of upregulation of bFGF protein expression in the ONL of rat retina after section of the optic nerve. There appear, however, to be no previous reports of the effect of nerve section on the ERG of the rat. Several previous studies in the cat17 18 and rabbit19 reported no effect of nerve section on the major components of the ERG. One study20 reported a transient suppression of the rabbit ERG after nerve section. The present evidence of major effects of nerve section on the rat ERG may reflect a species difference or our choice to test the retina at the particular time (3–4 weeks after nerve damage) at which the protection of photoreceptors is optimal4 and the upregulation of bFGF protein expression in the ONL is prominent.5
Regulation of CO and Synaptophysin
The upregulation of the expression of CO and synaptophysin
proteins induced by nerve section and bFGF injection was unexpected but
consistent. The increase in CO protein was apparent in inner segments,
where the enzyme plays a major role in the high oxidative metabolism of
the inner segment mitochondria21
required to maintain the
function of the outer segment.22
23
The upregulation of
synaptophysin expression was prominent in the OPL, where the protein
forms part of the membrane of presynaptic vesicles24
in
the terminals of photoreceptor axons. The upregulation of CO expression
in the inner segments suggests that the cell is able to generate
adenosine triphosphate by oxidative metabolism in larger quantities and
may be supporting high levels of dark current through the outer
segments. If so, the cell should be able to generate a stronger than
normal a-wave. The upregulation of synaptophysin expression in the OPL
suggests that synaptic vesicles are more numerous than usual in the
axon terminals of the photoreceptors. Their accumulation could result
from an increase in vesicle formation or from a slowing of their
release.
Suppression of the b-Wave: Site and Mechanism
The most likely site at which bFGF could selectively suppress the
b-wave would seem to be the OPL, but present results provide only
limited evidence of the mechanisms involved. bFGF may reduce the
light-induced modulation of the photoreceptors’ release of glutamate,
consistent with the bFGF-induced accumulation noted earlier of
synaptophysin-labeled structures, presumably vesicles, in the OPL.
Alternatively, bFGF may block the binding of glutamate to its receptors
on bipolar cells. Present evidence that both ON and OFF components of
the ERG were reduced by bFGF (Fig. 2A)
indicates that signals generated
through both metabotropic (ON) and ionotropic (OFF) glutamate receptors
in bipolar cells (reviewed in Ref. 25)
are both attenuated by increases
in bFGF protein levels. Further analysis of the action of bFGF requires
additional study, however. Recent evidence26
that the
growth factor brain-derived neurotrophic factor (BDNF) can upregulate
the expression of Ca2+ channels in motoneurons
raises the possibility that bFGF may regulate channel densities in
retinal neurons, but this possibility also requires further study.
Suppression of the b-Wave: Implications
The suppression of the b-wave induced by bFGF was clearest in
response to stimuli with the low contrast levels common in normal
vision. It seems possible therefore that increases in the levels of
bFGF protein in the retina degrade normal vision. If bFGF levels are
raised in the dystrophic human retina, as in the dystrophic rat and
mouse,9
10
then one component of the blindness of
retinitis pigmentosa may be a reversible bFGF-induced suppression of
the ability of surviving photoreceptors to activate the inner layers of
the retina. Human retina expresses bFGF,27
although there
is as yet no evidence of (or against) upregulation of bFGF expression
in human retinitis pigmentosa. Conversely if, as we have argued
elsewhere,13
photoreceptors surviving in dystrophic
retinas are under constant stress and stress upregulates bFGF protein
expression (reviewed in the introduction), then measures that relieve
that stress may not only slow the dystrophy but may, by reducing bFGF
levels, lead to a limited improvement in visual performance.
Regulation of bFGF Protein Levels
Comparison of the bFGF protein levels in the retina (Figs. 7A
7B) with bFGF mRNA levels (Figs. 7C
7D)
was surprising in two
ways. First, bFGF protein concentrates markedly in Müller somas
of the INL, whereas the mRNA is more diffusely distributed in
apparently all cells of the layer. This seems to suggest that the high
level of bFGF protein in Müller cells is the result of a
posttranslational movement of bFGF into Müller cells. The
mechanism of such movement is not known, and its function can only be
guessed. One possibility is that Müller cells store bFGF until
the retina is stressed or damaged, and then distribute it by way of
their extensive processes.
Second, we consistently observed major differences between nerve-sectioned and nerve-intact retinas in the levels of bFGF protein in the ONL and inner segments (Figs. 8A 8B 8C) and little difference, if any, in mRNA levels (Figs. 8D 8E 8F) . This contrast suggests that these differences in protein levels also result from posttranslational mechanisms, such as an increase in the stability of bFGF storage in the nerve-sectioned retina or the movement into the neural retina of bFGF generated in nearby structures, such as the retinal pigment epithelium. The regulation of bFGF expression by nerve section follows a slow course, requiring weeks to reach its maximum,5 so that even a limited increase in storage stability could produce major increase in bFGF protein levels. The abnormal distributions of bFGF protein observed in nerve-intact retinas from some nerve-section experiments were surprising and suggest some loss of bFGF stability in these retinas. The reason for such loss remains unclear, however.
How Does Optic Nerve Damage Affect the ONL?
Bush and Williams4
were the first to note an effect
of nerve section on photoreceptors, reporting that nerve section
protects photoreceptors from light damage. Their article and that of
Kostyk et al.5
showed, and the present results have
confirmed a centrifugal effect. What is its mechanism?
Three possibilities can be considered. One is that the effect is mediated by centrifugal neural pathways. Such pathways are not prominent in mammals, however, and those that have been described do not reach the ONL.28 A second possibility is retrograde transmission of a damage signal by the ganglion cells that reaches all regions of the retina. The dendrites of ganglion cells reach no deeper than the IPL, however. In either case, therefore, some further mechanism, such as the spread of the signal through Müller cells, would have to be invoked to account for transmission of the signal to the ONL. There is evidence of such spread, seen in the widespread upregulation in Müller cells of the expression of GFAP protein, after localized retinal damage.29 The third possibility is that nerve section activates a population of mobile cells, perhaps microglia, which migrate from the site of surgery through the retina, carrying the signal that induces the upregulation of bFGF protein expression in the retina.
Mechanical10 and light damage,11 30 laser burns,7 8 and hypoxia15 all cause photoreceptor damage, and all also cause an increase of bFGF protein in photoreceptors. When the damage is localized, as with needle-stick and laser burn injuries, the increases in bFGF protein levels is correspondingly localized. The signal released by nerve section may activate the same mechanisms of bFGF concentration.
Is There a Price for Protection?
The present results raise the question of whether the suppression
of the b-wave induced by bFGF is tightly linked to the protection also
provided by bFGF so that, teleologically, loss of function is the price
of protection. As yet, however, evidence is insufficient to answer the
question. Understanding of this linkage may be important in
understanding the protection provided by trophic factors and their
potential value in the treatment of photoreceptor dystrophies.
Acknowledgements
The authors thank Giulio Cappagli and Tania Novikova for skilled technical assistance.
Footnotes
Reprint requests: Professor Luigi Cervetto, Istituto di Neurofisiologia, CNR, Via S. Zeno 51, 56100 Pisa, Italy.
Supported by the Australian Retinitis Pigmentosa Association, the National Health and Medical Research Council of Australia; the Medical Foundation of the University of Sydney; Integrated project UNI/CNR, Italy (97.02454.PS04); and Telethon-Italy (Grant E.746).
Submitted for publication December 2, 1998; revised March 19, 1999; accepted April 12, 1999.
Proprietary interest category: N.
References
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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]
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A. R. Caffe, A. K. Soderpalm, I. Holmqvist, and T. van Veen A Combination of CNTF and BDNF Rescues rd Photoreceptors but Changes Rod Differentiation in the Presence of RPE in Retinal Explants Invest. Ophthalmol. Vis. Sci., January 1, 2001; 42(1): 275 - 282. [Abstract] [Full Text]
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D. Lau, L. H. McGee, S. Zhou, K. G. Rendahl, W. C. Manning, J. A. Escobedo, and J. G. Flannery Retinal Degeneration Is Slowed in Transgenic Rats by AAV-Mediated Delivery of FGF-2 Invest. Ophthalmol. Vis. Sci., October 1, 2000; 41(11): 3622 - 3633. [Abstract] [Full Text]
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