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Articles |
Intravitreal Injection of Ganglioside GM1 After Ischemia Reduces Retinal Damage in Rats
From the Laboratoire de Physiopathologie Rétinienne, INSERM CJF 92-02, Université Louis Pasteur, Strasbourg, and Clinique Ophthalmologique, Centre Hospitalo–Universitaire de Nantes (M.W., J.A.S.) (France).
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Abstract |
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Background and Purpose Gangliosides are normal components of cell membranes and contribute to structural rigidity and membrane function. They have been shown to protect against various insults in the brain. We have shown previously that GM1 administered intraperitoneally before the induction of retinal ischemia provides a protective effect. This study evaluates the protective effect of GM1 administered intravitreally after ischemia on retinal lesions.
Methods We induced retinal ischemia unilaterally in Long-Evans rats by increasing intraocular pressure to 160 mm Hg for 60 minutes. GM1 (20 µL · 10-5 mol/L) or saline (20 µL) was injected into the vitreous 15 minutes after ischemia, and the postischemic survival time was either 8 or 15 days. The degree of retinal damage was assessed by histopathological study.
Results Retinal ischemia led to reductions in thickness and cell number, principally in the inner retinal layers (39% to 80%) and to a lesser extent in the outer retinal layers (26% to 45%). Postischemic treatment with intravitreally injected GM1 conferred significant protection against retinal ischemic damage after both 8 and 15 days of survival time. After 8 days of reperfusion, the ischemia-induced loss in overall retinal thickness was reduced by 15% and those of the inner nuclear and plexiform layers by 44% and 17%, respectively. Ischemic-induced ganglion cell and inner nuclear cell density losses were reduced by 37% and 27%, respectively. After 15 days of reperfusion, approximately the same statistically significant differences could be observed in comparison with the 15-day saline-injected group.
Conclusions GM1 protects the rat retina from pressure-induced ischemic injury when given intravitreally after the insult. The protection provided by GM1 after initiation of retinal damage could be of therapeutic interest.
Key Words: animal models • gangliosides • neuroprotection • retina • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Gangliosides are glycosphingolipid components abundant in neuronal tissue,1 where they influence functional dynamics of the cellular membranes in several ways: they contribute to the structural rigidity of membranes, they are involved in the transfer of information between neighboring cells or between cell surfaces and the extracellular environment (neurotransmitters, hormones), and they modulate cell growth by regulating proliferative and maturational processes controlled by polypeptide growth factors.2 It has been shown that exogenously administered gangliosides can cross the blood-brain barrier, insert into plasma membranes, and be functional after their incorporation.3 4
In experimental models of cerebral ischemia, monosialoganglioside GM1 partially reduces ischemic neuronal damage.5 6 The mechanisms underlying this neuroprotection are not completely understood but may be related to protective effects on neuronal function, expressed as maintenance of Na+,K+-ATPase activity7 ; to blockade of excitatory amino acid–mediated neurotoxic- ity (both prevention of ischemia-induced downregulation of protein kinase C and reduction of membrane protein phosphorylation induced by toxic doses of glutamate, leading to a decrease in ischemia-induced intracellular calcium elevation and glutamate toxicity)8 9 10 ; and to response potentialization toward neurotrophic factors11 12 13 produced locally in increased quantities as a biochemical response to injury.14 15 GM1 also increases regeneration of crush-injured axons of the mammalian optic nerve.16 17
Recently, we have shown that GM1 administered intraperitoneally before the experimental induction of retinal ischemia provides a significant protective effect.18 However, in clinical situations such as acute ischemic retinal cell damage, a therapeutic approach would obviously need to be attempted after the initiation of the ischemic insult. Given the biological effects of gangliosides stated earlier, it is plausible that they could be effective even after the initial events of ischemic damage. Moreover, in view of both the impairment of blood supply to the eye in this experimental condition and of the side effects of systemic administration of gangliosides,19 20 21 an intravitreal injection might be more appropriate while limiting the risk of side effects.
To estimate the protective role of postischemic intravitreal injection of monosialoganglioside GM1, we performed histopathological studies on ischemia-induced lesions in the rat retina, with or without the use of GM1. We show that such treatments also significantly protect rat retina against ischemic damage.
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Materials and Methods |
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Experimental Protocol
Long-Evans rats (weight, 250 to 350 g) were assigned to one of three groups: group 1 (untreated): no retinal ischemia was induced, and no intravitreal injections were performed (n=5); group 2 (saline): retinal ischemia was induced, and the animals received an intravitreal injection of PBS vehicle (20 µL) 15 minutes after ischemia (n=8); and group 3 (GM1): retinal ischemia was induced, and the animals received an intravitreal injection of GM1 (20 µL · 10-5 mol/L) 15 minutes after ischemia (n=8).
All procedures involving rats adhered to the Association for Research in Vision and Ophthalmology Resolution on the Use of Animals in Research.
Ischemia Model and Histological Procedures
Fifteen minutes after the rat was anesthetized with an
intraperitoneal injection of 6% sodium pentobarbital (0.1 mL/100 g),
topical anesthetic (oxybuprocaine chlorhydrate) was applied to the eye.
The pupils were dilated with an eye drop of phenylephrine chlorhydrate
and tropicamide. A 30.5-gauge needle attached to a manometer/pump
assembly was inserted into the anterior chamber and sealed with
cyanoacrylate cement. The pressure in the eye was raised to 160
mm Hg for 60 minutes with air. Retinal ischemia was confirmed
by whitening of the fundus. After 60 minutes, the needle and
cyanoacrylate cement were removed.
The animals received saline or GM1 15 minutes after the end of the retinal ischemia and then were allowed to recover and survive for 8 days (n=4 in saline group and n=4 in GM1 group) or 15 days (n=4 in saline group and n=4 in GM1 group). After 8 or 15 days of reperfusion, the rats were killed with an overdose of sodium pentobarbital. The eye of interest was immediately enucleated and fixed overnight by immersion in Bouin's solution. After the eye was rinsed in a phosphate buffer, it was dehydrated, embedded in paraffin, sectioned with a microtome at 4 µm thickness, and finally stained with hematoxylin and eosin. Each section cut along the horizontal meridian of the eye contained all of the retina extending from the ora serrata in the temporal hemisphere to the ora serrata in the nasal hemisphere, while passing through the optic nerve head.
Quantification of Ischemic Damage and Rescue
To quantify the degree of cell loss due to ischemic
retinal damage, we measured different thicknesses (expressed in
micrometers) and cell densities (expressed as number of nuclei in a
50-µm-wide band) according to Hughes' quantification of
ischemic damage in the rat retina22 (Fig 1
).
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We measured the thickness of the overall retina from the outer to the
inner limiting membrane (OLM-ILM) and of the outer nuclear layer (ONL)
and outer plexiform layer (OPL) (pooled together as outer retinal
layers, ORL), inner nuclear layer (INL), and inner plexiform layer
(IPL) (Fig 1
). Nuclear cell density was defined as the number of cell
nuclei within a 50-µm-wide sector of each of the three nucleated
layers (ONL, INL, and ganglion cell layer [GCL]).
These parameters were measured, subsequent to a masking procedure, on retinal sections examined with an optical microscope (x40 objectives) and then digitalized by a CCD camera on a computer screen (Macintosh LC II Ci) with the aid of an Optiscan image analysis system. For each thickness and density, four sets of three measurements were determined in both the temporal and nasal hemispheres, giving a total of 24 measurements for each parameter. In this way, for each eye the entire retinal section was sampled while the differences in thickness and density in the posterior and peripheral regions of the retina were taken into account.23 These measurements, evaluated subsequent to a masking procedure by two of the authors (S.M.-S., M.W.), did not differ by more than 5%.
Statistical Analysis
Since the variables under evaluation do not follow a normal
distribution, all data were analyzed with the use of the Mann-Whitney
nonparametric test with BMDP Statistical Software (1993 version,
University of California, Berkeley).
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Results |
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Eight Days of Reperfusion
Saline-Treated Rats
Histological examination showed that the overall thickness of the retina was much less than in normal animals (Fig 2
). The
decrease in retinal thickness was due primarily to a loss of inner
retinal cells and processes, with less obvious changes in the outer
retina. Measurements of the various retinal layers confirmed the
histological observations. The overall thickness of the OLM-ILM was
reduced by approximately 44% in comparison with normal retina; the two
retinal layers that were reduced the most were the IPL (reduction by
75% of normal, P<.05) and the INL (reduction by 35% of
normal, P<.05). The ORL was reduced by 25% with respect to
normal (P<.05) (Fig 3). Cell densities also
confirmed the loss of inner cells after retinal ischemia: in
the ischemic group, GCL density was reduced by 60% of normal
(P<.05), INL density by 45% of normal (P<.05),
and ONL density by 30% of normal (P<.05) (Fig 3).
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Animals Treated With GM1
We observed clear protection of the retina from ischemic
damage: the GM1-treated animals showed a well-preserved architecture
with thicker inner retinal layers than the saline-injected animals (Fig 2). Measurements of layer thicknesses and cell densities of the
GM1-treated animals confirmed quantitatively that GM1 alleviated the
ischemia-induced injury (Fig 3). The overall thickness
(OLM-ILM) was not significantly greater than that in the
saline-injected animals (P>.05).
The IPL and INL thicknesses were significantly greater than those of the saline-treated group (P<.05), with ischemia-induced thickness losses diminished by 17% and 44%, respectively. Although loss in the ORL thickness was slightly greater in the GM1 group, this was not statistically significant compared with the saline group (P>.05). The cell densities were significantly greater than those of the saline group, with ischemia-induced GCL and INL cell density losses reduced by 37% and 27%, respectively. The ONL cell density loss was not reduced in GM1-treated animals.
Fifteen Days of Reperfusion
Saline-Injected Animals
All retinal thicknesses and densities were significantly reduced
in comparison with nonischemic retinas (P<.05) and
were not statistically different from 8 days after ischemia.
Overall thickness was reduced by 45% with respect to normal; IPL and
INL were reduced by 75% and 40%, respectively; and ORL thickness was
reduced by 30% (Fig 4). Similarly, the GCL, INL, and
ONL densities were reduced by 70%, 50%, and 30%, respectively,
compared with normal (Fig 4).
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Animals Treated With GM1
For all retinal thicknesses and densities apart from those of the
ORL, there was a statistically significant difference between the
saline-treated and GM1-treated 15-day postischemic groups
(P<.05) (Fig 4), as observed at 8 days of reperfusion. The
losses due to ischemia were blocked by 8% to 35%, which was
approximately 10% less than after 8 days of reperfusion.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As in earlier studies, we observed that pressure-induced retinal ischemia in the rat eye causes a decrease in thickness and loss of cells of the inner retina.22 23 The IPL thickness was the most reduced (75% in our study, 73% in the study of Hughes22 ) and provided a sensitive indication of neuronal damage in the adjacent nucleated layers. Highly significant decreases in nuclear densities were measured in the INL (50% loss) and in the GCL (70% loss). As also seen by Hughes, we observed a smaller but nevertheless significant decrease in ONL cell density (30% after 8 and 15 days of reperfusion). According to Hughes, this ONL density decrease is due to increased Müller glial cell volume through osmotic swelling rather than neuronal cell loss.
Measurements of retinal damage were performed along a nasal-temporal axis in the present study. Differences in the degree of light-induced photoreceptor damage between the superior and the inferior halves have been observed in rat retina,24 but such differences are less likely to exist in ischemic inner retinal damage because of the relatively uniform vascularization of the rat retina.25 In addition, Hughes22 did not report any regional differences in ischemic damage when measured along the vertical meridian. The greater damage to inner retinal neurons in the rat could be attributed to the greater proximity of these cells to the retinal circulation22 and/or to the widespread distribution of glutamatergic receptors in the inner retina.24 25 To date, the expression and distribution of four NMDA, four AMPA, and three high-affinity kainate receptor subunits have been described in the adult rat retina.26 27
The photoreceptors do not receive glutamatergic input and therefore are largely refractory to excitotoxic-mediated cell death.
Ischemia and reperfusion of neuronal tissue lead to the excessive generation of excitatory amino acids and free radicals that produce neuronal damage, predominantly through a massive intracellular influx of Ca2+.28 This Ca2+ overload leads to cell damage and death through the activation of enzymes such as lipases, proteases, and endonucleases that degrade cell membranes and organelles. In the case of retinal ischemia, the mechanism(s) by which GM1 permits protection against ischemic injury is not clear, although it has been implicated in decreasing the damage caused by elevated intracellular Ca2+ levels due to excitatory amino acids in other systems. The effects of gangliosides may conceivably take place at those amplification steps after the initiation of the ischemic process.29 30 31 32 33 Therefore, they could be effective even after the primary events of ischemic damage in clinical situations such as acute retinal ischemia.
Our results presented here indicate that monosialoganglioside GM1 injected into the vitreous, after induction of retinal ischemia, can significantly reduce development of retinal ischemic injury at 8 and 15 days after ischemia. The diminution of ischemia-induced loss by GM1 was observed essentially for the inner retinal layers with significant protection of INL thickness and density, IPL thickness, and GCL density. These regions are the most vulnerable to excitotoxicity, as has been shown by the majority of reports on retinal excitotoxicity.26 27 The rationale for the choice of the particular ganglioside species (GM1) and the dose used (10-5 mol/L) was based on data obtained from studies conducted on the brain.5 6 However, mammalian retinal ganglioside composition is substantially different from that of the brain with, for example, much less GM1 and much more disialoganglioside GD3 being found in the former.34 35 Further experiments to determine the degree of protection of other gangliosides will thus be of interest.
Although in the previous study intraperitoneal injections provided slightly better protection,18 intravitreal GM1 injections may be preferable. Indeed, the close match of saline-injected controls in the present study with those of the previous study18 indicates that injection of substances per se into the vitreous is not deleterious to inner retinal physiology. An intravitreal approach could make possible not only avoidance of adverse systemic effects, as observed in clinical trials (Guillain-Barré syndrome and demyelinative neuropathies),19 20 21 but also increased targeting of GM1 directly to the more vulnerable inner retinal layers, even when the retinal circulation is interrupted. Moreover, in ischemic conditions direct intravitreal injection might be the only useful method of delivery in view of the impairment of vascular supply to the retina.22 23
In conclusion, although the mechanism(s) of protection of GM1 in the context of retinal ischemia remains undefined by this study, GM1 treatment significantly reduces structural changes after ischemic insults to rat retina, suggesting that GM1 is a potential therapeutic modality for combating retinal ischemia. The observed protection afforded by postischemic intravitreal GM1 injection strengthens the clinical interest of such experimental paradigms and provides a more timely and appropriate pharmacokinetic approach.
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Selected Abbreviations and Acronyms |
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-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
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Acknowledgments |
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This study was supported in part by a European Human Capital Mobility Network grant and by funding from the Direction des Recherches, Etudes et Techniques–Délégué Général pour l'Armement and Institut National de la Santé et de la Recherche Médicale (INSERM). The authors would like to thank C. Bornier for technical assistance and F. Stoeckel for photographic work.
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Footnotes |
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Reprint requests to José Alain Sahel, Laboratoire de Physiopathologie Rétinienne, Clinique Ophtalmologique, Centre Hospitalo–Universitaire de Strasbourg, 1 place de l'hopital, 67091 Strasbourg cedex, France.
Received October 7, 1996; revision received December 4, 1996; accepted December 6, 1996.
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