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Protection by Eliprodil Against Excitotoxicity in Cultured Rat Retinal Ganglion Cells

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Protection by Eliprodil Against Excitotoxicity in Cultured Rat Retinal Ganglion Cells Protection by Eliprodil against Excitotoxicity in Cultured Rat Retinal Ganglion Cells Iok-Hou Pang,1 Eric M. Wexler,2 Scott Nawy,2 Louis DeSantis,1 and Michael A. Kapin1 PURPOSE. TO test whether eliprodil (SL 82.0715), a unique antagonist for the N-methyl-D-aspartate (NMDA) receptor, is protective in the glutamate-induced cytotoxicity model in cultured rat retinal ganglion cells (RGCs). METHODS. TWO to four days after a fluorescent dye, Di-I, was injected near the superior colliculi, neonatal rats were killed, and retinal cells were dissociated and cultured. Survival of RGCs after drug treatment was assayed by counting Di-I fluorescent cells. RESULTS. In rat RGCs, glutamate-induced toxicity with a mean EC50 of 10.7 JUM. Only 47% of RGCs survived after a 3-day treatment with 100 JUM glutamate. Studies using selective agonists and antagonists indicated that the glutamate-induced toxicity was mediated largely by the NMDA receptor. Pretreatment with eliprodil protected against such toxicity. Eliprodil exhibited a mean IC50 of 1.0 nM (log [IC50] = -9.00 ± 0.01, mean ± SEM, n = 3; against cell death produced by 100 /xM glutamate). At 1 /xM, eliprodil was maximally protective; cell survival in the presence of 100 piM glutamate challenge was 100% ± 5% (n = 3). This protective effect of eliprodil may be related to its reduction (by 78%) of NMDA-induced currents recorded under patch-clamp recording in these cells. CONCLUSIONS. Eliprodil is protective against glutamate cytotoxicity in retinal neurons. It may be a useful novel compound for the treatment of retinopathies including glaucoma in which excitotox- icity has been implicated. (Invest Ophthalmol Vis Sci. 1999;40:1170-1176) any pathologic changes in the retina and optic nerve treatment, a single intravitreal injection of glutamate or N- head, such as damage related to glaucoma or isch- methyl-D-aspartate (NMDA) in adult rats induces a dose-depen- emia, are thought to be mediated in part by excita- dent loss of cells in the GCL, without obvious alterations in the M 6 8 tory amino acids (EAA). For example, high intraocular pressure more distal retinal layers. " Such toxicity is blocked by has been regarded as an important risk factor for glaucomatous MK801, an NMDA receptor antagonist.6 In vitro studies using optic neuropathy. In ocular hypertensive monkeys, glutamate chick retina or isolated rat retinal ganglion cells (RGCs) also concentration in the vitreous was found to significantly in- showed that EAAs produce cytotoxicity that can be antago- crease compared with ocular normotensive eyes.1 Similarly, nized by pretreatment with antagonists for EAA receptors.9""' elevated vitreal glutamate concentration was also observed in In addition to glaucoma, retinal ischemia can also lead to open-angle glaucoma patients.' Excessive EAA is toxic to cells EAA-mediated retinal cell injury.15 In rabbits, retinal ischemia, in the retina, especially ganglion cells. Lucas and Newhouse2 induced by raising intraocular pressure, causes a reduction in demonstrated that systemic administration of glutamate in electroretinogram b-wave amplitude. Pretreatment with dex- young mice, whose blood-retina barrier is yet to be completed, tromethorphan, a weak NMDA receptor antagonist, enhances destroyed the inner retinal layers, primarily the ganglion cell the postischemic recovery of b-wave amplitude, suggesting the layer (GCL). More recent light microscopic and electron mi- involvement of NMDA receptors in this functional change of croscopic studies corroborated such findings.3"5 Azuma et al.3 the retina.l6 In agreement with this finding, a twofold increase further reported that treatment of neonatal rats with subcuta- of glutamate release in the rabbit vitreous has been detected neous glutamate caused a "deeply excavated" optic disc, a during retinal ischemia, and a sevenfold increase in glutamate condition characteristic of glaucoma. In addition to systemic release has been observed during initial reperfusion after re- lease of intraocular pressure.17 For the time being, the origin and mechanisms of this glutamate release are still unclear. However, it is believed that prolonged deprivation of oxygen From the 'Alcon Laboratories, Fort Worth, Texas; the depart- ment of Ophthalmology and Visual Sciences, Albert Einstein College of and nutrients to neuronal tissues leads to cell membrane de- Medicine, Bronx, New York. polarization, which, in turn, increases synaptic release of EAA Supported by Alcon Laboratories, Fort Worth, Texas. and reduces EAA reuptake, together resulting in a buildup of Presented in part at the annual meeting of the Association for extracellular EAA, causing lethal injury to sensitive neuronal Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 18 1997, and of the Society for Neuroscience, San Diego, California, cell types. November 1996. Eliprodil (SL 82.0715) is a potent, noncompetitive NMDA Submitted for publication March 27, 1998; revised July 29, 1998; receptor antagonist.19'20 It has been shown to be protective accepted September 21, 1998. against ischemia-induced neuronal death, while lacking many Proprietary interest category: E. Reprint requests: Iok-Hou Pang, Alcon Laboratories, R3-24, 6201 of the central nervous system side effects characteristic of 19 20 South Freeway, Fort Worth, TX 76134. other EAA antagonists, ' making it a good candidate for Investigative Ophthalmology & Visual Science, May 1999, Vol. 40, No. 6 1170 Copyright © Association for Research in Vision and Ophthalmology Downloaded from jov.arvojournals.org on 09/27/2021 IOVS, May 1999, Vol. 40, No. 6 Eliprodil Protects Retinal Ganglion Cells 1171 chronic retinoprotective therapy. Therefore, we assessed the Di-I-labeled fluorescent cells in 20 microscopic fields were effects of eliprodil on EAA-induced neuronal conductance and counted and averaged. delayed neuronal death of cultured rat RGCs. Electrophysiology of RGCs The cell-culturing technique used in the electrophysiological studies was slightly different from that involved in the survival MATERIALS AND METHODS studies. Retinae from newborn rats were isolated and incu- RGCs isolated from neonatal Sprague-Dawley rats were used in bated for 1 hour in 5 U/ml papain dissolved in DMEM contain- ing 25 mM Hepes and supplemented with 1.5 mM cysteine, 0.5 survival and electrophysiological studies. The treatment of an- 2+ imals and procedures used in these studies conformed to the mM EDTA, and 2 mM Ca . They were then gently triturated ARVO Statement on the Use of Animals in Ophthalmic and through a fire-polished Pasteur pipette and resuspended in Vision Research. growth medium containing DMEM, 2 mM glutamine, 17 mM KC1, 5% heat-inactivated fetal calf serum, and serum supple- ment (MITO; Collaborative Research, Grand Island, NY). Cells RGC Survival Assay were grown on glass coverslips coated with poly-D-lysine in Techniques for the isolation and culture of RGCs were adapted 24-well plates. 21 from those reported by Takahashi et al. The procedure in- Patch pipettes were pulled from hematocrit glass, fire- volved retrograde labeling of ganglion cells by injecting a polished to a resistance of 2 Mil to 4 Mil, and filled with a fluorescent dye, Di-I, into the superior colliculi. Two to 4 days solution containing NaH2PO4 120 mM, NaCl 10 mM, Hepes 10 later, retinal cells were dissociated. Cultured RGCs were iden- mM, EGTA 10 mM, and MgATP 4 mM. The extracellular solu- tified by sufficient Di-I fluorescence to allow them to be tion contained NaCl 160 mM, CaCl2 2 mM, and Hepes 5 mM. observed visually using a fluorescence microscope. The de- The pH values of both solutions were adjusted to 7.4 with tailed procedures follow. NaOH. Recordings were obtained using an Axopatch ID am- Neonatal Sprague-Dawley rats 2 to 5 days old were anes- plifier. Drugs were applied via a series of computer-controlled thetized by chilling on ice for 10 minutes, after which, a 2-mm flow pipes (outer diameter, 358 /am). midline opening was made in the scalp just caudal to the Whole-cell recordings were obtained from RGCs cultured traverse sinus. The tip of the injection needle (30-gauge) was for 10 to 14 days. Ganglion cells were distinguished from inserted 6 mm below top of the skull, and a 5-JLII Di-I solution, amacrine cells, the other class of neurons with regenerative containing 3 mg/ml Di-I (l,l'-dioctadecyl-3,3,3',3'-tetrameth- sodium currents, by their greater size and larger resting poten- ylindo-carbocyanine perchlorate; Molecular Probes, Eugene, tial, and a more slowly accommodating action potential.22 OR) in 90% ethanol and 10% dimethyl sulfoxide, was injected. Virtually every ganglion cell examined at this age responded to The wound was then covered with a drop of Flexible Collo- NMDA. dion (Amend Drug & Chemical, Irvington, NJ). Rats were returned to their mother after warming and recovery from Test Compounds anesthesia. Glutamate, quisqualate, NMDA, and MK801 (dizocilpine) were Two to 4 days after Di-I injection, rats were anesthetized obtained from Research Biochemicals (Natick, MA). Eliprodil by hypothermia and killed by decapitation. Their eyes were HC1 was provided by Synthelabo Recherche (Bagneux, enucleated and placed in Dulbecco's modified Eagle's medium: France). All other chemicals were obtained from Sigma Chem- Nutrient mixture F12 (1:1, DMEM/F12; Gibco, Grand Island, ical. NY). The retina from each eye was detached and isolated. Retinal cells were dissociated by combining 12 retinae with 5 ml of papain solution, containing 10 mg papain (34 units/ml; RESULTS Sigma, St. Louis, MO), 2 mg DL-cysteine (33 mM; Sigma), and 2 mg bovine serum albumin (0.4 mg/ml; Sigma) in 5 ml of Retrograde uptake of the fluorescent dye Di-I after its injection DMEM/F12, for 25 minutes at 37°C, then washed 3 times with into the superior colliculi should label only ganglion cells in the 5 ml RGC medium (DMEM [Gibco], supplemented with 10% retina. Thus, the presence of Di-I fluorescence distinguished fetal bovine serum [Hyclone, Logan, UT], 4 mM glutamine RGCs from other retinal cells in culture (Fig.
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