Skip to main content
Erschienen in: Documenta Ophthalmologica 1/2009

01.02.2009

Testing retinal toxicity of drugs in animal models using electrophysiological and morphological techniques

verfasst von: Ido Perlman

Erschienen in: Documenta Ophthalmologica | Ausgabe 1/2009

Einloggen, um Zugang zu erhalten

Abstract

Drugs are frequently tested for retinal toxicity in animal models in order to address applied and basic research questions. When a retinal toxicity study is designed, the researcher needs to consider several factors depending on his/her research questions. Among the factors that need to be addressed before a toxicity study is conducted are: the animal species to be used, choice of experimental (functional and/or morphological) techniques, procedure of testing, period of follow-up, and modes of data analysis. This review is a summary of 20 years’ experience of studying retinal toxicity of different drugs in rabbits and rats. The use of the electroretinogram and the visual evoked potential for assessment of outer and inner retinal function, respectively, is described as well as the use of morphological techniques (histology, histochemistry, and immunocytochemistry). The advantages and limitations of functional and morphological techniques are discussed with specific examples from my experience. Recommendations for future drug toxicity studies are summarized.
Literatur
1.
Zurück zum Zitat Loewenstein A, Zemel E, Lazar M, Perlman I (1991) The effects of depo-medrol preservative (MGP) on the rabbit visual system. Invest Ophthalmol Vis Sci 32:3053–3060PubMed Loewenstein A, Zemel E, Lazar M, Perlman I (1991) The effects of depo-medrol preservative (MGP) on the rabbit visual system. Invest Ophthalmol Vis Sci 32:3053–3060PubMed
2.
Zurück zum Zitat Zemel E, Loewenstein A, Lazar M, Perlman I (1993) The effects of myristyl γ-picolinium chloride on the rabbit retina: morphologic observations. Invest Ophthalmol Vis Sci 34:2360–2366PubMed Zemel E, Loewenstein A, Lazar M, Perlman I (1993) The effects of myristyl γ-picolinium chloride on the rabbit retina: morphologic observations. Invest Ophthalmol Vis Sci 34:2360–2366PubMed
5.
Zurück zum Zitat Ivanina TA, Zueva MV, Lebedeva MN, Bogoslovsky AI, Bunin AJ (1983) Ultrastructural alterations in rat and cat retina and pigment epithelium induced by chloroquine. Graefes Arch Clin Exp Ophthalmol 220:32–38. doi:10.1007/BF02307013 CrossRefPubMed Ivanina TA, Zueva MV, Lebedeva MN, Bogoslovsky AI, Bunin AJ (1983) Ultrastructural alterations in rat and cat retina and pigment epithelium induced by chloroquine. Graefes Arch Clin Exp Ophthalmol 220:32–38. doi:10.​1007/​BF02307013 CrossRefPubMed
7.
Zurück zum Zitat Sankar R, Wasterlain CG (1999) Is the devil we know the lesser of two evils? Vigabatrin and visual fields. Neurology 52:1537–1538PubMed Sankar R, Wasterlain CG (1999) Is the devil we know the lesser of two evils? Vigabatrin and visual fields. Neurology 52:1537–1538PubMed
8.
Zurück zum Zitat Butler WH, Ford GP, Newberne JW (1987) A study on the effects of vigabatrin on the central nervous system and retina of Sprague Dawley and Lister-Hooded rats. Toxicol Pathol 15:143–148PubMed Butler WH, Ford GP, Newberne JW (1987) A study on the effects of vigabatrin on the central nervous system and retina of Sprague Dawley and Lister-Hooded rats. Toxicol Pathol 15:143–148PubMed
9.
Zurück zum Zitat Kjellström U, Kjelleström S, Bruum A, Andreasson S, Ponjavic V (2006) Retinal function in rabbits does not improve 4–5 months after terminating treatment with vigabatrin. Doc Ophthalmol 112:35–41. doi:10.1007/s10633-006-0004-z CrossRefPubMed Kjellström U, Kjelleström S, Bruum A, Andreasson S, Ponjavic V (2006) Retinal function in rabbits does not improve 4–5 months after terminating treatment with vigabatrin. Doc Ophthalmol 112:35–41. doi:10.​1007/​s10633-006-0004-z CrossRefPubMed
10.
Zurück zum Zitat Tano Y, Chandler DB, Machemer R (1980) Treatment of intraocular proliferation with intravitreal injection of triamcinolone acetonide. Am J Ophthalmol 90:810–816PubMed Tano Y, Chandler DB, Machemer R (1980) Treatment of intraocular proliferation with intravitreal injection of triamcinolone acetonide. Am J Ophthalmol 90:810–816PubMed
11.
Zurück zum Zitat Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, Baumal C (2002) Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 109:920–927CrossRefPubMed Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, Baumal C (2002) Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 109:920–927CrossRefPubMed
13.
14.
Zurück zum Zitat Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthal Surg Laser Imaging 36:331–335 Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthal Surg Laser Imaging 36:331–335
15.
Zurück zum Zitat Armington JC (1974) The electroretinogram. Academic Press, New York Armington JC (1974) The electroretinogram. Academic Press, New York
16.
Zurück zum Zitat Berson EL (1981) Electrical phenomena in the retina. In: Moses RA (ed) Adler’s physiology of the eye. Mosby, St. Louis, pp 466–529 Berson EL (1981) Electrical phenomena in the retina. In: Moses RA (ed) Adler’s physiology of the eye. Mosby, St. Louis, pp 466–529
17.
Zurück zum Zitat Granit R (1933) The components of the retinal action potential in mammals and their relation to the discharge in the optic nerve. J Physiol 77:207–239PubMed Granit R (1933) The components of the retinal action potential in mammals and their relation to the discharge in the optic nerve. J Physiol 77:207–239PubMed
18.
Zurück zum Zitat Ripps H, Witkovsky P (1985) Neuron-glia interaction in the brain and retina. In: Osborne NN, Chader GJ (eds) Prog. Retinal Res. Pergamon, Oxford, pp 181–219 Ripps H, Witkovsky P (1985) Neuron-glia interaction in the brain and retina. In: Osborne NN, Chader GJ (eds) Prog. Retinal Res. Pergamon, Oxford, pp 181–219
21.
Zurück zum Zitat Robson JG, Frishman LJ (1995) Response linearity and kinetics of the cat retina: the bipolar cell component of the dark-adapted electroretinogram. Vis Neurosci 12:837–850PubMedCrossRef Robson JG, Frishman LJ (1995) Response linearity and kinetics of the cat retina: the bipolar cell component of the dark-adapted electroretinogram. Vis Neurosci 12:837–850PubMedCrossRef
26.
Zurück zum Zitat Sieving PA, Murayama K, Naarendorp F (1994) Push–pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave. Vis Neurosci 11:519–532PubMed Sieving PA, Murayama K, Naarendorp F (1994) Push–pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave. Vis Neurosci 11:519–532PubMed
28.
Zurück zum Zitat Holder GE (2001) Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis. In: Osborne NN, Chader GJ (eds) Prog. Retinal Eye Res. Elsevier, Amsterdam, pp 531–561 Holder GE (2001) Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis. In: Osborne NN, Chader GJ (eds) Prog. Retinal Eye Res. Elsevier, Amsterdam, pp 531–561
29.
Zurück zum Zitat Ben-Shlomo G, Bakalash S, Lambrou GN, Latour E, Dawson WW, Schwartz M, Ofri R (2005) Pattern electroretinography in a rat model of ocular hypertension: functional evidence for early detection of inner retinal damage. Exp Eye Res 81:340–349PubMed Ben-Shlomo G, Bakalash S, Lambrou GN, Latour E, Dawson WW, Schwartz M, Ofri R (2005) Pattern electroretinography in a rat model of ocular hypertension: functional evidence for early detection of inner retinal damage. Exp Eye Res 81:340–349PubMed
30.
Zurück zum Zitat Feghali JG, Jin J-C, Odom JV (1991) Effects of short-term intraocular pressure elevation on the rabbit electroretinogram. Invest Ophthalmol Vis Sci 32:2184–2189PubMed Feghali JG, Jin J-C, Odom JV (1991) Effects of short-term intraocular pressure elevation on the rabbit electroretinogram. Invest Ophthalmol Vis Sci 32:2184–2189PubMed
31.
Zurück zum Zitat Viswanathan S, Frishman LJ, Robson JG, Walters JW (2001) The photopic negative response of the flash electroretinogram in primary open angle glaucoma. Invest Ophthalmol Vis Sci 42:514–522PubMed Viswanathan S, Frishman LJ, Robson JG, Walters JW (2001) The photopic negative response of the flash electroretinogram in primary open angle glaucoma. Invest Ophthalmol Vis Sci 42:514–522PubMed
32.
Zurück zum Zitat Viswanathan S, Frishman LJ, Robson JG, Harwerth RS, Smith ELIII (1999) The photopic negative response of the macaque electroretinogram: Reduction by experimental glaucoma. Invest Ophthalmol Vis Sci 40:1124–1136PubMed Viswanathan S, Frishman LJ, Robson JG, Harwerth RS, Smith ELIII (1999) The photopic negative response of the macaque electroretinogram: Reduction by experimental glaucoma. Invest Ophthalmol Vis Sci 40:1124–1136PubMed
37.
Zurück zum Zitat Hood DC, Birch DG (1992) A computational model of the amplitude and implicit time of the b-wave of the human ERG. Vis Neurosci 8:107–126PubMed Hood DC, Birch DG (1992) A computational model of the amplitude and implicit time of the b-wave of the human ERG. Vis Neurosci 8:107–126PubMed
40.
Zurück zum Zitat Loewenstein A, Zemel E, Lazar M, Perlman I (1993) Drug-induced retinal toxicity in albino rabbits: effects of imipenem and aztreonam. Invest Ophthalmol Vis Sci 34:3466–3476PubMed Loewenstein A, Zemel E, Lazar M, Perlman I (1993) Drug-induced retinal toxicity in albino rabbits: effects of imipenem and aztreonam. Invest Ophthalmol Vis Sci 34:3466–3476PubMed
41.
Zurück zum Zitat Bignami A, Dahl D (1979) The radial glia of Müller in the rat retina and their response to injury: an immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein. Exp Eye Res 28:63–69. doi:10.1016/0014-4835(79)90106-4 CrossRefPubMed Bignami A, Dahl D (1979) The radial glia of Müller in the rat retina and their response to injury: an immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein. Exp Eye Res 28:63–69. doi:10.​1016/​0014-4835(79)90106-4 CrossRefPubMed
44.
Zurück zum Zitat Penn JS, Thum KA, Rhem MN, Dell SJ (1988) Effects of oxygen rearing on the electroretinogram and GFA-protein in the rat. Invest Ophthalmol Vis Sci 29:1623–1630PubMed Penn JS, Thum KA, Rhem MN, Dell SJ (1988) Effects of oxygen rearing on the electroretinogram and GFA-protein in the rat. Invest Ophthalmol Vis Sci 29:1623–1630PubMed
45.
Zurück zum Zitat Tassignon M-J, Stempels N, Nguyen-Legros J, De Wilde F, Brihaye M (1991) The effects of wavelength on glial fibrillary acidic protein immunoreactivity in laser-induced lesions in rabbit retina. Graefes Arch Clin Exp Ophthalmol 229:380–388. doi:10.1007/BF00170698 CrossRefPubMed Tassignon M-J, Stempels N, Nguyen-Legros J, De Wilde F, Brihaye M (1991) The effects of wavelength on glial fibrillary acidic protein immunoreactivity in laser-induced lesions in rabbit retina. Graefes Arch Clin Exp Ophthalmol 229:380–388. doi:10.​1007/​BF00170698 CrossRefPubMed
46.
Zurück zum Zitat Ekstrom P, Sanyal S, Narfstrom K, Chader GJ, van Veen T (1988) Accumulation of glial fibrillary acidic protein in Müller radial glia during retinal degeneration. Invest Ophthalmol Vis Sci 29:1363–1371PubMed Ekstrom P, Sanyal S, Narfstrom K, Chader GJ, van Veen T (1988) Accumulation of glial fibrillary acidic protein in Müller radial glia during retinal degeneration. Invest Ophthalmol Vis Sci 29:1363–1371PubMed
47.
Zurück zum Zitat Knowles RG, Palacois M, Palmer RM, Moncada S (1989) Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of soluble guanylate cyclase. Proc Natl Acad Sci USA 86:5159–5162. doi:10.1073/pnas.86.13.5159 CrossRefPubMed Knowles RG, Palacois M, Palmer RM, Moncada S (1989) Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of soluble guanylate cyclase. Proc Natl Acad Sci USA 86:5159–5162. doi:10.​1073/​pnas.​86.​13.​5159 CrossRefPubMed
48.
Zurück zum Zitat Oku H, Yamaguchi H, Sugiyama T, Kojima S, Ota M, Azuma I (1997) Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabbit. Invest Ophthalmol Vis Sci 38:2540–2544PubMed Oku H, Yamaguchi H, Sugiyama T, Kojima S, Ota M, Azuma I (1997) Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabbit. Invest Ophthalmol Vis Sci 38:2540–2544PubMed
49.
Zurück zum Zitat Sennlaub F, Courtois Y, Goureay O (2002) Inducible nitric oxide synthase mediates retinal apoptosis in ischemic proliferative retinopathy. J Neurosci 22:3987–3993PubMed Sennlaub F, Courtois Y, Goureay O (2002) Inducible nitric oxide synthase mediates retinal apoptosis in ischemic proliferative retinopathy. J Neurosci 22:3987–3993PubMed
50.
Zurück zum Zitat Barza M, McCue M (1983) Pharmacokinetics of aztreonam in rabbit eyes. Antimicrob Agents Chemother 24:468–473PubMed Barza M, McCue M (1983) Pharmacokinetics of aztreonam in rabbit eyes. Antimicrob Agents Chemother 24:468–473PubMed
52.
Zurück zum Zitat Green DG, Herreros de Tejada P, Glover MJ (1991) Are albino rats night blind? Invest Ophthalmol Vis Sci 32:2366–2371PubMed Green DG, Herreros de Tejada P, Glover MJ (1991) Are albino rats night blind? Invest Ophthalmol Vis Sci 32:2366–2371PubMed
53.
Zurück zum Zitat Zemel E, Loewenstein A, Lei B, Lazar M, Perlman I (1995) Ocular pigmentation protects the rabbit retina from gentamicin-induced toxicity. Invest Ophthalmol Vis Sci 36:1875–1884PubMed Zemel E, Loewenstein A, Lei B, Lazar M, Perlman I (1995) Ocular pigmentation protects the rabbit retina from gentamicin-induced toxicity. Invest Ophthalmol Vis Sci 36:1875–1884PubMed
54.
Zurück zum Zitat Barza M, Baum J, Kane A (1976) Inhibition of antibiotic activity in vitro by synthetic melanin. Antimicrob Agents Chemother 10:569–570PubMed Barza M, Baum J, Kane A (1976) Inhibition of antibiotic activity in vitro by synthetic melanin. Antimicrob Agents Chemother 10:569–570PubMed
56.
Zurück zum Zitat Chin GN, Almquist HT (1983) Bupivacaine and lidocaine retrobulbar anesthesia. A double blind clinical study. Ophthalmology 90:369–372PubMed Chin GN, Almquist HT (1983) Bupivacaine and lidocaine retrobulbar anesthesia. A double blind clinical study. Ophthalmology 90:369–372PubMed
57.
Zurück zum Zitat Loewenstein A, Zemel E, Vered Y, Lazar M, Perlman I (2001) Retinal toxicity of gentamicin after subconjunctival injection performed adjacent to thinned sclera. Ophthalmology 108:759–764CrossRefPubMed Loewenstein A, Zemel E, Vered Y, Lazar M, Perlman I (2001) Retinal toxicity of gentamicin after subconjunctival injection performed adjacent to thinned sclera. Ophthalmology 108:759–764CrossRefPubMed
59.
Zurück zum Zitat Burk SE, Da Mata AP, Snyder ME, Rosa RHJ, Foster RE (2000) Indocyanine green-assisted peeling of the retinal internal limiting membrane. Ophthalmology 107:2010–2014CrossRefPubMed Burk SE, Da Mata AP, Snyder ME, Rosa RHJ, Foster RE (2000) Indocyanine green-assisted peeling of the retinal internal limiting membrane. Ophthalmology 107:2010–2014CrossRefPubMed
60.
Zurück zum Zitat Eshita T, Ishida S, Shinoda K, Kitamura S, Inoue M, Oguchi Y, Yamazaki K (2002) Indocyanine green can distinguish posterior vitreous cortex from internal limiting membrane during vitrectomy with removal of epiretinal membrane. Retina 22:104–106. doi:10.1097/00006982-200202000-00018 CrossRefPubMed Eshita T, Ishida S, Shinoda K, Kitamura S, Inoue M, Oguchi Y, Yamazaki K (2002) Indocyanine green can distinguish posterior vitreous cortex from internal limiting membrane during vitrectomy with removal of epiretinal membrane. Retina 22:104–106. doi:10.​1097/​00006982-200202000-00018 CrossRefPubMed
61.
63.
Zurück zum Zitat Lang Y, Leibu R, Shoham N, Miller B, Perlman I (2007) Evaluation of intravitreal Kenalog toxicity in humans. Ophthalmology 114:724–731CrossRefPubMed Lang Y, Leibu R, Shoham N, Miller B, Perlman I (2007) Evaluation of intravitreal Kenalog toxicity in humans. Ophthalmology 114:724–731CrossRefPubMed
65.
Zurück zum Zitat Frishman LJ, Saszik S, Harwerth RS, Viswanathan S, Li Y, Smith EL III, Robson JG, Barnes G (2000) Effects of experimental glaucoma in macaques on the multifocal ERG. Multifocal ERG in laser-induced glaucoma. Doc Ophthalmol 100:231–251. doi:10.1023/A:1002735804029 CrossRef Frishman LJ, Saszik S, Harwerth RS, Viswanathan S, Li Y, Smith EL III, Robson JG, Barnes G (2000) Effects of experimental glaucoma in macaques on the multifocal ERG. Multifocal ERG in laser-induced glaucoma. Doc Ophthalmol 100:231–251. doi:10.​1023/​A:​1002735804029 CrossRef
Metadaten
Titel
Testing retinal toxicity of drugs in animal models using electrophysiological and morphological techniques
verfasst von
Ido Perlman
Publikationsdatum
01.02.2009
Verlag
Springer-Verlag
Erschienen in
Documenta Ophthalmologica / Ausgabe 1/2009
Print ISSN: 0012-4486
Elektronische ISSN: 1573-2622
DOI
https://doi.org/10.1007/s10633-008-9153-6

Weitere Artikel der Ausgabe 1/2009

Documenta Ophthalmologica 1/2009 Zur Ausgabe

Acknowledgments

List of reviewers

Neu im Fachgebiet Augenheilkunde

Update Augenheilkunde

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.