MK-801 has neuroprotective and antiproliferative effects in retinal laser injury.

PURPOSE Treatment of the retina by laser photocoagulation often is complicated by an immediate side effect of visual impairment, caused by unavoidable, laser-induced destruction of healthy tissue adjacent to the lesion. A neuroprotective therapy that salvages this healthy tissue might enhance the benefit obtained from the treatment. This study was proposed to determine whether glutamate-receptor blockers can provide adjuvant neuroprotection during laser photocoagulation. The effect of MK-801, an NMDA-receptor antagonist, on laser-induced retinal injury was examined, in a rat model. METHODS Argon laser lesions were created in the retinas of 36 DA rats, and were followed immediately by intraperitoneal injections of MK-801 (2 mg/kg) or saline. The animals were killed after 3, 20, or 60 days and the retinal lesions were evaluated histologically and morphometrically. RESULTS Photoreceptor-cell loss was significantly less in MK-801-treated rats than in control animals. The proliferative membrane composed of retinal pigment epithelial cells and neovascular blood vessels, which was seen at the base of the lesion in control group retinas, was smaller in the MK-801-treated retinas. In rats treated with a higher dose of MK-801, the lesions showed almost no proliferative reaction. CONCLUSIONS A potent noncompetitive NMDA-receptor blocker, MK-801 exhibits neuroprotective and antiproliferative properties in the retina. Glutamate-receptor blockers should be investigated further as potential adjuvant therapy in retinal photocoagulation treatments.

[1]  M A Rogawski,et al.  Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. , 1990, Pharmacological reviews.

[2]  S. Lipton,et al.  Greater sensitivity of larger retinal ganglion cells to NMDA-mediated cell death. , 1994, Neuroreport.

[3]  N. Sucher,et al.  N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  C. Casanova,et al.  Effects of dextromethorphan on ischemia induced electroretinogram changes in rabbit. , 1994, Current eye research.

[5]  J. Garthwaite,et al.  Excitatory amino acid neurotoxicity and neurodegenerative disease. , 1990, Trends in pharmacological sciences.

[6]  S M Podos,et al.  Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. , 1996, Archives of ophthalmology.

[7]  H. Wässle,et al.  Glutamate receptor expression in the rat retina , 1992, Neuroscience Letters.

[8]  J. Sturman,et al.  Excitatory amino acid receptors in membranes from cultured human retinal pigment epithelium. , 1994, Current eye research.

[9]  Robert N. Johnson,et al.  Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. , 1991, Archives of ophthalmology.

[10]  E. Yoles,et al.  HU-211, a nonpsychotropic cannabinoid, produces short- and long-term neuroprotection after optic nerve axotomy. , 1996, Journal of neurotrauma.

[11]  B. Siesjö,et al.  Mechanisms of ischemic brain damage , 1988, Critical care medicine.

[12]  D. Wallace,et al.  Excitatory amino acid involvement in retinal degeneration , 1990, Brain Research.

[13]  L. Facci,et al.  Excitatory amino acid neurotoxicity in cultured retinal neurons: Involvement of N‐methyl‐D‐Aspartate (NMDA) and Non‐NMDA receptors and effect of ganglioside GM1 , 1990, Journal of neuroscience research.

[14]  K. Lees,et al.  Clinical experience with excitatory amino acid antagonist drugs. , 1995, Stroke.

[15]  J. Wroblewski,et al.  Modulation of glutamate receptors: molecular mechanisms and functional implications. , 1989, Annual review of pharmacology and toxicology.

[16]  O. Lindvall,et al.  Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Choi,et al.  The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. , 1990, Annual review of neuroscience.

[18]  A. Ames,et al.  Effects of glucose and oxygen deprivation on function of isolated mammalian retina. , 1963, Journal of neurophysiology.

[19]  J. Olney THE TOXIC EFFECTS OF GLUTAMATE AND RELATED COMPOUNDS IN THE RETINA AND THE BRAIN , 1982, Retina.

[20]  A. Reder,et al.  MK-801 protects retinal neurons from hypoxia and the toxicity of glutamate and aspartate. , 1992, Investigative ophthalmology & visual science.

[21]  Bengt Anderberg,et al.  Battlefield laser weapons: An assessment of systems, hazards, injuries and ophthalmic resources required for treatment , 1991 .

[22]  B. Scatton Excitatory amino acid receptor antagonists: a novel treatment for ischemic cerebrovascular diseases. , 1994, Life sciences.

[23]  J. Marshall,et al.  A comparative histopathological study of argon and krypton laser irradiations of the human retina. , 1979, The British journal of ophthalmology.

[24]  S. Lipton,et al.  Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Faden,et al.  Pharmacological strategies in CNS trauma. , 1992, Trends in pharmacological sciences.

[26]  S. Massey,et al.  Chapter 11 Cell types using glutamate as a neurotransmitter in the vertebrate retina , 1990 .

[27]  S. Rothman,et al.  Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  R Birngruber,et al.  Clinical observations of six cases of laser injury to the eye. , 1989, Health physics.

[29]  別所 康全 Selective up-regulation of an NMDA receptor subunit mRNA in cultured cerebellar granule cells by K[+]-induced depolarization and NMDA treatment , 1994 .

[30]  Keizo Yoshida,et al.  Non-competitive NMDA antagonists, FR115427 and MK801, enhance neuronal survival in primary culture , 1995, Neuroscience Letters.

[31]  W. Kernohan,et al.  Lasers in medicine--a review. , 1993, Journal of medical engineering & technology.

[32]  C. Curcio,et al.  Photoreceptor loss in age-related macular degeneration. , 1996, Investigative ophthalmology & visual science.

[33]  J. Olney,et al.  Blockade of both NMDA and non-NMDA receptors is required for optimal protection against ischemic neuronal degeneration in the in vivo adult mammalian retina , 1991, Experimental Neurology.

[34]  S. Lipton Molecular mechanisms of trauma-induced neuronal degeneration. , 1993, Current opinion in neurology and neurosurgery.

[35]  S. Nakanishi,et al.  Molecular diversity of glutamate receptors and their physiological functions. , 1994, EXS.

[36]  Xu Jm,et al.  Ocular Injuries from Accidental Laser Exposure , 1989 .

[37]  S. Lipton,et al.  Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. , 1996, Investigative ophthalmology & visual science.

[38]  I. Wallow,et al.  Sub-pigment epithelial membranes after photocoagulation for diabetic macular edema. , 1993, Archives of ophthalmology.

[39]  M. Marmor,et al.  Dextromethorphan protects retina against ischemic injury in vivo. , 1989, Archives of ophthalmology.

[40]  C. Parsons,et al.  Glutamate in CNS disorders as a target for drug development: an update. , 1998, Drug news & perspectives.

[41]  M. Lavail,et al.  Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Conterato A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. , 1991, The New England journal of medicine.

[43]  C. Barnstable Glutamate and GABA in retinal circuitry , 1993, Current Opinion in Neurobiology.

[44]  D. Puro The Retina. An Approachable Part of the Brain , 1988 .

[45]  D. Lam,et al.  L-glutamic acid: a neurotransmitter candidate for cone photoreceptors in human and rat retinas. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[46]  R. H. Evans,et al.  Excitatory amino acid transmitters. , 1981, Annual review of pharmacology and toxicology.

[47]  D. Choi,et al.  Glutamate neurotoxicity and diseases of the nervous system , 1988, Neuron.

[48]  N. Bressler,et al.  Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. , 1990, Archives of ophthalmology.

[49]  S. Massey,et al.  Acetylcholine release from the rabbit retina mediated by kainate receptors , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[50]  Myron L. Wolbarsht Permanent blindness from laser exposures in laboratory and industrial accidents , 1996, Photonics West.

[51]  A. Faden Pharmacotherapy in spinal cord injury: a critical review of recent developments. , 1987, Clinical neuropharmacology.

[52]  S T Schuschereba,et al.  Accelerated healing of laser-injured rabbit retina by basic fibroblast growth factor. , 1994, Investigative ophthalmology & visual science.

[53]  Fowler Bj Accidental industrial laser burn of macula. , 1983 .

[54]  Harry Zwick,et al.  Accidental human laser retinal injuries from military laser systems , 1996, Photonics West.

[55]  M. Marmor,et al.  Mannitol, dextromethorphan, and catalase minimize ischemic damage to retinal pigment epithelium and retina. , 1993, Archives of ophthalmology.

[56]  S. Lipton,et al.  Calcium channel antagonists attenuate NMDA receptor-mediated neurotoxicity of retinal ganglion cells in culture , 1991, Brain Research.

[57]  W R Green,et al.  Senile macular degeneration: a histopathologic study. , 1977, Transactions of the American Ophthalmological Society.

[58]  G. Carmignoto,et al.  N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina , 1992, Visual Neuroscience.

[59]  J. Olney,et al.  Excitotoxicity and the NMDA receptor - still lethal after eight years , 1995, Trends in Neurosciences.

[60]  P. Wender,et al.  The use of MK-801, a novel sympathomimetic, in adults with attention deficit disorder, residual type. , 1986, Psychopharmacology bulletin.

[61]  M. Lavail,et al.  Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor , 1990, Nature.

[62]  G. Lombardi,et al.  Glutamate receptor antagonists protect against ischemia-induced retinal damage. , 1994, European journal of pharmacology.

[63]  R. Brancato,et al.  Photocoagulation scar expansion after laser therapy for choroidal neovascularization in degenerative myopia. , 1990, Retina.

[64]  M. Kalloniatis Amino acids in neurotransmission and disease. , 1995, Journal of the American Optometric Association.

[65]  J. Krieglstein,et al.  Mechanisms of drug actions against neuronal damage caused by ischemia — An overview , 1993, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[66]  S. Lipton,et al.  Comparison of delayed administration of competitive and uncompetitive antagonists in preventing NMDA receptor‐mediated neuronal death , 1990, Neurology.

[67]  J. Besharse,et al.  Reconstitution of the photoreceptor-pigment epithelium interface: L-glutamate stimulation of adhesive interactions and rod disc shedding after recombination of dissociated Xenopus laevis eyecups. , 1992, Experimental eye research.