Necrosis and apoptosis after retinal ischemia: Involvement of NMDA- mediated excitotoxicity and p53

Choun Ki Joo, Jun Sub Choi, Hyuk W. Ko, Kye Yoon Park, Seonghyang Sohn, Myung H. Chun, Young J. Oh, Byoung J. Gwag

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

PURPOSE. Accumulated evidence has shown that apoptosis and necrosis contribute to neuronal death after ischemia The present study was performed to study the temporal and spatial patterns of neuronal necrosis and apoptosis after ischemia in retina and to outline mechanisms underlying necrosis and apoptosis. METHODS. Retinal ischemia was induced by increasing intraocular pressure to a range of 160 mm Hg to 180 mm Hg for 90 minutes in adult rats. The patterns of neuronal cell death were determined using light and electron microscopy and were visualized by TdT-dUTP nick-end labeling (TUNEL). The mRNA expression profile of p53 was examined using reverse transcription- polymerase chain reaction (RT-PCR) and in situ hybridization histochemistry. Immunohistochemistry was performed using anti-p53, anti-microtubule associated protein-2, and anti-glial fibrillary acidic protein antibodies. RESULTS. Within 4 hours after ischemia, neurons in the inner nuclear cell layer (INL) and ganglion cell layer (GCL) underwent marked necrosis, made apparent by swelling of the cell body and mitochondria, early fenestration of the plasma membrane, and irregularly scattered condensation of nuclear chromatin. After 3 days, the INL and GCL neurons showed further degeneration through apoptosis marked by cell body shrinkage, aggregation, and condensation of nuclear chromatin. Apoptotic neurons were also observed sparsely in the outer nuclear cell layer. Intravitreal injections of MK-801 prevented early neuronal degeneration after ischemia. Of note, mRNA and protein levels of p53, the tumor suppressor gene known to induce apoptosis, were increased in the retinal areas undergoing apoptosis 1 to 3 days after ischemic injury. CONCLUSIONS. Ischemia produces the N-methyl-D-aspartate- mediated necrosis and slowly evolving apoptosis of neurons in the retina. The latter may depend on the expression of the p53 proapoptosis gene.

Original languageEnglish
Pages (from-to)713-720
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume40
Issue number3
Publication statusPublished - 1999 Mar 11

Fingerprint

N-Methylaspartate
Necrosis
Ischemia
Apoptosis
Neurons
Ganglia
Chromatin
Retina
Messenger RNA
Intravitreal Injections
Microtubule-Associated Proteins
Dizocilpine Maleate
Glial Fibrillary Acidic Protein
p53 Genes
Tumor Suppressor Genes
Intraocular Pressure
Reverse Transcription
In Situ Hybridization
Electron Microscopy
Mitochondria

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Joo, C. K., Choi, J. S., Ko, H. W., Park, K. Y., Sohn, S., Chun, M. H., ... Gwag, B. J. (1999). Necrosis and apoptosis after retinal ischemia: Involvement of NMDA- mediated excitotoxicity and p53. Investigative Ophthalmology and Visual Science, 40(3), 713-720.
Joo, Choun Ki ; Choi, Jun Sub ; Ko, Hyuk W. ; Park, Kye Yoon ; Sohn, Seonghyang ; Chun, Myung H. ; Oh, Young J. ; Gwag, Byoung J. / Necrosis and apoptosis after retinal ischemia : Involvement of NMDA- mediated excitotoxicity and p53. In: Investigative Ophthalmology and Visual Science. 1999 ; Vol. 40, No. 3. pp. 713-720.
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Necrosis and apoptosis after retinal ischemia : Involvement of NMDA- mediated excitotoxicity and p53. / Joo, Choun Ki; Choi, Jun Sub; Ko, Hyuk W.; Park, Kye Yoon; Sohn, Seonghyang; Chun, Myung H.; Oh, Young J.; Gwag, Byoung J.

In: Investigative Ophthalmology and Visual Science, Vol. 40, No. 3, 11.03.1999, p. 713-720.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Necrosis and apoptosis after retinal ischemia

T2 - Involvement of NMDA- mediated excitotoxicity and p53

AU - Joo, Choun Ki

AU - Choi, Jun Sub

AU - Ko, Hyuk W.

AU - Park, Kye Yoon

AU - Sohn, Seonghyang

AU - Chun, Myung H.

AU - Oh, Young J.

AU - Gwag, Byoung J.

PY - 1999/3/11

Y1 - 1999/3/11

N2 - PURPOSE. Accumulated evidence has shown that apoptosis and necrosis contribute to neuronal death after ischemia The present study was performed to study the temporal and spatial patterns of neuronal necrosis and apoptosis after ischemia in retina and to outline mechanisms underlying necrosis and apoptosis. METHODS. Retinal ischemia was induced by increasing intraocular pressure to a range of 160 mm Hg to 180 mm Hg for 90 minutes in adult rats. The patterns of neuronal cell death were determined using light and electron microscopy and were visualized by TdT-dUTP nick-end labeling (TUNEL). The mRNA expression profile of p53 was examined using reverse transcription- polymerase chain reaction (RT-PCR) and in situ hybridization histochemistry. Immunohistochemistry was performed using anti-p53, anti-microtubule associated protein-2, and anti-glial fibrillary acidic protein antibodies. RESULTS. Within 4 hours after ischemia, neurons in the inner nuclear cell layer (INL) and ganglion cell layer (GCL) underwent marked necrosis, made apparent by swelling of the cell body and mitochondria, early fenestration of the plasma membrane, and irregularly scattered condensation of nuclear chromatin. After 3 days, the INL and GCL neurons showed further degeneration through apoptosis marked by cell body shrinkage, aggregation, and condensation of nuclear chromatin. Apoptotic neurons were also observed sparsely in the outer nuclear cell layer. Intravitreal injections of MK-801 prevented early neuronal degeneration after ischemia. Of note, mRNA and protein levels of p53, the tumor suppressor gene known to induce apoptosis, were increased in the retinal areas undergoing apoptosis 1 to 3 days after ischemic injury. CONCLUSIONS. Ischemia produces the N-methyl-D-aspartate- mediated necrosis and slowly evolving apoptosis of neurons in the retina. The latter may depend on the expression of the p53 proapoptosis gene.

AB - PURPOSE. Accumulated evidence has shown that apoptosis and necrosis contribute to neuronal death after ischemia The present study was performed to study the temporal and spatial patterns of neuronal necrosis and apoptosis after ischemia in retina and to outline mechanisms underlying necrosis and apoptosis. METHODS. Retinal ischemia was induced by increasing intraocular pressure to a range of 160 mm Hg to 180 mm Hg for 90 minutes in adult rats. The patterns of neuronal cell death were determined using light and electron microscopy and were visualized by TdT-dUTP nick-end labeling (TUNEL). The mRNA expression profile of p53 was examined using reverse transcription- polymerase chain reaction (RT-PCR) and in situ hybridization histochemistry. Immunohistochemistry was performed using anti-p53, anti-microtubule associated protein-2, and anti-glial fibrillary acidic protein antibodies. RESULTS. Within 4 hours after ischemia, neurons in the inner nuclear cell layer (INL) and ganglion cell layer (GCL) underwent marked necrosis, made apparent by swelling of the cell body and mitochondria, early fenestration of the plasma membrane, and irregularly scattered condensation of nuclear chromatin. After 3 days, the INL and GCL neurons showed further degeneration through apoptosis marked by cell body shrinkage, aggregation, and condensation of nuclear chromatin. Apoptotic neurons were also observed sparsely in the outer nuclear cell layer. Intravitreal injections of MK-801 prevented early neuronal degeneration after ischemia. Of note, mRNA and protein levels of p53, the tumor suppressor gene known to induce apoptosis, were increased in the retinal areas undergoing apoptosis 1 to 3 days after ischemic injury. CONCLUSIONS. Ischemia produces the N-methyl-D-aspartate- mediated necrosis and slowly evolving apoptosis of neurons in the retina. The latter may depend on the expression of the p53 proapoptosis gene.

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