Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation

A perspective on the contributions of apoptosis and necrosis

Lee J Martin, Nael A. Al-Abdulla, Ansgar M. Brambrink, Jeffrey R. Kiesch, Frederick Sieber, Carlos Portera-Cailliau

Research output: Contribution to journalArticle

Abstract

In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult- onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N- methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitetoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in non-neuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.

Original languageEnglish (US)
Pages (from-to)281-309
Number of pages29
JournalBrain Research Bulletin
Volume46
Issue number4
DOIs
StatePublished - Jul 1 1998

Fingerprint

Brain Ischemia
Necrosis
Apoptosis
Cell Death
Neurons
Nervous System Trauma
Axotomy
Glutamate Receptors
Vulnerable Populations
N-Methyl-D-Aspartate Receptors
Wounds and Injuries
Brain
Ischemia
Central Nervous System
Animal Models
D-Aspartic Acid
Amyotrophic Lateral Sclerosis
Heart Arrest
Brain Injuries
Spinal Cord

Keywords

  • Axotomy
  • Glutamate receptor
  • Mitochondria
  • Oxidative injury
  • Programmed cell death

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation : A perspective on the contributions of apoptosis and necrosis. / Martin, Lee J; Al-Abdulla, Nael A.; Brambrink, Ansgar M.; Kiesch, Jeffrey R.; Sieber, Frederick; Portera-Cailliau, Carlos.

In: Brain Research Bulletin, Vol. 46, No. 4, 01.07.1998, p. 281-309.

Research output: Contribution to journalArticle

Martin, Lee J ; Al-Abdulla, Nael A. ; Brambrink, Ansgar M. ; Kiesch, Jeffrey R. ; Sieber, Frederick ; Portera-Cailliau, Carlos. / Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation : A perspective on the contributions of apoptosis and necrosis. In: Brain Research Bulletin. 1998 ; Vol. 46, No. 4. pp. 281-309.
@article{1653c29dba36477a9ff12c5d0ee34b99,
title = "Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis",
abstract = "In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult- onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N- methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitetoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in non-neuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.",
keywords = "Axotomy, Glutamate receptor, Mitochondria, Oxidative injury, Programmed cell death",
author = "Martin, {Lee J} and Al-Abdulla, {Nael A.} and Brambrink, {Ansgar M.} and Kiesch, {Jeffrey R.} and Frederick Sieber and Carlos Portera-Cailliau",
year = "1998",
month = "7",
day = "1",
doi = "10.1016/S0361-9230(98)00024-0",
language = "English (US)",
volume = "46",
pages = "281--309",
journal = "Brain Research Bulletin",
issn = "0361-9230",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation

T2 - A perspective on the contributions of apoptosis and necrosis

AU - Martin, Lee J

AU - Al-Abdulla, Nael A.

AU - Brambrink, Ansgar M.

AU - Kiesch, Jeffrey R.

AU - Sieber, Frederick

AU - Portera-Cailliau, Carlos

PY - 1998/7/1

Y1 - 1998/7/1

N2 - In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult- onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N- methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitetoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in non-neuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.

AB - In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult- onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N- methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitetoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in non-neuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.

KW - Axotomy

KW - Glutamate receptor

KW - Mitochondria

KW - Oxidative injury

KW - Programmed cell death

UR - http://www.scopus.com/inward/record.url?scp=0032125488&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032125488&partnerID=8YFLogxK

U2 - 10.1016/S0361-9230(98)00024-0

DO - 10.1016/S0361-9230(98)00024-0

M3 - Article

VL - 46

SP - 281

EP - 309

JO - Brain Research Bulletin

JF - Brain Research Bulletin

SN - 0361-9230

IS - 4

ER -