Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection

doi:10.1016/j.pneurobio.2013.03.002

Progress in Neurobiology

Volume 105, June 2013, Pages 24-48

https://doi.org/10.1016/j.pneurobio.2013.03.002 Get rights and content

Highlights

•
There are at least three different morphological types of cell death.
•
Each type is controlled by multiple death mechanisms, and there is cross-talk between them.
•
Inhibition of a single mechanism leaves the brain vulnerable to alternative ones.
•
This review analyzes the multiple death mechanisms in excitotoxicity and ischemic brain damage.
•
The importance of this multiplicity for attempts at neuroprotection is discussed.

Abstract

There is currently no approved neuroprotective pharmacotherapy for acute conditions such as stroke and cerebral asphyxia. One of the reasons for this may be the multiplicity of cell death mechanisms, because inhibition of a particular mechanism leaves the brain vulnerable to alternative ones. It is therefore essential to understand the different cell death mechanisms and their interactions. We here review the multiple signaling pathways underlying each of the three main morphological types of cell death – apoptosis, autophagic cell death and necrosis – emphasizing their importance in the neuronal death that occurs during cerebral ischemia and hypoxia-ischemia, and we analyze the interactions between the different mechanisms. Finally, we discuss the implications of the multiplicity of cell death mechanisms for the design of neuroprotective strategies.

Introduction

Despite a considerable research effort, there is still no approved neuroprotective pharmacotherapy for acute neurological conditions such as stroke (Stankowski and Gupta, 2011, Yuan, 2009) and neonatal cerebral asphyxia (van Bel and Groenendaal, 2008). The reasons for this are multiple, but one of the problems appears to be the multiplicity of cell death mechanisms, because inhibition of a particular death mechanism will be ineffective if alternative mechanisms are able to kill the cell. It is therefore essential to understand the different cell death mechanisms and their interactions.

Morphological studies indicate that there are three main types of cell death (Fig. 1): type 1 or apoptosis, type 2 or autophagic death, and type 3 or necrotic/cytoplasmic death. Initial arguments for this trichotomy focused on cell death during normal development (Clarke, 1990), but a similar classification appears to be valid in both adult and neonatal pathological situations including ischemic brain damage (Bredesen, 2008, Clarke, 1999). The coverage of neonatal ischemic (including hypoxic-ischemic) models in the present review is limited to ages at which the brain damage is mainly in the gray matter – after postnatal day (P) 7. Very early cerebral ischemia (P2–P4) causes primarily white matter lesions, by entirely different mechanisms, which is beyond our present concern.

We here review critically, in the context of cerebral ischemia and hypoxia-ischemia, the available evidence on the multiple mechanisms underlying the three types of cell death. In particular, we focus on four problem areas. (1) The factors that determine whether a given type predominates. (2) The interactions between the multiple mechanisms and the hybrid forms of cell death that can result. (3) The current controversy about whether autophagy is a death mediator in type 2 cell death (Clarke and Puyal, 2012, Shen et al., 2012, Yuan and Kroemer, 2010). (4) The challenge that the multiple mechanisms constitute for the design of neuroprotective strategies.

The multiplicity of cell death mechanisms in excitotoxicity and cerebral ischemia results from the fact that these events trigger multiple pathways. Excitotoxicity, defined as toxicity due to the excessive activation of ionotropic and metabotropic glutamate receptors, is well known to be the main cell death mechanism in cerebral ischemia and hypoxia-ischemia. Glutamate receptor activation depolarizes the neuron and raises the level of intracellular calcium due to its influx through N-methyl-d-aspartate (NMDA) channels and other voltage-sensitive channels and its release from intracellular stores, which triggers a variety of death pathways and leads organelle dysfunction, the production of free radicals and nitric oxide, and the activation of proteases, lipases and kinases). Excitotoxicity is not the only mechanism – transient receptor potential channels, acid-sensing channels, pannexins and hemichannels can all play a role as well (Tymianski, 2011) – but we here focus on excitotoxicity since it is the main toxic mechanism in hypoxic and hypoxic-ischemic brain injury. Moreover, the best understood influences of the nonexcitotoxic mechanisms converge on the same intracellular pathways as excitotoxicity; for example, transient receptor potential channels and acid-sensing channels mediate the entry of calcium and sodium (Tymianski, 2011).

Section snippets

Morphological definition of apoptosis

Type 1 cell death, or apoptosis, has also been called the nuclear type of cell death because it is characterized by striking morphological changes in the nucleus: compaction of chromatin and nuclear condensation leading to its pyknosis and then its fragmentation (Fig. 1). These modifications of the nuclear morphology are accompanied by shrinkage of the cytoplasm and a distorsion of the plasma membrane into folds that break off to form apoptotic bodies. These portions of the cell will be

Type 2 cell death: Autophagic

Autophagy is a catabolic process that is complementary to the proteasome pathway. It degrades long-lived proteins and organelles (including mitochondria, portions of ER and peroxisomes). Even though the role of autophagy in healthy cells is moderate and physiological, some dying cells exhibit grossly enhanced autophagy, which has led to the identification of “type 2” or “autophagic” cell death as a distinct type of cell death (Fig. 1, Fig. 2). We first provide a brief review of the cell biology

Morphological definition of type 3 cell death

Type 3 cell death was initially defined in the context of normal development (Schweichel and Merker, 1973), whereas necrosis (also called coagulative necrosis by pathologists) was initially considered to occur only in severely damaged tissues (Wyllie et al., 1980), but the two types resemble each other morphologically, and are now generally considered to be variants of a single type of cell death.

In the context of development, type 3 cell death was divided into two main variants, 3A and 3B (

Brain maturity

The age at which hypoxia-ischemia is performed is another important parameter affecting the severity of the lesion (Towfighi et al., 1997). The conclusions of studies on neuroprotection in adult models of cerebral ischemia cannot be transposed to the neonatal situation without further confirmation, because the different physiological and metabolic properties of immature brains lead to different molecular consequences. For example, the basal activity of caspase-3 is much higher in immature

Interconnections between necrosis and apoptosis

Necrosis and apoptosis can share common initial events such as Fas activation (Kawahara et al., 1998) or mitochondrial permeabilization (Baines, 2011). A cell's decision to die by apoptosis or necrosis can be dependent on different factors including its capacity for caspase activation (Hartmann et al., 2001, Lemaire et al., 1998, Prabhakaran et al., 2004), production level of reactive oxygen species (Kalai et al., 2002) and the degree of lysosomal membrane disruption (Brunk et al., 1997), but

Development of neuroprotective strategies in the light of the multiple cell death mechanisms

Despite the increasing knowledge on neuronal death and the important effort in research to identify neuroprotective agents, none have so far been translated to patients suffering from cerebral ischemia. The only pharmacological molecules approved in clinical conditions are tissue-plasminogen activators (t-PA) to restore perfusion to adult ischemic brain. However t-PA has to be administrated within about 3 h of stroke onset because of increased risk of intracranial hemorrhage and neurotoxic

Conclusions

There are at least three main types of cell death, all of which are triggered by active signaling and involve multiple signaling pathways. All the main types of cell death occur in neurons exposed to ischemia or to hypoxia-ischemia, and the multiple pathways interact. In particular situations a single pathway may predominate, in which case inhibition of a single group of enzymes, such as caspases, may give neuroprotection. But, in most situations, multiple pathways are involved and the

Acknowledgements

Our research and the writing of this article were supported by grants from the Swiss National Science Foundation (310030-130769) and from the Faculty of Biology and Medicine of the University of Lausanne. We thank the Electron Microscopy Facility of the University of Lausanne for long term technical support.

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Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection

Highlights

Abstract

Introduction

Section snippets

Morphological definition of apoptosis

Type 2 cell death: Autophagic

Morphological definition of type 3 cell death

Brain maturity

Interconnections between necrosis and apoptosis

Development of neuroprotective strategies in the light of the multiple cell death mechanisms

Conclusions

Acknowledgements

American Journal of Pathology

Neuron

Experimental Cell Research

Trends in Neuroscience

Cell

Journal of Biological Chemistry

Molecular Cell

Experimental Neurology

Free Radical Biology and Medicine

Neuroscience

Neurobiology of Disease

Neurobiology of Disease

Neuron

Neuropharmacology

Cell

Seminars in Fetal & Neonatal Medicine

Biochemical and Biophysical Research Communications

Current Biology

Neuroscience

Cell

Journal of Biological Chemistry

Neuroscience Letters

Current Opinion in Neurobiology

Molecular Cell

Journal of Stroke & Cerebrovascular Diseases

Neuroscience

European Journal of Pharmacology

Neuroscience

International Review of Cell and Molecular Biology

American Journal of Pathology

Lancet

Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions

Science

Dissection of autophagosome biogenesis into distinct nucleation and expansion steps

Journal of Cell Biology

Combination effect of systemic hypothermia and caspase inhibitor administration against hypoxic-ischemic brain damage in neonatal rats

Pediatric Research

NAD(+) depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death

Journal of Neuroscience

Gender-linked brain injury in experimental stroke

Stroke

Necrotic death of neurons following an excitotoxic insult is prevented by a peptide inhibitor of c-jun N-terminal kinase

Journal of Neurochemistry

Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

Journal of Cell Biology

Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3

Autophagy

Moderate hypothermia to treat perinatal asphyxial encephalopathy

New England Journal of Medicine

Insulin withdrawal-induced cell death in adult hippocampal neural stem cells as a model of autophagic cell death

Autophagy

The mitochondrial permeability transition pore and the cardiac necrotic program

Pediatric Cardiology

Specific caspase pathways are activated in the two stages of cerebral infarction

Journal of Neuroscience

Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis

Journal of Cell Science

The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes

European Journal of Biochemistry

Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome

Pediatric Research

N-methyl-d-aspartate-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c-Jun N-terminal kinase pathway

European Journal of Neuroscience

Key note lecture – toward a mechanistic taxonomy for cell death programs

Stroke

Programmed cell death mechanisms in neurological disease

Current Molecular Medicine