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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

  • This title is an author manuscript version first made accessible on the NCBI Bookshelf website July 2, 2012.

This title is an author manuscript version first made accessible on the NCBI Bookshelf website July 2, 2012.

Cover of Jasper's Basic Mechanisms of the Epilepsies

Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

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Programmed Necrosis After Status Epilepticus

, PhD, , PhD, and , MD, LSc.

Author Information and Affiliations

We review recent progress in the field of seizure-induced neuronal injury. Clinical data suggest that seizures trigger neuronal death, but its mechanism is not well understood. We are beginning to understand the role of neuronal necrosis, the dominant form of death in the adult brain. In a postnatal model of status epilepticus (SE), apoptosis is mainly found in immature neurons, while necrosis is the main form of death in mature neurons, suggesting that the degree of maturity of individual neurons is more important that the level of maturity of the whole organism in determining the mode of neuronal death induced by seizures. It is traditionally thought that necrosis is a passive process which does not require the activation of orderly cell death program(s). Experimental models of SE helped elucidating the contribution of cell death pathways in some active forms of necrosis. SE-induced neuronal necrosis can be an active mechanism requiring the execution of a mitochondrial death program and/or the activation of a caspase cascade. Altogether, these data suggest that the neuronal death landscape is complex and redundant, and that successfully targeting cell death pathways may require polytherapy.

INTRODUCTION

In this review, we will discuss the most recent advances in the field of neuronal injury following epileptic seizures, with an emphasis on the mechanism of neuronal necrosis. The ultrastructure of cell death and the ubiquity of endogenous cell death programs were first described in the 1970’s, and the two main categories of cell death, apoptosis and necrosis, were originally defined according to morphological criteria1. The role of glutamate and its analogues in excitotoxic cell death, and the concept of excitotoxicity -- including its role in seizures-- derived from the pioneering studies of John Olney and his disciples2–5. Multiple cell death factors and cell death programs have been identified in developmental and disease-induced neuronal apoptosis6–8, and there is mounting clinical and experimental evidence of their contribution to seizure-induced neuronal injury9–16. Because these death factors were originally identified in classic apoptosis, any form of cell death in which they are expressed is often called apoptotic, even if its morphology suggests necrosis. This has caused considerable confusion in the literature, and should be discouraged17–20. In this chapter, we will discuss the involvement of cell death factors in morphologically-defined necrosis, the main mode of SE-induced cell death in the adult and even in the developing brain. We find that necrosis is frequently an active form of neuronal death, requiring the expression or activation of some of the same cell death factors usually identified with apoptosis. While this finding raises the hope that targeting common cell death pathways might have therapeutic benefits for both necrosis and apoptosis, the multiplicity and redundancy of cell death pathways for both modes of neuronal death also raises formidable problems when we consider the potential therapeutic applications of these mechanisms.

SEIZURE-INDUCED NEURONAL INJURY

Neuronal Injury and Status Epilepticus

Neuronal injury is widespread in the hippocampus and other brain regions of children or adults who died from SE21–24, or of patients with childhood-onset epilepsy who come to surgery for intractable seizures25, although epidemiologic evidence of the deleterious effects of SE is lacking26. DeGiorgio et al. found decreased hippocampal neuronal densities in five patients who died after SE, compared to epileptic patients without SE and to controls27. Neuron-specific enolase, a marker of neuronal injury, is increased in the serum of patients with SE even when the seizures are non-convulsive28–29. A number of anecdotal studies using MRI and other imaging techniques found cerebral edema acutely, and atrophy chronically, after non-convulsive SE30–32, but other studies failed to find lesions33. Hippocampal atrophy has also been reported after complex or prolonged febrile seizures 34–35. The presence of a normal brain MRI before non-convulsive SE, evolving into brain atrophy after SE, has been documented36, and neuronal loss was found at autopsy in areas that became atrophic after non-convulsive SE37. Atrophy (as seen on MRI) is strongly associated with areas of intense seizure activity in anecdotal cases38–40, and in one instance atrophy was shown at autopsy to correspond to neuronal necrosis and neuronal loss39, suggesting that neuronal loss and cerebral atrophy can result from SE in humans, although the incidence and severity of these complications after SE are not known.

Is Seizure-Associated Neuronal Injury Due To The Seizures Themselves Or To Seizure-Associated Systemic Factors?

Complex Partial SE

As mentioned above, the limited evidence available shows elevation of cell death markers in the serum of patients after non-convulsive complex partial SE, in the absence of systemic complications. However, there is also anecdotal evidence that complex partial SE is not always followed by cerebral atrophy or behavioral deficits41, and there is little evidence of any type of brain damage or neurological deficit after petit mal absence SE42. This suggests that seizures per se can cause neuronal injury in humans, but that seizure type is a key determinant of injury.

Evidence From Animal Models

Meldrum and collaborators proved that seizures in paralyzed, ventilated monkeys caused neuronal loss43–45. The occurrence of neuronal injury in remote areas synaptically connected to the epileptic focus suggested an excitotoxic mechanism46, and Sloviter and Damiona showed that excessive neuronal firing by itself induced neuronal death47. In the immature brain, Thompson et al.10–11 and Sankar et al.12 demonstrated that severe, prolonged seizures cause neuronal death, although the extent of neuronal injury was highly model-dependent48. Recent evidence suggests that under circumstances approximating the clinical situation seen in patients with uncontrolled seizures, the mixture of the death-inducing action of severe seizures with the neuroprotective effect of seizure-associated preconditioning, in which mild seizure-associated injury mitigates the neuronal loss resulting from subsequent severe seizures, results in a neuropathological picture resembling hippocampal sclerosis49. Thus, the experimental evidence seems clear: systemic complications associated with seizures greatly aggravate mortality and morbidity from experimental seizures45;50, but in their absence, seizures per se are quite capable of causing neuronal injury and death, even in the immature brain10–11, and appears to do so by a variety of excitotoxic mechanisms16.

NECROSIS AND APOPTOSIS IN EXPERIMENTAL MODELS OF EPILEPSY

Necrosis And Apoptosis: A Morphological Definition

Necrosis and apoptosis have been originally defined by morphological criteria1. In necrosis, early cytoplasmic changes, including severe mitochondrial and organelle swelling and rupture of the plasma membrane, precede late tigroid condensation of the nucleus with scattered, irregular small chromatin clumps (Figure 1). By contrast, in the early stage of apoptosis, chromatin condensation with loss of the nuclear membrane occurs in the presence of relatively preserved organelles and plasma/mitochondrial membranes. The advanced stages of apoptosis are characterized by the presence of multiple large rounded chromatin masses. The picture can be complicated by the occurrence of both processes in the same cell. Following excitotoxic exposure, for example, apoptotic cells may undergo secondary necrosis, with severe swelling of the organelles and breakdown of the plasma membrane.

Figure 1. Example of necrotic and apoptotic morphologies in rat pup brain.

Figure 1

Example of necrotic and apoptotic morphologies in rat pup brain. Images A–E show the ultrastructure of CA1 neurons in control (A) and experimental animals 6 hours (B), 24 hours (C) and 72 hours (D–E) following SE in postnatal day 14. Control (more...)

Following Status Epilepticus, Necrosis Is The Main Form Of Neuronal Death In The Adult Brain…

In the adult rat brain, several models of SE show that necrosis is the dominant form of neuronal death. In models of SE induced by lithium-pilocarpine or systemic injection of kainic acid in adult rats, Fujikawa et al17–18 and Tokuhara et al51 found necrosis in diverse areas of the brain, including the hippocampus, amygdala, and entorhinal, piriform and frontal cortices 24h–7 days following SE. The apoptotic morphology could not be found even when SE duration is reduced to 60 min, suggesting that seizure severity is not a determining factor in the mode of death.20 While necrosis is certainly the main form of seizure-associated death in the adult brain, apoptotic morphologies have been described in some models of SE, and their role cannot be cannot be disregarded.52–54

… And In The Developing Brain Too

It is now well-established that experimental seizures can induce neuronal injury in the developing brain.12;55–58 Both apoptotic and necrotic morphologies have been clearly reported by light and electron microscopy in the developing brain following SE. In postnatal day 14 (P14) rat pups, apoptosis is notably found in the inner granule cell layer of the dentate gyrus.12;16 In the same rats, SE-induced neuronal injury is extensive in the CA1 pyramidal cell layer. Twenty-four hours after SE, electron microscopy observations showed that 47 of 50 injured CA1 neurons had a necrotic morphology (Figure 1C). Seventy-two hours after SE, 50 of 50 injured neurons were necrotic (Niquet et al, 2007) (Figure 1D–E). In a model of lithium-pilocarpine SE in P12 rat pups, EM observations revealed that necrosis is the mode of death of injured neurons in the mediodorsal nucleus of the thalamus56. Altogether, these results show that necrosis is the main form of SE-induced neuronal death even in the immature brain.

Mechanisms Of Seizure-Induced Neuronal Necrosis

The Traditional View on Necrosis and Apoptosis

Traditionally, necrosis is viewed as a passive mechanism that does not require the activation of orderly cell death programs and/or synthesis of new proteins. However, many histological studies dispute this view. Following experimental SE, morphologically necrotic neurons display TUNEL staining12;59–60, Bax immuoreactivity61, caspase expression16;60, or caspase-independent cell death programs.62 Interestingly, nuclear expression of caspase-3, and nuclear translocation of Apoptosis-Inducing Factor (AIF) were found in injured neurons from patients with temporal lobe epilepsy.63

Are these “apoptotic” factors actively involved in the execution of necrosis? Alternatively, does their expression represent an epiphenomenon? The reduction of neuronal necrosis by caspase inhibitors in several models16;64–66 supports the view that “apoptotic” factors play an important role in neuronal necrosis. We will describe below the experimental data suggesting the existence of active forms of necrosis.

By contrast, apoptotic neuronal death following brain insults is conceptualized as an active form of death which results from the execution of cellular programs that resemble those involved in developmentally programmed cell death. The best characterized programs are the extrinsic and intrinsic pathways, offering many alternative routes of activation of caspases, a family of cysteine proteases.67 When the “extrinsic” pathway of programmed cell death is induced, the first step involves the activation of extracellular cell death receptors of the TNF superfamily, which recruit other proteins to form a complex that activates caspase-8, which in turn activates caspase-3. This “executioner” caspase kills the cell through its widespread proteolytic effects, activating DNA breakdown, inactivating DNA repair enzymes, and attacking the cytoskeleton, among other activities. In the “intrinsic” pathway of programmed cell death, the mitochondrion plays a critical role by releasing cytochrome c from its intermembrane space to the cytosol, where, in association with apoptotic protease-activating factor-1 and dATP, it forms the apoptosome complex, activating caspase-9, which in turn activates caspase-3.68 We show below evidence suggesting that these processes are not exclusively involved in apoptotic death, but can also participate in necrotic forms of seizure-induced neuronal death.

Evidence for Caspase-Dependent Forms of Neuronal Necrosis In Culture

In primary neuronal cultures, chemical hypoxia or glutamate excitotoxicity can activate initiator caspase-9 and cell executioner caspase-3 in necrotic neurons. In the minutes-to-hours following the insult, cytochrome c is released from swollen mitochondria at a time when the nucleus is still intact (a sign of early stage of necrosis) and later co-localizes with active caspase-3, suggesting the activation of the intrinsic pathway. Caspase inhibitors reduce neuronal necrosis, showing that this caspase cascade is not an epiphenomenon but does contribute to neuronal necrosis. We called this active form of necrosis “programmed necrosis”.64–66

Seizures and hypoxia/ischemia profoundly inhibit neuronal protein synthesis69–72 and therefore inhibit processes requiring macromolecular synthesis (such as some forms of apoptosis). In opposition to “classical apoptosis”, “programmed necrosis” does not require protein synthesis. In primary neuronal cultures, the protein synthesis inhibitor cycloheximide reduced caspase-3 activation in staurosporine-induced apoptosis but had no effect on hypoxic neuronal necrosis.64 Since the caspase-3 precursor is already expressed in control cultures, the execution of “programmed necrosis” does not require the energy-intensive process of expressing new genes, which is often necessary in classical apoptosis.

Evidence for a Caspase-Dependent Form of Necrosis Induced By SE

In a lithium-pilocarpine model of SE in rat pups16, upregulation of initiator caspase-8 precedes caspase-3 activation in CA1 (Figure 2). Post-embedding immunohistochemical studies show that caspase-3-immunoreactive CA1 neurons have a necrotic morphology. Pretreatment with a pan-caspase inhibitor reduces neuronal necrosis in CA1, showing that caspase activation is not an epiphenomenon but does contribute to SE-induced neuronal necrosis.16 These results suggest that the caspase cascade of the extrinsic pathway (upregulation of initiator caspase-8 followed by caspase-3 activation) can also contribute to necrotic neuronal death.

Figure 2. Putative neuronal death pathways induced by SE in the immature hippocampus.

Figure 2

Putative neuronal death pathways induced by SE in the immature hippocampus. Fluorescent images show caspase-3a (green), caspase-8 (red), caspase-9a (green) and DCX (red) immunoreactivity and Hoechst staining (chromatin dye, white) in CA1 and the dentate (more...)

There is indirect evidence suggesting that “programmed necrosis” can be found in other models of brain injury. In adult rats, kainic acid-induced SE caused two types of pyramidal cell death in CA1: early necrosis (1 day after SE) and delayed TUNEL-positive and caspase-3-dependent programmed cell death (3–7 days following SE). Despite evidence of caspase-3 activation, apoptotic morphology could not be found at 1, 3 and 7 days following seizures, suggesting that necrosis is the main form of CA1 neuronal death.51

Influence of Cell Maturity and Inflammation on “Programmed Necrosis”

Following brain injury, apoptosis has been considered to be more susceptible to occur in the developing brain than in the adult one,73 maybe because of an age-dependent downregulation of apoptotic death factors, such as caspases.74–75 In the lithium-pilocarpine model of SE in rat pups described above, the same seizures trigger two distinct caspase pathways leading to two different modes of death: the extrinsic pathway leading to necrosis in CA1 (as described above), and the intrinsic pathway (caspase-9 and -3 activation) leading to apoptosis in the dentate gyrus (Figure 2). One possible explanation for these results is the degree of cell maturity of these two neuronal populations. In the dentate gyrus, active caspase-3-immunoreactive cells had features of immature neurons: they expressed doublecortin (a marker of immature neurons76) and failed to express calbindin immunoreactivity (a marker of mature granule cells). Immature dentate gyrus cells may be more susceptible to die by apoptosis than CA1 pyramids, whose maturation occurs much earlier.77–79 From these studies, we may speculate that the degree of cell maturity is more important that the level of maturation of the whole organism. Alternative explanations might involve environmental factors, i.e. independent of the intrinsic properties of the neurons, such as inflammation or metabolic changes.

Caspase-Independent Forms Of Active Necrosis

Caspases are not the only “apoptotic” factors that may be involved in neuronal necrosis (Figure 3). There is evidence that some form of necrosis depend on the release of mitochondrial death factors, such as AIF and endonuclease G. Originally characterized for their role in apoptosis80–82, their release from mitochondria to cytosol and translocation to the nucleus can induce DNA fragmentation in a caspase-independent manner. AIF translocation is involved in many models of neuronal injury often associated with a necrotic morphology. In cultured neurons, neurons with a reduced AIF expression are more resistant to glutamate excitotoxicity or oxygen/glucose deprivation. Harlequin mice (expressing over 80% AIF expression reduction) exhibit less neuronal injury following ischemia or KA-induced seizures.83–85 However, in the latter study84, seizure severity was not properly monitored and it is unclear whether Harlequin and control mice display the same susceptibility to seizures. In a model of lithium-pilocarpine SE in adult rats62, nuclear translocation of mitochondrial factors AIF and endonuclease G occur within 60 min of seizure onset (i.e before sign of irreversible neuronal death), suggesting their involvement in nuclear pyknosis and DNA fragmentation. In the same study, nuclear translocation of other factors (cytochrome c, DNAse II) has been reported, suggesting the activation of various pathways leading to SE-neuronal necrosis.

Figure 3. Putative mechanisms of ‘programmed necrosis’.

Figure 3

Putative mechanisms of ‘programmed necrosis’. Following hypoxia, excitotoxicity and/or seizures, calcium entry into the mitochondria and/or energy failure contribute to mitochondrial swelling, outer membrane rupture, release of mitochondrial (more...)

The term necroptosis has been proposed for a kind of necrotic cell death that can be avoided by inhibiting the activity of the serine/threonine kinase RIP1, either through genetic or pharmacological methods. Necrostatins, specific and potent inhibitors of RIP1, have been used as an operational definition of necroptosis.86–88 By contrast with “programmed necrosis”, necroptosis involves caspase-independent pathways and other cell death factors have been implicated, including cyclophilin D, poly(ADP-ribose) polymerase 1 (PARP-1), and AIF (for review see Galluzzi and Kroemer89). Necroptosis has not been reported following SE, but may contribute to NMDA-induced excitotoxicity in cultured cortical neurons.90

Therapeutic Implication Of Programmed Necrosis

Blocking neuronal necrosis is an important therapeutic goal. Plasma membrane rupture in late stage of necrosis leads to release of cytoplasmic and/or nuclear material in the extracellular space, which may trigger an inflammatory response followed by secondary necrosis in neighboring neurons. The evidence of active forms of necrosis suggests the possibility of therapeutic interventions. An experimental model of SE showed that treatment with the cell permeable, irreversible pan-caspase inhibitor Q-VD-OPH can block active necrosis.16 Intraperitoneal delivery of fusion proteins composed of an anti-apoptotic element and a transduction domain which enables the molecule to cross the blood-brain barrier has shown neuroprective potential in models of SE.91–92 Recent literature has also shown that cytokines, T-cells and macrophages can add to the damage induced by seizures, and that targeting the innate and adaptive immune mechanisms may be a promising therapeutic approach.93 However, the multiplicity of cell death pathways (caspase-dependent, caspase-independent) suggests that no magic bullet will be able to block simultaneously all forms of neuronal death.94

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Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

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