Caspase‐3 is not activated in seizure‐induced neuronal necrosis with internucleosomal DNA cleavage

Fujikawa, Denson G.; Ke, Xingrao; Trinidad, Rosen B.; Shinmei, Steve S.; Wu, Aiguo

doi:10.1046/j.1471-4159.2002.01152.x

Cited by 52 publications

(41 citation statements)

References 39 publications

(142 reference statements)

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“…We estimated the numbers of acidophilic neurons on a 0-3 grading scale, 0 = none, 0.5 = slight (<10%), 1.0 = mild (10-25%), 1.5 = mild-to-moderate (26-45%), 2.0 = moderate (46-54%), 2.5 = moderate-tosevere (55-75%), and 3.0 = severe (>75%), as previously published (Fujikawa, 1995(Fujikawa, , 1996(Fujikawa, , 1994(Fujikawa, , 2002(Fujikawa, , 1999(Fujikawa, , 2000(Fujikawa, , 2007(Fujikawa, , 2010Zhao et al, 2010).…”

Section: Semi-quantitative Assessment Of Normal and Acidophilic Neuronssupporting

confidence: 73%

“…Previous METH studies have shown Fluoro-Jade-positive neurons in hippocampus, hippocampal "remnants" (Schmued and Bowyer, 1997), amygdala and hippocampus (Bowyer and Ali, 2006) and parietal cortex in rats (Eisch et al, 1998). This method cannot provide the information about the nucleus that the H&E stain provides, but the outline of the shrunken neurons conforms to what we have found in acidophilic neurons, which are by ultrastructural examination necrotic (Fujikawa et al, 2002(Fujikawa et al, , 1999(Fujikawa et al, , 2000. A previous study claimed that apoptotic neurons were induced by METH, but they showed pyknotic nuclei that were TUNEL-positive, which is a finding characteristic of necrotic, not apoptotic neurons (Fujikawa et al, 2002(Fujikawa et al, , 1999(Fujikawa et al, , 2000.…”

Section: Discussionmentioning

confidence: 57%

“…The semi-quantitative assessment of normal and acidophilic (necrotic) neurons in four hippocampal subregions (CA1, CA2, CA3 and hilus) and in amgydala, piriform cortex and entorhinal cortex) was performed as we have described previously for rats (Fujikawa, 1995(Fujikawa, , 1996(Fujikawa, , 1994(Fujikawa, , 2002(Fujikawa, , 1999(Fujikawa, , 2000(Fujikawa, , 2007(Fujikawa, , 2010Zhao et al, 2010). We estimated the numbers of acidophilic neurons on a 0-3 grading scale, 0 = none, 0.5 = slight (<10%), 1.0 = mild (10-25%), 1.5 = mild-to-moderate (26-45%), 2.0 = moderate (46-54%), 2.5 = moderate-tosevere (55-75%), and 3.0 = severe (>75%), as previously published (Fujikawa, 1995(Fujikawa, , 1996(Fujikawa, , 1994(Fujikawa, , 2002(Fujikawa, , 1999(Fujikawa, , 2000(Fujikawa, , 2007(Fujikawa, , 2010Zhao et al, 2010).…”

Section: Semi-quantitative Assessment Of Normal and Acidophilic Neuronsmentioning

confidence: 99%

“…Cadet and colleagues have suggested that METH-induced neuronal death is apoptotic, based on low-magnification photomicrographs of cells with pyknotic, TUNEL-positive nuclei (Deng et al, 2001). This is precisely the morphology of seizure-induced necrotic neurons (Fujikawa et al, 2002(Fujikawa et al, , 1999(Fujikawa et al, , 2000(Fujikawa et al, , 2007. We and others have shown that apoptotic neurons have large, usually round chromatin clumps, with relatively early disruption of nuclear membranes (Fujikawa et al, 2000;Ikonomidou et al, 2000Ikonomidou et al, , 1999Ishimaru et al, 1999), so that fragmented DNA mingles with cytoplasm, producing apoptotic neurons with TUNEL-positive cell bodies and TUNEL-negative chromatin clumps (Fujikawa et al, 1999(Fujikawa et al, , 2000) (see also Fig.…”

Section: Introductionmentioning

confidence: 99%

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Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges

Fujikawa

Aviles

et al. 2016

NeuroToxicology

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We have evidence that methamphetamine (METH)-induced neuronal death is morphologically necrotic, not apoptotic, as is currently believed, and that electrographic seizures may be responsible. We administered 40 mg/kg i.p. to 12 male C57BL/6 mice and monitored EEGs continuously and rectal temperatures every 15 min, keeping rectal temperatures <41.0 °C. Seven of the 12 mice had repetitive electrographic seizure discharges (RESDs) and 5 did not. The RESDs were often not accompanied by behavioral signs of seizures-i.e., they were often not accompanied by clonic forelimb movements. The 7 mice with RESDs had acidophilic neurons (the H&E lightmicroscopic equivalent of necrotic neurons by ultrastructural examination) in all of 7 brain regions (hippocampal CA1, CA2, CA3 and hilus, amygdala, piriform cortex and entorhinal cortex), the same brain regions damaged following generalized seizures, 24 h after METH administration. The 5 mice without RESDs had a few acidophilic neurons in 4 of the 7 brain regions, but those with RESDs had significantly more in 6 of the 7 brain regions. Maximum rectal temperatures were comparable in mice with and without RESDs, so that cannot explain the difference between the two groups with respect to METH-induced neuronal death. Our data show that METH-induced neuronal death is morphologically necrotic, that EEGs must be recorded to detect electrographic seizure activity in rodents without behavioral evidence of seizures, and that RESDs may be responsible for METH-induced neuronal death.

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Section: Semi-quantitative Assessment Of Normal and Acidophilic Neuronssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 57%

Section: Semi-quantitative Assessment Of Normal and Acidophilic Neuronsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges

Fujikawa

Aviles

et al. 2016

NeuroToxicology

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“…Although apoptosis through activation of caspase 3 has been proposed to be a major pathway leading to neuronal death following status epilepticus [64], more recent evidence suggests that this pathway plays no or only a minor role [65,66].…”

Section: Enzymes Activated By Intracellular Calcium Accumulationmentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

109

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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Death‐associated protein kinase expression in human temporal lobe epilepsy

Henshall

Schindler

So³

et al. 2004

Annals of Neurology

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Experimental and human data suggest programmed (active) cell death may contribute to the progressive hippocampal atrophy seen in patients with refractory temporal lobe epilepsy. Death-associated protein (DAP) kinase is a novel calcium/calmodulin-activated kinase that functions in apoptosis mediated by death receptors. Because seizure-induced neuronal death involves both death receptor activation and calcium, we examined DAP kinase expression, localization, and interactions in hippocampal resections from patients with intractable temporal lobe epilepsy (n = 10) and autopsy controls (n = 6). Expression and phosphorylation of DAP kinase was significantly increased in epilepsy brain compared with control. DAP kinase and DAP kinase-interacting protein 1 (DIP-1) localized to mitochondria in control brain, whereas levels of both were increased in the cytoplasm and microsomal (endoplasmic reticulum) fraction in epilepsy samples. Coimmunoprecipitation analysis showed increased DAP kinase binding to calmodulin, DIP-1, and the Fas-associated protein with death domain (FADD) in epilepsy samples. Finally, immunohistochemistry determined DAP kinase was coexpressed with DIP-1 in neurons. This study provides the first description of DAP kinase and DIP-1 in human brain and suggests DAP kinase is a novel molecular regulator of neuronal death in epilepsy.

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Caspase‐3 is not activated in seizure‐induced neuronal necrosis with internucleosomal DNA cleavage

Cited by 52 publications

References 39 publications

Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges

Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges

Pathophysiology of status epilepticus

Death‐associated protein kinase expression in human temporal lobe epilepsy

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