Increased Bcl-w expression following focally evoked limbic seizures in the rat

doi:10.1016/S0304-3940(01)01849-3

Neuroscience Letters

Volume 305, Issue 3, 15 June 2001, Pages 153-156

https://doi.org/10.1016/S0304-3940(01)01849-3 Get rights and content

Abstract

Control of seizure-induced neuronal death may involve members of the Bcl-2 family of cell death regulating proteins. Bcl-w is a newly described anti-apoptotic member of this family that may confer neuroprotective effects. We therefore investigated Bcl-w expression in rat brain following focally evoked limbic seizures. Seizures were induced by unilateral microinjection of kainic acid into the amygdala of the rat and terminated after 40 min by diazepam. Constitutive Bcl-w expression was detected by Western blotting and immunohistochemistry. Bcl-w expression was increased 4–72 h following seizures within the injured hippocampus. Immunohistochemistry determined Bcl-w was predominantly expressed in neurons and seizures increased Bcl-w immunoreactivity within piriform cortex and surviving regions of the injured hippocampus. These data suggest Bcl-w may be involved in the modulation of seizure-induced brain injury.

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Acknowledgements

This work was supported by NIH grant NS39016 (D.C.H.).

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Intrinsic apoptosis is initiated by DNA damage, hypoxia, calcium overload, growth factor withdrawal, oxidative stress, and misfolded proteins [195,196]. Seizures can downregulate the expression of antiapoptotic genes, such as, Bcl-2 [197], Bcl-w [198,199], and Mcl-1 [200], and upregulate the expression of proapoptotic genes, such as, Bax [201–203], Bid [137], Bad [202], Bim [204], Puma [137], and Bmf [203]. Relevant evidence showed that downregulation of proapoptotic genes, such as, Puma, Bak, and Bmf, can protect against seizure-induced neuronal death.
Epilepsy is a common neurological disease characterized by recurrent seizures. About 70 million people were affected by epilepsy or epileptic seizures. Epilepsy is a complicated complex or symptomatic syndromes induced by structural, functional, and genetic causes. Meanwhile, several comorbidities are accompanied by epileptic seizures. Cognitive dysfunction is a long-standing complication associated with epileptic seizures, which severely impairs quality of life. Although the definitive pathogenic mechanisms underlying epilepsy-related cognitive dysfunction remain unclear, accumulating evidence indicates that multiple risk factors are probably involved in the development and progression of cognitive dysfunction in patients with epilepsy. These factors include the underlying etiology, recurrent seizures or status epilepticus, structural damage that induced secondary epilepsy, genetic variants, and molecular alterations. In this review, we summarize several theories that may explain the genetic and molecular basis of epilepsy-related cognitive dysfunction.
Bcl-w protects hippocampus during experimental status epilepticus
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Citation Excerpt :
Despite reports of expressional regulation of anti-apoptotic Bcl-2 family proteins by seizures,39,40 their functional significance remains primarily untested. Experiments here show that in mice, as in rats using the same model,21,38,39 seizures have modest or no effect on hippocampal levels of Bcl-2 or Bcl-xl. Rather, seizures cause several changes to Bcl-w levels and localization, including its up-regulation after brief electroshock seizures that are known to confer tolerance against seizure damage.26
Experimentally evoked seizures can activate the intrinsic mitochondrial cell death pathway, components of which are modulated in the hippocampus of patients with temporal lobe epilepsy. Bcl-2 family proteins are critical regulators of mitochondrial dysfunction, but their significance in this setting remains primarily untested. Presently, we investigated the mitochondrial pathway and role of anti-apoptotic Bcl-2 proteins using a mouse model of seizure-induced neuronal death. Status epilepticus was evoked in mice by intra-amygdala kainic acid, causing cytochrome c release, processing of caspases 9 and 7, and death of ipsilateral hippocampal pyramidal neurons. Seizures caused a rapid decline in hippocampal Bcl-w levels not seen for either Bcl-2 or Bcl-xl. To test whether endogenous Bcl-w was functionally significant for neuronal survival, we investigated hippocampal injury after seizures in Bcl-w-deficient mice. Seizures induced significantly more hippocampal CA3 neuronal loss and DNA fragmentation in Bcl-w-deficient mice compared with wild-type mice. Quantitative electroencephalography analysis also revealed that Bcl-w-deficient mice display a neurophysiological phenotype whereby there was earlier polyspike seizure onset. Finally, we detected higher levels of Bcl-w in hippocampus from temporal lobe epilepsy patients compared with autopsy controls. These data identify Bcl-w as an endogenous neuroprotectant that may have seizure-suppressive functions.
Bcl-2 family members and disease
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Apoptosis plays an important role during development and in the maintenance of multicellular organisms. Bcl-2 family members affect cell death in either a positive or negative fashion. Although some redundancy exists between family members, expression of certain family members is important during development in an organ-specific manner. The founding family member bcl-2 tends to be highly expressed in the embryo and declines postnatally following differentiation and maturation. Altered expression of bcl-2, as well as other family members, has been observed in disease states potentially affecting treatment modalities. Here we examine the distribution and role death repressors bcl-2, bcl-x_L and bcl-w as well as death effectors bax and bak play regulating apoptosis in a tissue-specific manner. Understanding the normal role of these proteins during embryogenesis and in the mature organ will give us important insight into what goes awry in various disease states.
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2004, Neuroscience Letters
The molecular regulation of seizure-induced neuronal death may involve interactions between proteins of the Bcl-2 and 14-3-3 families. To further examine these pathways we performed subcellular fractionation on hippocampi obtained following a brief period of status epilepticus in the rat. Western blotting determined seizures induced caspase-8 cleavage and increased Bcl-w levels within the cytoplasm. Bax, Bad and Bid were largely present within the cytoplasm before and after seizures, although some Bax and, following seizures, truncated Bid was detected in mitochondria. Levels of 14-3-3 were significantly reduced in the cytoplasm and microsomal fractions. These data establish the expression and distribution profile of key Bcl-2 family proteins and the signaling chaperone 14-3-3 in the rat and provide additional evidence for the activation of programmed cell death pathways by seizures.
To die or not to die foyr neurons in ischemia, traumatic brain injury and epilepsy: A review on the stress-activated signaling pathways and apoptotic pathways
2003, Progress in Neurobiology
After a severe episode of ischemia, traumatic brain injury (TBI) or epilepsy, it is typical to find necrotic cell death within the injury core. In addition, a substantial number of neurons in regions surrounding the injury core have been observed to die via the programmed cell death (PCD) pathways due to secondary effects derived from the various types of insults. Apart from the cell loss in the injury core, cell death in regions surrounding the injury core may also contribute to significant losses in neurological functions. In fact, it is the injured neurons in these regions around the injury core that treatments are targeting to preserve. In this review, we present our cumulated understanding of stress-activated signaling pathways and apoptotic pathways in the research areas of ischemic injury, TBI and epilepsy and that gathered from concerted research efforts in oncology and other diseases. However, it is obvious that our understanding of these pathways in the context of acute brain injury is at its infancy stage and merits further investigation. Hopefully, this added research effort will provide a more detailed knowledge from which better therapeutic strategies can be developed to treat these acute brain injuries.
Neuronal apoptosis after brief and prolonged seizures
2002, Progress in Brain Research
Evidence has accumulated that apoptotic cell death contributes to brain damage following experimental seizures. A substantial number of degenerating neurons within limbic regions display morphological features of apoptosis following prolonged seizures evoked by systemic or local injections of kainic acid, systemic injections of pilocarpine and sustained stimulation of the perforant path. Although longer periods of seizures consistently result in brain damage, it has previously not been clear whether brief single or intermittent seizures lead to cell death. However, recent results indicate that also single seizures lead to apoptotic neuronal death. A brief, non-convulsive seizure evoked by kindling stimulation was found to produce apoptotic neurons bilaterally in the rat dentate gyrus. The mechanism triggering and mediating apoptotic degeneration is at present being studied. Alterations in the expression and activity of cell-death regulatory proteins such as members of the Bcl-2 family and the cysteinyl aspartate-specific proteinase (caspase) family occur in regions vulnerable to cell degeneration, suggesting an involvement of these factors in mediating apoptosis following seizures. Findings of decreased apoptotic cell death following administration of caspase inhibitors prior to and following experimentally induced status epilepticus, further suggest a role for caspases in seizure-evoked neuronal degeneration. Intermediate forms of cell death with both necrotic and apoptotic features have been found after seizures and investigation into the detailed mechanisms of the different forms of cell degeneration is needed before attempts to specific prevention can be made.

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Increased Bcl-w expression following focally evoked limbic seizures in the rat

Abstract

Section snippets

Acknowledgements

bcl-w, a novel member of the bcl-2 family, promotes cell survival

Oncogene

Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain

Neurosci. Lett.

Expression of the proto-oncogene bcl-2 is increased in the rat brain following kainate-induced seizures

Restor. Neurol. Neurosci.

Differential expression of bcl-w and bcl-x messenger RNA in the developing and adult rat nervous system

Neuroscience

Alterations in bcl-2 and caspase gene family protein expression in human temporal lobe epilepsy

Neurology

Spatio-temporal profile of DNA fragmentation and its relationship to patterns of epileptiform activity following focally evoked limbic seizures

Brain Res.