Reduced hippocampal damage and epileptic seizures after
            <i>status epilepticus</i>
            in mice lacking proapoptotic Puma

Engel, Tobías; Murphy, Brona M.; Hatazaki, Seiji; Jiménez-Mateos, Eva M.; Concannon, Caoimhín G.; Woods, Ina; Prehn, Jochen H.M.; Henshall, David C.

doi:10.1096/fj.09-145870

Cited by 58 publications

(117 citation statements)

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“…Specifically, neuronal death is reduced by approximately 50% in the hippocampus of puma-deficient mice [52]. Supporting the concept that apoptotic pathway activation is a trigger of epileptogenesis, data have been reported which show that genetic deletion of the proapoptotic protein, puma, acting acutely influences neuronal death and subsequently alters the phenotype of epilepsy in the long-term [53]. In a rodent model, in comparison to puma-expressing mice, puma-deficient mice had significantly smaller hippocampal lesions following status epilepticus [53].…”

Section: Discussionmentioning

confidence: 99%

“…Supporting the concept that apoptotic pathway activation is a trigger of epileptogenesis, data have been reported which show that genetic deletion of the proapoptotic protein, puma, acting acutely influences neuronal death and subsequently alters the phenotype of epilepsy in the long-term [53]. In a rodent model, in comparison to puma-expressing mice, puma-deficient mice had significantly smaller hippocampal lesions following status epilepticus [53]. Long-term EEG recording detected an approximately 60% reduction in the frequency of epileptic seizures in puma-deficient mice compared to puma-expressing mice [53].…”

Section: Discussionmentioning

confidence: 99%

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Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy

et al. 2013

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To identify the upstream signals of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy (TLE), we evaluated by immunohistochemistry and confocal microscopy brain tissues of 13 TLE patients and 5 control patients regarding expression of chemokines and cell-cycle proteins. The chemokine RANTES (CCR5) and other CC-chemokines and apoptotic markers (caspase-3, -8, -9) were expressed in lateral temporal cortical and hippocampal neurons of TLE patients, but not in neurons of control cases. The chemokine RANTES is usually found in cytoplasmic and extracellular locations. However, in TLE neurons, RANTES was displayed in an unusual location, the neuronal nuclei. In addition, the cell-cycle regulatory transcription factor E2F1 was found in an abnormal location in neuronal cytoplasm. The pro-inflammatory enzyme cyclooxygenase-2 and cytokine interleukin-1β were expressed both in neurons of patients suffering from temporal lobe epilepsy and from cerebral trauma. The vessels showed fibrin leakage, perivascular macrophages and expression of IL-6 on endothelial cells. In conclusion, the cytoplasmic effects of E2F1 and nuclear effects of RANTES might have novel roles in neuronal apoptosis of TLE neurons and indicate a need to develop new medical and/or surgical neuroprotective strategies against apoptotic signaling by these molecules. Both RANTES and E2F1 signaling are upstream from caspase activation, thus the antagonists of RANTES and/or E2F1 blockade might be neuroprotective for patients with medically intractable temporal lobe epilepsy. The results have implications for the development of new medical and surgical therapies based on inhibition of chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy

et al. 2013

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“…15 Seizure mice received intraperitoneal injection of either vehicle (PBS) or PFT (4 mg/kg) 24 h before and 1 h after the induction of SE. We have previously reported that this PFT dosing regimen does not alter severity of SE.…”

Section: Methodsmentioning

confidence: 99%

Deletion of the BH3-only protein Noxa alters electrographic seizures but does not protect against hippocampal damage after status epilepticus in mice

et al. 2017

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Several members of the Bcl-2 gene family are dysregulated in human temporal lobe epilepsy and animal studies show that genetic deletion of some of these proteins influence electrographic seizure responses to chemoconvulsants and associated brain damage. The BH3-only proteins form a subgroup comprising direct activators of Bax–Bak that are potently proapoptotic and a number of weaker proapoptotic BH3-only proteins that act as sensitizers by neutralization of antiapoptotic Bcl-2 family members. Noxa was originally characterized as a weaker proapoptotic, ‘sensitizer' BH3-only protein, although recent evidence suggests it too may be potently proapoptotic. Expression of Noxa is under p53 control, a known seizure-activated pathway, although Noxa has been linked to energetic stress and autophagy. Here we characterized the response of Noxa to prolonged seizures and the phenotype of mice lacking Noxa. Status epilepticus induced by intra-amygdala kainic acid caused a rapid increase in expression of noxa in the damaged CA3 subfield of the hippocampus but not undamaged CA1 region. In vivo upregulation of noxa was reduced by pifithrin-α, suggesting transcription may be partly p53-dependent. Mice lacking noxa developed less severe electrographic seizures during status epilepticus in the model but, surprisingly, displayed equivalent hippocampal damage to wild-type animals. The present findings indicate Noxa does not serve as a proapoptotic BH3-only protein during seizure-induced neuronal death in vivo. This study extends the comprehensive phenotyping of seizure and damage responses in mice lacking specific Bcl-2 gene family members and provides further evidence that these proteins may serve roles beyond control of cell death in the brain.

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“…The greatest abundance of kainate receptors is present in the hippocampal CA3 region, and their activation results in neuronal loss of selective populations in the hippocampus and other brain structures. Moreover, numerous studies have demonstrated that neuronal loss observed in this excitotoxic model involves, at least in part, apoptotic cell death [10,11]. Likewise, KA can stimulate CA3 neurons directly through stimulation of their own KA receptors and also indirectly by favouring glutamate release secondary to KA stimulation of mossy fibres [4].…”

Section: Introductionmentioning

confidence: 95%

“…Thus, a large number of studies have been conducted to identify the potential biochemical pathways involved in KA-induced apoptosis, such as oxidative stress, cell cycle re-entry and calpain/cdk5 activation [8,[10][11][12][13][14][15][16]. Programmed cell death is primarily mediated by the extrinsic or death receptor pathway, and the intrinsic or mitochondrial pathway, which converge to activate mitochondria [17,18].…”

Section: Introductionmentioning

confidence: 99%

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

et al. 2014

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The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT 2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the upregulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase-4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy.

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Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma

Cited by 58 publications

References 58 publications

Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy

Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy

Deletion of the BH3-only protein Noxa alters electrographic seizures but does not protect against hippocampal damage after status epilepticus in mice

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

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