Elevated p53 and lower MDM2 expression in hippocampus from patients with intractable temporal lobe epilepsy

Engel, Tobías; Murphy, Brona M.; Schindler, Clara K.; Henshall, David C.

doi:10.1016/j.eplepsyres.2007.09.001

Cited by 42 publications

(29 citation statements)

References 21 publications

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“…This is consistent with immunohistochemical data that showed up‐regulation of p53 in the hippocampi of TLE patients (Xu et al ., ) along with a correlation between seizure‐activated neuronal death in rat hippocampi and p53 responses (Sakhi et al ., ; Araki et al ., ). However, neuropathological studies reveal that seizure‐mediated cellular death in TLE happens in a very limited manner (Bernasconi et al ., ; Mathern et al ., ; Liu et al ., ; Engel et al ., ). This might suggest a pro‐apoptotic effect of p53; this study suggested induced activities for several anti‐apoptotic and cytoprotective signalling cascades including AKT and RSK.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy

Salman

Sheilabi

Bhattacharyya

et al. 2017

Eur J of Neuroscience

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Epilepsies are common disorders of the central nervous system (CNS), affecting up to 2% of the global population. Pharmaco-resistance is a major clinical challenge affecting about 30% of temporal lobe epilepsy (TLE) patients. Water homeostasis has been shown crucial for regulation of neuronal excitability. The control of water movement is achieved through a family of small integral membrane channel proteins called aquaporins (AQPs). Despite the fact that changes in water homeostasis occur in sclerotic hippocampi of people with TLE, the expression of AQPs in the epileptic brain is not fully characterised. This study uses microarray and ELISA methods to analyse the mRNA and protein expression of the human cerebral AQPs in sclerotic hippocampi (TLE-HS) and adjacent neocortex tissue (TLE-NC) of TLE patients. The expression of AQP1 and AQP4 transcripts was significantly increased, while that of the AQP9 transcript was significantly reduced in TLE-HS compared to TLE-NC. AQP4 protein expression was also increased while expression of AQP1 protein remained unchanged, and AQP9 was undetected. Microarray data analysis identified 3333 differentially regulated genes and suggested the involvement of the MAPK signalling pathway in TLE pathogenesis. Proteome array data validated the translational profile for 26 genes and within the MAPK pathway (e.g. p38, JNK) that were identified as differentially expressed from microarray analysis. ELISA data showed that p38 and JNK inhibitors decrease AQP4 protein levels in cultured human primary cortical astrocytes. Elucidating the mechanism of selective regulation of different AQPs and associated regulatory proteins may provide a new therapeutic approach to epilepsy treatment.

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Section: Discussionmentioning

confidence: 99%

Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy

Salman

Sheilabi

Bhattacharyya

et al. 2017

Eur J of Neuroscience

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“…Years later and after several other reports on altered TP53 expression in seizure models, including the already mentioned study of Tan and colleagues [ 33 ], Xu et al found TP53 positive cells in the sclerotic hippocampus from TLE patients [ 31 ]. In the same year, Engel and colleagues detected significantly higher levels of TP53 by Western blotting in hippocampal tissues from TLE patients [ 50 ]. Our result on the elevated TP53 mRNA level extends and reinforces this data.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis through Death Receptors in Temporal Lobe Epilepsy-Associated Hippocampal Sclerosis

Teocchi

D’Souza-Li

2016

Mediators of Inflammation

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Seizure models have demonstrated that neuroinflammation and neurodegeneration are preponderant characteristics of epilepsy. Considering the lack of clinical studies, our aim is to investigate the extrinsic pathway of apoptosis in pharmacoresistant temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) patients, TLE(HS). By a specific death receptor-mediated apoptosis array plate, 31 upregulated targets were revealed in the sclerotic hippocampus from TLE(HS) patients. Amongst them are the encoding genes for ligands (FASLG, TNF, and TNFSF10) and death receptors (FAS, TNFRSF1A, TNFRSF10A, and TNFRSF10B). In addition, we evaluated the hippocampal relative mRNA expression of the two TNF receptors, TNFRSF1A and TNFRSF1B, in patients, being both upregulated (n = 14; P < 0.01 and P < 0.04, resp.) when compared to the post mortem control group (n = 4). Our results have clearly suggested that three different death receptor apoptotic systems may be associated with the maintenance and progression of TLE-associated HS: (1) TNF-TNFRSF1A, (2) FASLG-FAS, and (3) TNFSF10-TNFRSF10A/B. Their effects on epilepsy are still scarcely comprehended. Our study points out to TNF and TNF receptor superfamily pathways as important targets for pharmacological studies regarding the benefits of an anti-inflammatory therapy in these patients.

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“…Indeed, in human temporal epilepsy and animal temporal epilepsy models, the levels of normal p53 were elevated in the hippocampus, and the absence of p53 was related to worse seizure outcomes because of seizureinduced neuronal death. [37][38][39] Duan et al reported that epilepsy nerve cell apoptosis is regulated by the genes such as p53, Bcl, and Bax, and they exhibit a neuroprotective effect. 40) Therefore, p53 abnormalities might facilitate further intractability of seizures when epileptogenesis is established.…”

Section: The Role Of P53 In the Control Of Seizures In Patients With Lggmentioning

confidence: 99%

Molecular Aberrations Associated with Seizure Control in Diffuse Astrocytic and Oligodendroglial Tumors

Suzuki

Mikuni

Sugita

et al. 2020

Neurol. Med. Chir.(Tokyo)

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Diffuse astrocytic and oligodendroglial tumors are frequently associated with symptomatic epilepsy, and predictive seizure control is important for the improvement of patient quality of life. To elucidate the factors related to drug resistance of brain tumor-associated epilepsy from a pathological perspective. From January 2012 to October 2017, 36 patients diagnosed with diffuse astrocytic or oligodendroglial tumors were included. Assessment for seizure control was performed according to the Engel classification of seizures. Patient clinical, radiological, and pathological data were stratified based on the following 16 variables: age, sex, location of tumor, existence of the preoperative seizure, extent of resection, administration of temozolomide, radiation therapy, recurrence, Karnofsky performance scale, isocitrate dehydrogenase 1, 1p/19q co-deletion, Olig2, platelet-derived growth factor receptor alpha, p53, ATRX, and Ki67. These factors were compared between the well-controlled group and drug-resistant seizure group. Twenty-seven patients experienced seizures; of these, 14 cases were well-controlled, and 13 cases were drug-resistant. Neither clinical nor radiological characteristics were significantly different between these two groups, though p53 immunodetection levels were significantly higher, and the frequency of 1p/19q co-deletion was significantly lower in the group with drug-resistant seizures than in the wellcontrolled group. In the multivariate analysis, only one item was selected according to stepwise methods, and a significant difference was observed for p53 (OR, 21.600; 95% CI, 2.135-218.579; P = 0.009). Upregulation of p53 may be a molecular mechanism underlying drug resistant epilepsy associated with diffuse astrocytic and oligodendroglial tumors.

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Elevated p53 and lower MDM2 expression in hippocampus from patients with intractable temporal lobe epilepsy

Cited by 42 publications

References 21 publications

Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy

Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy

Apoptosis through Death Receptors in Temporal Lobe Epilepsy-Associated Hippocampal Sclerosis

Molecular Aberrations Associated with Seizure Control in Diffuse Astrocytic and Oligodendroglial Tumors

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