Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study compared temporal lobe epilepsy patients, along with kindled animals and self sustained limbic status epilepticus (SSLSE) rats for parallels in hippocampal AMPA and NMDA receptor subunit expression. Hippocampal sclerosis patients (HS), non-HS cases, and autopsies were studied for: hippocampal AMPA GluR1-3 and NMDAR1&2b mRNA levels using in situ hybridization: GluR1, GluR2/3, NMDAR1, and NMDAR2(a&b) immunoreactivity (IR); and neuron densities. Similarly, spontaneously seizing rats after SSLSE, kindled rats, and control animals were studied for: fascia dentata neuron densities: GluR1 and NMDAR2(a&b) IR; and neo-Timm's staining. In HS and non-HS cases, the mRNA hybridization densities per granule cell, as well as molecular layer IR, showed increased GluR1 (relative to GluR2/3) and increased NMDAR2b (relative to NMDAR1) compared to autopsies. Likewise, the molecular layer of SSLSE rats with spontaneous seizures demonstrated more neo-Timm's staining, and higher levels of GluR1 and NMDAR2(a&b) IR compared to kindled animals and controls. These results indicate that hippocampal AMPA and NMDA receptor subunit mRNAs and their proteins are differentially increased in association with spontaneous, but not kindled, seizures. Furthermore, there appears to be parallels in fascia dentata AMPA and NMDA receptor subunit expression between HS (and non-HS) epileptic patients and SSLSE rats. This finding supports the hypothesis that spontaneous seizures in humans and SSLSE rats involve differential alterations in hippocampal ionotrophic glutamate receptor subunits. Moreover, non-HS hippocampi were more like HS cases than hippocampi from kindled animals with respect to glutamate receptors; therefore, hippocampi from kindled rats do not accurately model human non-HS cases, despite some similarities in neuron densities and mossy fiber axon sprouting.
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PMID:Hippocampal AMPA and NMDA mRNA levels and subunit immunoreactivity in human temporal lobe epilepsy patients and a rodent model of chronic mesial limbic epilepsy. 976 17

Hippocampal sclerosis describes a pattern of neuronal loss and gliosis involving the medial temporal structures most often encountered in patients with epilepsy. It is still a matter for debate as to whether this lesion is acquired during the course of the patient's seizure history or is present at the outset. Early febrile seizures, episodes of status epilepticus as well as repetitive brief seizures may all contribute to the evolution of hippocampal sclerosis. In addition, genetic factors and developmental abnormalities of the hippocampus may both increase vulnerability to seizures and hippocampal injury. Recent human studies have addressed neuropathological changes in young adults and children undergoing surgery for refractory seizures with hippocampal sclerosis. Post-mortem examination, however, provides the opportunity to evaluate the effect of a lifetime of seizures on both left and right hippocampi, and the presence of any co-existing malformation. Post-mortem stereological analysis of 28 patients with poorly controlled seizures has confirmed a subgroup with absence of significant hippocampal neuronal loss despite decades of generalized seizures, including status epilepticus. The presence of granule cell dispersion correlated to the severity of hippocampal neuronal loss. Furthermore, in patients with confirmed hippocampal sclerosis at post-mortem examination, stereological assessment of the neocortex failed to confirm significant white matter neuronal heterotopia that might indicate an underlying developmental abnormality. In conclusion, seizures do not invariably lead to hippocampal injury and white matter heterotopia is not invariably associated with hippocampal sclerosis.
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PMID:Quantitative post-mortem study of the hippocampus in chronic epilepsy: seizures do not inevitably cause neuronal loss. 1575 32

Hippocampal sclerosis is a common pathological finding in patients with temporal lobe epilepsy, including children, but a causal relationship to early-life seizures remains in question. Neonatal status epilepticus in animals can result in neuronal death within the hippocampus, although macroscopic features of hippocampal shrinkage are not evident at adulthood. Here, we examined electrophysiological and pathological consequences of focally evoked status epilepticus triggered by intra-amygdala microinjection of kainic acid in postnatal day 10 rat pups. Neonatal status epilepticus resulted in extensive neuronal death in the ipsilateral hippocampal CA1 and CA3 subfields and hilus, as assessed by DNA fragmentation and Fluoro-Jade B staining 72 hours later. The contralateral hippocampus was not significantly damaged. Histopathology at P55/P65 revealed unilateral hippocampal sclerosis (grade IV, modified Wyler/Watson scale) comprising >50% CA1 and CA3 neuron loss and astrogliosis. Additional features included hydrocephalus ex vacuo, modest dentate granule cell layer widening, and altered neuropeptide Y immunoreactivity indicative of synaptic rearrangement. Hippocampal atrophy was also evident on magnetic resonance imaging. Depth electrode recordings at adulthood detected spontaneous seizures that involved the ipsilateral hippocampus and amygdala. A significant positive correlation was found between hippocampal pathology grade and both frequency and duration of epileptic seizures at adulthood. The current study demonstrates that experimental neonatal status epilepticus can result in classical unilateral hippocampal sclerosis and temporal lobe epilepsy.
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PMID:Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis. 1994 25

Hippocampal sclerosis is a frequent pathological finding in patients with temporal lobe epilepsy and can be caused by prolonged single or repeated brief seizures. Both DNA damage and endoplasmic reticulum stress have been implicated as underlying molecular mechanisms in seizure-induced brain injury. The CCAAT/enhancer-binding protein homologous protein (CHOP) is a transcriptional regulator induced downstream of DNA damage and endoplasmic reticulum stress, which can promote or inhibit apoptosis according to context. Recent work has proposed inhibition of CHOP as a suitable neuroprotective strategy. Here, we show that transcript and protein levels of CHOP increase in surviving subfields of the hippocampus after prolonged seizures (status epilepticus) in mouse models. CHOP was also elevated in the hippocampus from epileptic mice and patients with pharmacoresistant epilepsy. The hippocampus of CHOP-deficient mice was much more vulnerable to damage in mouse models of status epilepticus. Moreover, compared with wild-type animals, CHOP-deficient mice subject to status epilepticus developed more spontaneous seizures, displayed protracted hippocampal neurodegeneration and a deficit in a hippocampus-dependent object-place recognition task. The absence of CHOP was associated with a supra-maximal induction of p53 after status epilepticus, and inhibition of p53 abolished the cell death-promoting consequences of CHOP deficiency. The protective effect of CHOP could be partly explained by activating transcription of murine double minute 2 that targets p53 for degradation. These data demonstrate that CHOP is required for neuronal survival after seizures and caution against inhibition of CHOP as a neuroprotective strategy where excitotoxicity is an underlying pathomechanism.
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PMID:CHOP regulates the p53-MDM2 axis and is required for neuronal survival after seizures. 2336 Oct 66

Hippocampal sclerosis is the commonest cause of drug-resistant epilepsy in adults, and is associated with alterations to structures and networks beyond the hippocampus.In addition to being a cause of epilepsy, the hippocampus is vulnerable to damage from seizure activity. In particular, prolonged seizures (status epilepticus) can result in hippocampal sclerosis. The hippocampus is also vulnerable to other insults including traumatic brain injury, and inflammation. Hippocampal sclerosis can occur in association with other brain lesions; the prevailing view is that it is probably a secondary consequence. In such instances, successful surgical treatment usually involves the resection of both the lesion and the involved hippocampus. Experimental data have pointed to numerous neuroprotective strategies to prevent hippocampal sclerosis. Initial neuroprotective strategies aimed at glutamate receptors may be effective, but later, metabolic pathways, apoptosis, reactive oxygen species, and inflammation are involved, perhaps necessitating the use of interventions aimed at multiple targets. Some of the therapies that we use to treat status epilepticus may neuroprotect. However, prevention of neuronal death does not necessarily prevent the later development of epilepsy or cognitive deficits. Perhaps, the most important intervention is the early, aggressive treatment of seizure activity, and the prevention of prolonged seizures.
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PMID:Hippocampal Sclerosis: Causes and Prevention. 2606 Aug 98

Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.
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PMID:KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. 2953 45

Hippocampal sclerosis (HS) is the most common neuropathological condition in adults with drug-resistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy (MTLE) syndrome. Although epileptogenic brain tissue is associated with glutamate excitotoxicity leading to oxidative stress, the proteins that are targets of oxidative damage remain to be determined. In the present study we designed comprehensive analyses of changes in protein expression level and protein oxidation status in the hippocampus or neocortex to highlight proteins associated with excitotoxicity by comparing MTLE patients with relatively mild excitotoxicity (MTLE patients without HS, MTLE-non-HS) and those with severe excitotoxicity (MTLE patients with HS, MTLE-HS). We performed 2-dimensional fluorescence difference gel electrophoresis, 2D-oxyblot analysis, and mass spectrometric amino acid sequencing. We identified 16 proteins at 18 spots in which the protein expression levels differed between sclerotic and non-sclerotic hippocampi. In the sclerotic hippocampus, the expression levels of several synaptic proteins were decreased, and those of some glia-associated proteins increased. We confirmed histologically that all MTLE-HS cases examined exhibited severe neuronal cell loss and remarkable astrocytic gliosis in the hippocampi. In all MTLE-non-HS cases examined, neurons were spared and gliosis was unremarkable. Therefore, we consider that decreased synaptic proteins are a manifestation of loss of neuronal cell bodies and dendrites, whereas increased glia-associated proteins are a manifestation of proliferation and hypertrophy of astrocytes. These are considered to be the result of hippocampal sclerosis. In contrast, the expression level of d-3-phosphoglycerate dehydrogenase (PHGDH), an l-serine synthetic enzyme expressed exclusively by astrocytes, was decreased, and that of stathmin 1, a neurite extension-related protein expressed by neurons, was increased in the sclerotic hippocampus. These findings cannot be explained solely as the result of hippocampal sclerosis. Rather, these changes can be involved in the continuation of seizure disorders in MTLE-HS. In addition, the protein carbonylation detection, an indicator of protein oxidation caused by excitotoxicity of multiple seizures and/or status epilepticus, revealed that the carbonyl level of collapsin response mediator protein 2 (CRMP2) increased significantly in the sclerotic hippocampus. In conclusion, protein identification following profiling of protein expression levels and detection of oxidative proteins indicated potential pathognomonic protein changes. The decreased expression of PHGDH, increased expression of stathmin 1, and carbonylation of CRMP2 differentiate between MTLE with and without HS. Therefore, further investigations of PHGDH, stathmin 1 and CRMP2 are promising to study more detailed effects of excitotoxicity on epileptogenic hippocampal tissue.
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PMID:Proteomic profile differentiating between mesial temporal lobe epilepsy with and without hippocampal sclerosis. 3319 83