Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and experimental studies clearly demonstrate that prolonged seizures and status epilepticus induce neuronal cell death in the brain. Recent evidence suggests that induction of apoptosis contributes greatly to seizure-induced brain damage. We recently demonstrated that intrahippocampal delivery of botulinum neurotoxin E (BoNT/E) in the rat hippocampus is able to prevent neuronal loss, which occurs after kainic-acid-induced seizures. Here, we investigated the molecular mechanisms of BoNT/E-mediated neuroprotection. We found that intrahippocampal administration of BoNT/E prevents the upregulation of apoptotic proteins (phosphorylated c-Jun and cleaved caspase 3), which occurs in hippocampal neurones following kainic acid seizures. These results demonstrate that the neuroprotective action of BoNT/E on seizure-injured hippocampal neurons involves the blockade of well-characterized apoptotic pathways.
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PMID:BoNT/E prevents seizure-induced activation of caspase 3 in the rat hippocampus. 1741 60

Clinical and experimental studies clearly demonstrate that prolonged seizures and status epilepticus induce neuronal cell death in the brain. Recent evidence suggests that induction of apoptosis contributes greatly to seizure-induced brain damage. We recently demonstrated that intrahippocampal delivery of botulinum neurotoxin E (BoNT/E) in the rat hippocampus is able to prevent neuronal loss, which occurs after kainic-acid-induced seizures. Here, we investigated the molecular mechanisms of BoNT/E-mediated neuroprotection. We found that intrahippocampal administration of BoNT/E prevents the upregulation of apoptotic proteins (phosphorylated c-Jun and cleaved caspase 3), which occurs in hippocampal neurones following kainic acid seizures. These results demonstrate that the neuroprotective action of BoNT/E on seizure-injured hippocampal neurons involves the blockade of well-characterized apoptotic pathways.
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PMID:BoNT/E prevents seizure-induced activation of caspase 3 in the rat hippocampus. 1744 Dec 89

We examined whether acupuncture can reduce both the incidence of seizures and hippocampal cell death using a mouse model of kainic acid (KA)-induced epilepsy. ICR mice were given acupuncture once a day at acupoint HT8 (sobu) bilaterally during 2 days before KA injection. After an intracerebroventricular injection of 0.1 microg of KA, acupuncture treatment was subsequently administered once more (total 3 times), and the degree of seizure was observed for 20 min. Three hours after injection, the survival of neuronal cells and the expressions of c-Fos, c-Jun, and glutamate decarboxylase (GAD)-67 in the CA1 and CA3 were determined using immunohistochemistry and Western blotting techniques. Acupuncture reduced the severity of the KA-induced epileptic seizure and the rate of neural cell death, and it also decreased the expressions of c-Fos and c-Jun induced by KA in the hippocampus. Furthermore, acupuncture increased GAD-67 expressions in the same areas. These results demonstrated that it could inhibit the KA-induced epileptic seizure and hippocampal cell death by increasing GAD-67 expressions.
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PMID:Acupuncture inhibits kainic Acid-induced hippocampal cell death in mice. 1818 56

Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6.PSD-95.MLK3 signaling module and subsequent JNK activation. In our previous studies, we demonstrated the neuroprotective role of a GluR6 c-terminus containing peptide against KA or cerebral ischemia-induced excitotoxicity in vitro and in vivo. Here, we first report that overexpression of the PDZ1 domain of PSD-95 protein exerts a protective role against neuronal death induced by cerebral ischemia-reperfusion in vivo and can prevent neuronal cell death induced by oxygen-glucose deprivation. Further studies show that overexpression of PDZ1 can perturb the interaction of GluR6 with PSD-95 and suppress the assembly of the GluR6.PSD-95.MLK3 signaling module and therefore inhibit JNK activation. Thus, it not only inhibits phosphorylation of c-Jun and down-regulates Fas ligand expression but also inhibits phosphorylation of 14-3-3 and decreases Bax translocation to mitochondria, decreases the release of cytochrome c, and decreases caspase-3 activation. Overall, the essential role of the PDZ1 domain of PSD-95 in apoptotic cell death in neurons provides an experimental foundation for gene therapy of neurodegenerative diseases with overexpression of the PDZ1 domain.
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PMID:Overexpression of the PDZ1 domain of PSD-95 diminishes ischemic brain injury via inhibition of the GluR6.PSD-95.MLK3 pathway. 1961 93

Prolonged seizures (status epilepticus) are associated with brain region-specific regulation of apoptosis-associated signaling pathways. Bcl-2 homology domain 3-only (BH3) members of the Bcl-2 gene family are of interest as possible initiators of mitochondrial dysfunction and release of apoptogenic molecules after seizures. Previously, we showed that expression of the BH3-only protein, Bcl-2 interacting mediator of cell death (Bim), increased in the rat hippocampus but not in the neocortex after focal-onset status epilepticus. In this study, we examined Bim expression in mice and compared seizure damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid (KA) caused extensive neuronal death within the ipsilateral hippocampal CA3 region. Hippocampal activation of factors associated with transcriptional and posttranslational activation of Bim, such as CHOP and c-Jun NH(2)-terminal kinases, was significant within 1 h. Upregulation of bim mRNA was evident after 2 h and Bim protein increased between 4 and 24 h. Hippocampal CA3 neurodegeneration was reduced in Bim-deficient mice compared with wild-type animals after seizures in vivo, and short interfering RNA molecules targeting bim reduced cell death after KA treatment of hippocampal organotypic cultures. In contrast, neocortical Bim expression declined after status epilepticus, and neocortex damage in Bim-deficient mice was comparable with that in wild-type animals. These results show region-specific differential contributions of Bim to seizure-induced neuronal death.
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PMID:Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus. 1977 95

The temporal and spatial expression of three immediate early genes was investigated at the level of both mRNA and protein in the brains of rats undergoing ethanol withdrawal. Animals were made dependent by chronic vapor inhalation. All animals showed behavioral signs of withdrawal between 8 and 17 h after removal from ethanol vapor. A large, transient increase in the expression of whole brain c-fos, c-jun, and zif/268 mRNA was observed 12 h after withdrawal, and expression of their protein products was detected 15 to 24 h after withdrawal. Spatial variation in the expression of each protein was detected. All three proteins were present in the cerebral cortex, the olfactory bulb, the inferior colliculus, the granular cell layer of the cerebellum, and in the brain stem, but only C-JUN and ZIF/268 were detected in the hippocampus of animals undergoing withdrawal without overt seizures. C-FOS was detected in the hippocampus only in animals with overt seizures. These data reveal a complex pattern of immediate early gene expression during ethanol withdrawal, which may be associated with changes in neuronal plasticity and/or cell repair.
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PMID:Immediate Early Gene Expression in the Rat Brain during Ethanol Withdrawal. 1991 55

Excitotoxicity is one of the main features responsible for neuronal cell death after acute brain injury and in several neurodegenerative disorders, for which only few therapeutic options are currently available. In this work, RNA interference was employed to identify and validate a potential target for successful treatment of excitotoxic brain injury, the transcription factor c-Jun. The nuclear translocation of c-Jun and its upregulation are early events following glutamate-induced excitotoxic damage in primary neuronal cultures. We present evidence for the efficient knockdown of this transcription factor using a non-viral vector consisting of cationic liposomes associated to transferrin (Tf-lipoplexes). Tf-lipoplexes were able to deliver anti-c-Jun siRNAs to neuronal cells in culture, resulting in efficient silencing of c-Jun mRNA and protein and in a significant decrease of cell death following glutamate-induced damage or oxygen-glucose deprivation. This formulation also leads to a significant c-Jun knockdown in the mouse hippocampus in vivo, resulting in the attenuation of both neuronal death and inflammation following kainic acid-mediated lesion of this region. Furthermore, a strong reduction of seizure activity and cytokine production was observed in animals treated with anti-c-Jun siRNAs. These findings demonstrate the efficient delivery of therapeutic siRNAs to the brain by Tf-lipoplexes and validate c-Jun as a promising therapeutic target in neurodegenerative disorders involving excitotoxic lesions.
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PMID:Tf-lipoplex-mediated c-Jun silencing improves neuronal survival following excitotoxic damage in vivo. 1991 61

Systemic injections of kainic acid (KA) cause epileptic seizures with delayed neuronal damage in the limbic system, particularly in the hippocampus. KA excitotoxicity activates complex signal transduction events that trigger apoptotic cell death. The c-Jun N-terminal kinase (JNK) pathway plays an important role in cell death, and the peptide D-JNKI1, a competitive JNK inhibitor, is a potent neuroprotective agent. To analyse the role of JNK and the effects of D-JNKI1 administration on excitotoxic neuronal death, we induced epileptic seizures by intraperitoneal (i.p.) injection of KA in adult male Sprague-Dawley rats; a group of rats received i.p. D-JNKI1 2 h after KA. KA caused massive cell death in the hippocampus: in Nissl-stained sections, stereological counts showed a significant decrease in neuronal density in all CA fields, both at 1 and 5 days after seizures, which was partially prevented by D-JNKI1 treatment. These results were confirmed by counts of degenerating neurons in CA3 in FluoroJade B-stained sections. Seizure activity also induced marked gliosis as observed with glial fibrillary acidic protein (GFAP) immunohistochemistry. We also analysed c-Jun activation as a target of JNK and central transcriptional effector in the adult rat brain following KA injection. Phospho-c-Jun immunoreactivity was absent in the hippocampus of untreated animals, whereas strong nuclear neuronal labeling could be observed, starting from 3 h after KA administration, in microtubule-associated protein-2-positive neurons but not in GFAP-positive astrocytes. D-JNKI1 treatment also reduced the positivity for phospho-c-Jun in the hippocampus, thus confirming the specificity of the peptide in blocking JNK. Therefore, JNK is a promising target for blocking seizure-induced cell death.
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PMID:c-Jun N-terminal kinase signaling pathway in excitotoxic cell death following kainic acid-induced status epilepticus. 2034 8

The pancreatitis-associated protein (PAP) family (also known as the regenerating gene (Reg) family) is a group of 16 kDa secretory proteins structurally classified as the calcium dependent-type lectin superfamily. Some PAP family members are expressed in neurons following peripheral nerve injury and traumatic brain injury. To determine whether PAP family members are expressed in non-traumatic brain injury, expressions were analyzed following kainic acid (KA)-induced seizure. PAP-I (also known as Reg2 in rat and RegIII-beta in mouse) and pancreatitis associated protein-III (PAP-III; RegIII-gamma in mouse) messenger ribonucleic acid (mRNA) was transiently expressed in some restricted areas, such as the hippocampus and parahippocampal area; expression was observed immediately at a maximal level 1 day after seizure. Expression disappeared within 3 days after seizure. In situ hybridization (ISH) and immunohistochemistry revealed neuronal PAP-I and PAP-III expression in the hippocampal dentate gyrus, perirhinal and entorhinal cortices, and the posterior cortical nucleus of the amygdala. The number of PAP-III mRNA-positive neurons was significantly greater than PAP-I mRNA-positive neurons. The majority of positive neurons co-localized with c-Jun, but not with glutamic acid decarboxylase (GAD). These results may suggest that PAP-I and PAP-III induction in non-GABAergic neurons would protect neurons against damage following seizure.
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PMID:Pancreatitis-associated protein-I and pancreatitis-associated protein-III expression in a rat model of kainic acid-induced seizure. 2109 49

Kainic acid (KA) induced seizures provokes an extensive neuronal degeneration initiated by c-Jun N-terminal kinases (JNK) as central mediators of excitotoxicity. However, the actions of their individual isoforms in cellular organelles including mitochondria remain to be elucidated. Here, we have studied the activation of JNK1, JNK2 and JNK3 and their activators, mitogen-activated protein kinase kinase (MKK) 4/7, in brain mitochondria, cytosolic and nuclear fractions after KA seizures. In the mitochondrial fraction, KA significantly increased the presence of JNK1, JNK3 and MKK4 and stimulated their phosphorylation i.e. activation. The pro-apoptotic proteins, Bim and Bax were induced and, consequently, the ratio Bcl-2-Bax decreased. These changes were paralleled by the release of cytochrome c and cleavage of poly(ADP-ribose)-polymerase (PARP). The JNK peptide inhibitor, D-JNKI-1 (XG-102) reversed these pathological events in the mitochondria and almost completely abolished cytochrome c release and PARP cleavage. Importantly, JNK3, but not JNK1 or JNK2, was associated with Bim in mitochondria and D-JNKI-1 prevented the formation of this apoptotic complex. Apart from of the attenuation of c-Jun phosphorylation in the nucleus, D-JNKI-1 did not affect the level of JNK3 isoform in the nuclear and cytosolic fractions. These findings provide novel insights into the mode of action of individual JNK isoforms in cell organelles and points to the JNK3 pool in mitochondria as a target of the JNK inhibitor D-JNKI-1 to confer neuroprotection.
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PMID:The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria. 2220 97


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